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Joseph T. Flynn
Julie R. Ingelfinger
Tammy M. Brady
Editors

Pediatric
Hypertension
Fifth Edition
Pediatric Hypertension
Joseph T. Flynn • Julie R. Ingelfinger •
Tammy M. Brady
Editors

Pediatric Hypertension
Fifth Edition

With 104 Figures and 111 Tables

Editors
Joseph T. Flynn Julie R. Ingelfinger
Department of Pediatrics Pediatric Nephrology Unit
University of Washington Mass General for Children at MGB
School of Medicine Harvard Medical School
Seattle, WA, USA Boston, MA, USA
Division of Nephrology
Seattle Children’s Hospital
Seattle, WA, USA

Tammy M. Brady
Department of Pediatrics
Division of Pediatric Nephrology
Johns Hopkins University School of Medicine
Baltimore, MD, USA

ISBN 978-3-031-06230-8 ISBN 978-3-031-06231-5 (eBook)

https://doi.org/10.1007/978-3-031-06231-5
1st edition: © Humana Press 2004
2nd edition: © Springer Science+Business Media, LLC 2011
3rd edition: © Springer Science+Business Media New York 2013
4th edition: © Springer International Publishing AG 2018
© Springer Nature Switzerland AG 2023
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software, or
by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, expressed or implied, with respect to the material contained
herein or for any errors or omissions that may have been made. The publisher remains neutral with
regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland.
Preface to the Fifth Edition

The importance of good cardiovascular health in adulthood is obvious but

cannot be overemphasized, especially for children with health problems such
as obesity and elevated blood pressure. This new edition of Pediatric Hyper-
tension emphasizes data that have appeared over the last several years that are
relevant to children with elevated blood pressure, as well as to children with
obesity and other health challenges. Cross-sectional and longitudinal studies in
large cohorts have led to notable advances in the field of pediatric hyperten-
sion. While there is still much work remaining, important knowledge gaps
have been narrowed by new studies. Advances include improved understand-
ing of which blood pressure thresholds lead to intermediate outcomes in
children such as left ventricular hypertrophy, changes in carotid intima
media thickness, and other markers as well as long-term cardiovascular out-
comes in adults; enhanced assessment and interpretation of noninvasive mea-
sures of cardiovascular disease risk and early vascular aging; recognition of
nontraditional cardiovascular disease risk factors in youth such as the role of
early life stress; and the evolving description of the neurocognitive sequelae of
hypertension. Further, the results of work over the last several years have
demonstrated the importance of emergency preparedness and adaptability in
the face of natural disasters and pandemics.
These substantial advancements, some of which challenge prevailing
thought and have already prompted changes in professional society and expert
clinical recommendations, are summarized in this Fifth Edition. As with the
Fourth Edition, this current text is part of the Springer Major Reference Work
program, which is available both in print and online, a format that allows for
real-time updating. In addition to new chapters that address the topics noted
above, this Edition provides updates to previously published chapters, includ-
ing those exploring the epidemiology of hypertension; the genetic, perinatal,
and lifestyle contributions to pediatric blood pressure and hypertension; sec-
ondary causes of hypertension and comorbidities; and the practical and prag-
matic approaches to auscultatory, home, and ambulatory blood pressure
measurement.
We are proud of the breadth of topics covered in this Edition of Pediatric
Hypertension. It truly does take a village, and we are most grateful to our
expert contributors, who shared their expertise and time to make this Edition as
compelling and current as we believe it to be. We hope that this text will not

v
vi Preface to the Fifth Edition

only inform and educate existing clinicians and experts immersed in the field,
but that it will also inspire students and trainees to choose a career that focuses
on cardiovascular health promotion across the lifespan.

Seattle, USA Joseph T. Flynn

Boston, USA Julie R. Ingelfinger
Baltimore, USA Tammy M. Brady
December 2022
Preface to the Fourth Edition

We are delighted to present this expanded fourth edition of Pediatric Hyper-

tension, which is intended to capture and update the ongoing progress in
childhood hypertension. There is a growing recognition that adult cardiovas-
cular disease has its origins in childhood, supported by many recent studies.
Additionally, the assessment of the short-term sequelae of childhood hyper-
tension is providing new and important data, reviewed herein. Further, there
are increasing numbers of studies that are delineating mechanisms of blood
pressure elevation in the young. While the obesity epidemic appears to be
leveling off (at least in the United States), it remains an important contributor
to the higher prevalence of childhood hypertension reported in recent years;
numerous epidemiologic studies have become available since publication of
the third edition of this text and are detailed here. With publication of this new
fourth edition, we hope to bring further focus on the importance of under-
standing and addressing the role of the obesity epidemic in pediatric
hypertension.
As our publisher, Springer, has transitioned this text to its Major Reference
Work program, which is available not only in print but also online, which
allows for continual updating, we have been able not only to retain the topics
covered in previous editions of Pediatric Hypertension but also to add new
chapters that address additional and important aspects of childhood hyperten-
sion. One new chapter addresses the controversy over routine childhood blood
pressure screening raised by the 2014 US Preventive Services Task Force
Report. Obesity hypertension is now covered in two chapters, one focusing on
mechanisms and the other on clinical aspects. Another important mechanism
of cardiovascular disease, vascular dysfunction, is covered in a new chapter in
the first section of the text. We also now address the important topic of home
blood pressure measurement, while continuing to cover casual and ambulatory
blood pressure measurement in detail. Expanded chapters on ESRD-related
hypertension, substance-induced hypertension, hypertension in oncology
patients, and hypertension in young adults should be of substantial interest
to clinicians who care for such patients. We have also expanded the section on
hypertension research with a new chapter on cohort studies and meta-analyses
and their role in studying childhood hypertension. Finally, we have added a
short Appendix summarizing the major changes of the 2017 American Acad-
emy of Pediatrics clinical practice guideline on childhood hypertension, which
was completed as this new edition was in progress.

vii
viii Preface to the Fourth Edition

It is impossible to put together a comprehensive text such as Pediatric

Hypertension without more than “a little help from our friends.” We are greatly
indebted to our returning authors as well as to our new authors, all of whom
were asked to contribute to the text because of their acknowledged expertise in
childhood hypertension. We also thank Daniela Graf and Rebecca Urban from
Springer for helping keep everyone on task. We are certain that you will agree
that the tremendous amount of work that has been devoted to this edition of
Pediatric Hypertension has led to a comprehensive and useful text, which we
hope you will consult often in your clinics and research laboratories.

Seattle, WA, USA Joseph T. Flynn

Boston, MA, USA Julie R. Ingelfinger
Boise, ID, USA Karen M. Redwine
Preface to the Third Edition

We are excited to offer you this third edition of Pediatric Hypertension.

Interest in childhood hypertension has increased markedly since the publica-
tion of the prior editions of this text, fueled in part by the increase in the
prevalence of hypertension in children and adolescents, owing to the obesity
epidemic. Investigators have continued to explore many aspects of hyperten-
sion in the young, resulting in better understanding of the mechanisms,
manifestations and management of this important clinical problem. Cardio-
vascular disease remains the leading medical cause of death in the world. Only
by understanding important risk factors such as hypertension at the earliest
stages of disease, during childhood, can substantial progress at eradicating this
disease be made.
In this edition, we have retained most of the topics from the prior two
editions, but have made some important additions and replacements that we
feel will increase the usefulness of the text to clinicians and researchers alike.
New clinically oriented chapters on obesity-related hypertension, endocrine
hypertension and renovascular hypertension should help guide the evaluation
and management of these major causes of hypertension in the young. A new
chapter on models of hypertension should help both researchers and clinicians
to better understand the investigative approaches that have been employed to
study childhood hypertension. There are also new chapters on hypertension in
pregnancy and ethnic influences on hypertension in the young, which should
be of particular interest to those who care for large numbers of teens and
minority patients, respectively.
A text such as this would not have been possible without contributions from
many busy people, all of whom are acknowledged experts in the field. We are
profoundly grateful to our colleagues who agreed to contribute chapters to this
text, especially those who willingly took on new topics only 2–3 years after
writing their chapters for the second edition! It has been a privilege to work
with such a talented and generous group of collaborators, and we are sure that
you will agree that their efforts have resulted in an enhanced third edition.

Seattle, WA, USA Joseph T. Flynn

Boston, MA, USA Julie R. Ingelfinger
Princeton, NJ, USA Ronald J. Portman

ix
Preface to the Second Edition

Interest in pediatric hypertension dates back nearly half a century, when it was
first recognized that a small percentage of children and adolescents had elevated
blood pressures – and in those days, the same normal values for adult blood
pressure were utilized in children! The many advances since that time have led to
a much clearer understanding of how to identify, evaluate, and treat hypertensive
children and adolescents. At the same time, many questions remain: What causes
hypertension in children without underlying systemic conditions? What are the
long-term consequences of high blood pressure in the young? What is the
optimal therapy of childhood hypertension? and Does such treatment benefit
the affected child or adolescent? Can we identify children at risk of developing
hypertension and intervene to prevent its occurrence? Readers conversant with
the history of hypertension in the young will recognize that these questions were
being asked decades ago and may still be unanswered for many years to come.
The first text focusing on pediatric hypertension was published in 1982.
The book you are about to read is a direct descendant of that first effort to
summarize what is known about hypertension in the young. We are fortunate
to have been given the first opportunity to produce a second edition of such a
text, which reflects the increased interest in hypertension in the young that has
developed since the publication of the first edition of Pediatric Hypertension.
Many chapters from the first edition have been revised and updated by their
original authors; others have been written by new authors. New chapters on
topics of recent interest in pediatric hypertension such as the metabolic
syndrome and sleep disorders have been added. We hope that the reader will
find this new edition of Pediatric Hypertension to be an up-to-date, clinically
useful reference as well as a stimulus to further research in the field.
It is also our hope that the advances summarized in this text will ultimately
lead to increased efforts toward the prevention of hypertension in the young,
which, in turn, should ameliorate the burden of cardiovascular disease in
adults. We thank our many colleagues who have taken time from their busy
schedules to contribute to this text – and we are sure that you will agree with us
that their combined efforts have resulted in a valuable reference to those
interested in hypertension in the young.

Seattle, WA, USA Joseph T. Flynn

Boston, MA, USA Julie R. Ingelfinger
Princeton, NJ, USA Ronald J. Portman

xi
Preface to the First Edition

More than a quarter of a century has elapsed since the first Task Force on Blood
Pressure Control in Children was published in 1977. Since that seminal
publication, normative data have been obtained for both casual and ambulatory
children’s blood pressure. Blood pressure measurement in infants, children,
and adolescents, once an afterthought, has become routine. Pediatric Hyper-
tension discusses the many aspects of pediatric hypertension – a multi-
disciplinary subspecialty that is comprised of pediatric nephrologists,
cardiologists, endocrinologists, pharmacologists, and epidemiologists.
Although some areas of our discipline have become well established, others,
such as routine use of ambulatory blood pressure recording and well-designed
trials in pediatric hypertension, are still emerging. Accordingly, we have
included chapters that focus on aspects of blood pressure control and hyper-
tension in the very young that are particularly relevant to those caring for
infants, children, and adolescents.
Pediatric Hypertension opens with chapters concerning blood pressure
regulation in the very young: the transition from fetal life to infant circulation,
the factors that regulate blood pressure in early childhood, and the chronobi-
ology of pediatric blood pressure. We then move on to the assessment of blood
pressure in children. The book addresses both casual and ambulatory blood
pressure measurement methodologies and norms, as well as the epidemiology
of hypertension in children.
Definitions of hypertension in children, predictors of future hypertension,
risk factors, and special populations are discussed at length. Comprehensive
chapters on both primary and secondary hypertension in children point out
differences in presentation of hypertension in the pediatric, in comparison to
the adult, population. The contributions of genetics to the understanding of
hypertension are presented, as well as those events during gestation and
perinatal life that may influence the development of later hypertension. Risk
factors that are discussed include the influences of race and ethnicity, diet,
obesity, and society. Special populations, including the neonate with hyper-
tension and the child with chronic renal failure or end-stage renal disease, are
each discussed in a separate chapter. In those chapters, the pathophysiology
insofar as it is known is also considered.
This text concludes with a section that focuses on the evaluation and
management of pediatric hypertension. Suggestions for evaluation are pre-
sented, and both nonpharmacologic and pharmacologic therapy are discussed

xiii
xiv Preface to the First Edition

at length. The 1997 Food and Drug Administration Modernization Act, which
offers extension of market exclusivity in return for approved clinical trials of
medications with pediatric indication, has had a major impact on the conduct
of pediatric antihypertensive medication trials. The current status of such
pediatric antihypertensive trials is presented. In the appendix, the reader will
find the latest tables for the definition of hypertension in children from the
Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood
Pressure in Children and Adolescents, to be published in Pediatrics in the
summer of 2004.
We hope that Pediatric Hypertension provides a catalyst for more interest in
pediatric hypertension as well as a guide for the interested clinician or clinical
researcher already active in this discipline. Very shortly, the results of addi-
tional trials concerning new antihypertensive agents in children will be avail-
able with the mandate that new antihypertensive medications be evaluated in
children. An update by the Task Force on Blood Pressure Control in Children
will also be completed in 2004. A number of groups that have a special interest
in blood pressure and its control in the very young will continue to contribute
to the field, among them, most notably, the International Pediatric Hyperten-
sion Association; the National Heart, Lung, and Blood Institute; the American
Society of Hypertension; and the American Society of Pediatric Nephrology.
These initiatives will lead to a better understanding of the definition, causes,
consequences, prevention, and treatment of pediatric hypertension. In addition
to advances in molecular and genetics laboratories, new technologies in
assessment of human cardiac and vascular anatomy and physiology will help
to elucidate the pathophysiology of hypertension and its response to manage-
ment. In so doing, our hope is that the trend towards reduction in cardiovas-
cular morbidity and mortality will continue for the current generation of
children.
Finally, we wish to acknowledge the pioneering work of so many in the
field of pediatric hypertension that has given us the foundation and tools to
advance our field.

International Pediatric Hypertension Association Ronald J. Portman, M.D.

Jonathan M. Sorof, M.D.
Julie R. Ingelfinger, M.D.
Contents

Part I Regulation of Blood Pressure and Pathophysiological

Mechanisms of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1 Neurohumoral and Autonomic Regulation of Blood

Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Empar Lurbe and Josep Redon
2 Cardiovascular Influences on Blood Pressure . . . . . . . . . . . . 21
Manish D. Sinha and Phil Chowienczyk
3 Vasoactive Factors and Blood Pressure in Children . . . . . . . 41
Ihor V. Yosypiv
4 Ions and Fluid Dynamics in Hypertension . . . . . . . . . . . . . . . 59
Avram Z. Traum
5 Uric Acid in the Pathogenesis of Hypertension . . . . . . . . . . . 71
Daniel I. Feig
6 Insulin Resistance and Other Mechanisms of Obesity
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Vidhu Thaker and Bonita Falkner
7 Monogenic and Polygenic Contributions to
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Julie R. Ingelfinger
8 Antenatal Programming of Blood Pressure . . . . . . . . . . . . . . 133
Andrew M. South
9 Familial Aggregation of Blood Pressure and the
Heritability of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Sujane Kandasamy and Rahul Chanchlani
10 The Role of Dietary Electrolytes and Childhood Blood
Pressure Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Dawn K. Wilson, Tyler C. McDaniel, and Sandra M. Coulon
11 Endothelial Dysfunction and Vascular Remodeling in
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Julie Goodwin

xv
xvi Contents

12 Adverse Childhood Experiences and Their Relevance to

Hypertension in Children and Youth . . . . . . . . . . . . . . . . . . . 217
Julie R. Ingelfinger
13 Salt Sensitivity in Childhood Hypertension . . . . . . . . . . . . . . 229
Coral D. Hanevold
14 Early Vascular Aging in Pediatric Hypertension
Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Mieczysław Litwin

Part II Assessment of Blood Pressure in Children:

Measurement, Normative Data, and Epidemiology . . . . . . . . . . . . 271

15 Methodology of Office Blood Pressure Measurement . . . . . . 273

Tammy M. Brady
16 Value of Routine Screening for Hypertension in
Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Joseph T. Flynn
17 Development of Blood Pressure Norms and Definition of
Hypertension in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Bonita Falkner
18 Ambulatory Blood Pressure Monitoring Methodology and
Norms in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Elke Wühl
19 Methodology and Applicability of Home Blood Pressure
Monitoring in Children and Adolescents . . . . . . . . . . . . . . . . 345
George S. Stergiou and Angeliki Ntineri
20 Epidemiology of Hypertension and Cardiovascular
Disease in Children and Adolescents . . . . . . . . . . . . . . . . . . . 367
Elyse O. Kharbanda

Part III Hypertension in Children: Etiologies and Special

Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

21 Ethnic Differences in Childhood Blood Pressure . . . . . . . . . . 389

Joshua Samuels and Xamayta Negroni-Balasquide
22 Obesity Hypertension: Clinical Aspects . . . . . . . . . . . . . . . . . 405
Ian Macumber and Joseph T. Flynn
23 Hypertension in Children with Type 2 Diabetes or the
Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Grace Kim and Joseph T. Flynn
24 Primary Hypertension in Children . . . . . . . . . . . . . . . . . . . . . 439
Manpreet K. Grewal, Tej K. Mattoo, and Gaurav Kapur
Contents xvii

25 White Coat and Masked Hypertension . . . . . . . . . . . . . . . . . 461

Yosuke Miyashita and Coral D. Hanevold
26 Hypertension in Chronic Kidney Disease . . . . . . . . . . . . . . . . 477
Susan M. Halbach
27 Hypertension in End-Stage Kidney Disease: Dialysis . . . . . . 499
Franz Schaefer
28 Hypertension in End-Stage Kidney Disease:
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Tomáš Seeman
29 Renovascular Hypertension, Vasculitis, and Aortic
Coarctation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Kjell Tullus and Jelena Stojanovic
30 Endocrine Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Perrin C. White
31 Neonatal and Infant Hypertension . . . . . . . . . . . . . . . . . . . . . 573
Janis M. Dionne
32 Obstructive Sleep Apnea and Hypertension in Children . . . 601
Amee Revana and Alisa A. Acosta
33 Hypertension in the Pregnant Teenager . . . . . . . . . . . . . . . . . 615
Tracy E. Hunley and Deborah P. Jones
34 Neurocognition in Childhood Hypertension . . . . . . . . . . . . . 645
Marc B. Lande and Juan C. Kupferman
35 Stroke and Childhood Hypertension . . . . . . . . . . . . . . . . . . . 659
Juan C. Kupferman, Marc B. Lande, and Stella Stabouli
36 Medication and Substance-Induced Hypertension:
Mechanisms and Management . . . . . . . . . . . . . . . . . . . . . . . . 683
Sandeep K. Riar and Douglas L. Blowey
37 Hypertension in Oncology and Stem Cell Transplant
Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Benjamin L. Laskin and Sangeeta R. Hingorani
38 Hypertension in Older Adolescents and Young Adults . . . . . 723
Matthew B. Rivara
39 Hypertension in the Developing World . . . . . . . . . . . . . . . . . 739
Vera H. Koch

Part IV Evaluation and Management of Pediatric

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753

40 Diagnostic Evaluation of Pediatric Hypertension . . . . . . . . . 755

Nicholas Larkins and Derek Roebuck
xviii Contents

41 Sequelae of Hypertension in Children and Adolescents . . . . 771

Donald J. Weaver Jr. and Mark M. Mitsnefes
42 Cardiovascular Assessment of Childhood Hypertension . . . 785
Edem Binka and Elaine M. Urbina
43 The Role of ABPM in Evaluation of Hypertensive
Target-Organ Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Stella Stabouli and Vasilios Kotsis
44 Exercise Testing in Hypertension and Hypertension
in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
Carissa M. Baker-Smith and Takeshi Tsuda
45 Nonpharmacologic Treatment of Pediatric Hypertension . . . 843
Stephen R. Daniels and Sarah C. Couch
46 Pharmacologic Treatment of Pediatric Hypertension . . . . . . 857
Michael A. Ferguson and Deborah R. Stein
47 Management of Hypertensive Emergencies . . . . . . . . . . . . . . 883
Craig W. Belsha
48 Hypertension Care During Emergencies and Pandemics . . . 899
Joyce P. Samuel and Bradley K. Hyman

Part V Hypertension Research in Pediatrics . . . . . . . . . . . . . . . . . . 907

49 Hypertensive Models and Their Relevance to Pediatric

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
Julie R. Ingelfinger
50 Cohort Studies, Meta-analyses, and Clinical Trials in
Childhood Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
Nicholas Larkins and Jonathan Craig
51 Changes in Drug Development Regulations and Their
Impact on Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
Elizabeth J. Thompson, Kevin D. Hill, Rachel D. Torok, and
Jennifer S. Li
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
About the Editors

Dr. Joseph T. Flynn MD, MS, is the Dr. Robert

O. Hickman Endowed Chair in Pediatric Nephrol-
ogy; Professor of Pediatrics, University of
Washington; and Chief, Division of Nephrology,
Seattle Children’s Hospital. He is an internation-
ally recognized expert in the treatment of hyper-
tension in children and recently chaired the
American Academy of Pediatrics Subcommittee
that developed the updated clinical practice guide-
line on high blood pressure in children and ado-
lescents. Dr. Flynn served on the Council of the
International Pediatric Nephrology Association
from 2010 to 2019, and also on the Council of
the American Society of Pediatric Nephrology,
including 2 years as ASPN President
(2012–2014). He currently is a board member of
the Renal Physicians Association and a member of
the Nephrology sub-board of the American Board
of Pediatrics. He currently serves as one of the
Editors-in-Chief of the journal Pediatric Nephrol-
ogy and is a member of the editorial boards of
Hypertension, Blood Pressure Monitoring, and
The Journal of Pediatrics. He has contributed
chapters to all five editions of the Pediatric Hyper-
tension and edited the three previous editions.

Julie R. Ingelfinger MD, is Professor of Pediat-

rics at Harvard Medical School, Senior Consultant
in pediatric nephrology at Mass General for Chil-
dren at MGB, and Deputy Editor of the New
England Journal of Medicine. She is an interna-
tionally recognized hypertension specialist and
consultative pediatric nephrologist. Her commit-
ment to teaching has been reflected by receiving
the Henry L. Barnett Award from the AAP in
2009, the Founders Award from the American
xix
xx About the Editors

Society of Pediatric Nephrology in 2012, the

National Kidney Foundation’s Honors Award in
2018, the Alumni Lifetime Achievement Award
from Albert Einstein College of Medicine (2018),
and the Barbara T. Murphy Award from the Amer-
ican Society of Nephrology (2022).
Dr. Ingelfinger has been involved in studies of
the intrarenal renin angiotensin aldosterone sys-
tem (RAAS) for many years. Her current projects
focus on the role of the intrarenal renin angioten-
sin system in disease states and the role of mater-
nal diabetes in kidney development and perinatal
programming.
She is interested in innovative ways to teach
writing and communication and has been an editor
of Pediatric Hypertension in each of its five
editions.

Dr. Tammy M. Brady MD, PhD, is Associate

Professor of Pediatrics at Johns Hopkins Univer-
sity School of Medicine where she serves as Vice
Chair for Clinical Research and as the Associate
Director of the Welch Center for Prevention, Epi-
demiology and Clinical Research. She has
focused her career on improving the care of chil-
dren at increased cardiovascular disease risk
through research and clinical innovation. She
serves as the Medical Director of the Harriet
Lane Kidney Center Pediatric Hypertension Pro-
gram, and she directs a multidisciplinary obesity
hypertension clinic (ReNEW clinic; Reversing the
Negative cardiovascular Effects of Weight).
Dr. Brady is an expert in blood pressure measure-
ment and blood pressure device validation. She is
the co-chair of the Association for the Advance-
ment of Medical Instrumentation (AAMI) Sphyg-
momanometer committee, the American
professional society that develops American
National Standards and technical reports regard-
ing sphygmomanometer devices. She was Chair
of a two-day meeting at the WHO where
published guidance and specifications on blood
pressure measuring devices were updated. She is
also Co-chair of the American Medical Associa-
tion’s Validated Device Listing Committee.
Contributors

Alisa A. Acosta Department of Pediatrics Renal Section, Baylor College of

Medicine/Texas Children’s Hospital, Houston, TX, USA

Carissa M. Baker-Smith Nemours Cardiac Center, Nemours Children’s

Hospital, Wilmington, DE, USA

Craig W. Belsha SSM Health Cardinal Glennon Children’s Medical Center,

Saint Louis University, St. Louis, MO, USA

Edem Binka Division of Pediatric Cardiology, University of Utah, Salt Lake

City, UT, USA

Douglas L. Blowey Pediatric Nephrology, Children’s Mercy Hospital, Uni-

versity of Missouri, Kansas City, MO, USA

Tammy M. Brady Department of Pediatrics, Division of Pediatric Nephrol-

ogy, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Rahul Chanchlani Division of Nephrology, Department of Pediatrics,

McMaster University, Hamilton, ON, Canada

Phil Chowienczyk Kings College London British Heart Foundation Centre,

London, UK

Sarah C. Couch Department of Rehabilitation, Exercise and Nutrition Sci-

ences, University of Cincinnati Medical Center, Cincinnati, OH, USA

Sandra M. Coulon West Texas Veterans Healthcare System, Big Spring, TX,
USA

Jonathan Craig College of Medicine and Public Health, Flinders University,

Adelaide, SA, Australia

Stephen R. Daniels Department of Pediatrics, University of Colorado School

of Medicine, Children’s Hospital Colorado, Aurora, CO, USA

Janis M. Dionne Division of Nephrology, Department of Pediatrics, Univer-

sity of British Columbia, BC Children’s Hospital, Vancouver, BC, Canada

Bonita Falkner Departments of Medicine and Pediatrics, Thomas Jefferson

University, Philadelphia, PA, USA

xxi
xxii Contributors

Daniel I. Feig Division of Nephrology, Department of Pediatrics, University

of Alabama, Birmingham, AL, USA
Michael A. Ferguson Division of Nephrology, Boston Children’s Hospital,
Harvard Medical School, Boston, MA, USA
Joseph T. Flynn Department of Pediatrics, University of Washington School
of Medicine, Seattle, WA, USA
Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA
Julie Goodwin Department of Pediatrics, Yale University School of Medi-
cine, New Haven, CT, USA
Manpreet K. Grewal Division of Nephrology and Hypertension, Depart-
ment of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA
Susan M. Halbach Division of Nephrology, Seattle Children’s Hospital,
University of Washington School of Medicine, Seattle, WA, USA
Coral D. Hanevold Division of Nephrology, Department of Pediatrics, Uni-
versity of Washington School of Medicine, Seattle, WA, USA
Kevin D. Hill Department of Pediatrics, Duke Clinical Research Institute,
Durham, NC, USA
Sangeeta R. Hingorani Division of Nephrology, Seattle Children’s Hospital,
Seattle, WA, USA
Tracy E. Hunley Pediatric Nephrology, Monroe Carell Jr. Children’s Hospi-
tal at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA
Bradley K. Hyman Department of Pediatrics- Division of Pediatric Nephrol-
ogy & Hypertension, McGovern Medical School at University of Texas Health
Science Center, Houston, TX, USA
Julie R. Ingelfinger Pediatric Nephrology Unit, Mass General for Children at
MGB, Harvard Medical School, Boston, MA, USA
Deborah P. Jones Pediatric Nephrology, Monroe Carell Jr. Children’s Hos-
pital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA
Sujane Kandasamy Department of Health Research Methods, Evidence &
Impact, McMaster University, Hamilton, ON, Canada
Gaurav Kapur Division of Nephrology and Hypertension, Department of
Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA
Pediatric Nephrology, Central Michigan University, Detroit, MI, USA
Elyse O. Kharbanda Research, HealthPartners Institute, Minneapolis, MN,
USA
Grace Kim Division of Endocrinology and Diabetes, Seattle Children’s
Hospital, Seattle, WA, USA
Department of Pediatrics, University of Washington School of Medicine,
Seattle, WA, USA
Contributors xxiii

Vera H. Koch Pediatric Nephrology, University of Sao Paulo Medical

School, São Paulo, Brazil
Department of Pediatrics, Pediatric Nephrology Unit, Instituto da Criança
Hospital das Clinicas, University of São Paulo Medical School, Sao Paulo,
Brazil
Medical Residency, University of Sao Paulo Medical School, Sao Paulo,
Brazil
Vasilios Kotsis Department of Internal Medicine, Aristotle University of
Thessaloniki, Thessaloniki, Greece
Juan C. Kupferman Department of Pediatrics, Division of Pediatric
Nephrology and Hypertension, Maimonides Medical Center, Brooklyn, NY,
USA
Marc B. Lande Department of Pediatrics, Division of Pediatric Nephrology,
University of Rochester Medical Center, Rochester, NY, USA
Nicholas Larkins Department of Nephrology and Hypertension, Perth Chil-
dren’s Hospital, Nedlands, WA, Australia
Paediatrics Division, Medical School, University of Western Australia, Perth,
WA, Australia
Benjamin L. Laskin Division of Nephrology, The Children’s Hospital of
Philadelphia, Philadelphia, PA, USA
Jennifer S. Li Department of Pediatrics, Duke Clinical Research Institute,
Durham, NC, USA
Mieczysław Litwin Department of Nephrology and Arterial Hypertension,
The Children’s Memorial Health Institute, Warsaw, Poland
Empar Lurbe Pediatric Department, Consorcio Hospital General, Univer-
sity of Valencia, Valencia, Spain
CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud
Carlos III, Madrid, Spain
Ian Macumber Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA
Division of Nephrology, Children’s Hospital Los Angeles, Los Angeles, CA,
USA
Tej K. Mattoo Departments of Pediatrics (Nephrology) and Urology, Wayne
State University School of Medicine, Detroit, MI, USA
Tyler C. McDaniel Department of Psychology, Barnwell College, University
of South Carolina, Columbia, SC, USA
Mark M. Mitsnefes Division of Nephrology and Hypertension, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA
Yosuke Miyashita Department of Pediatrics, University of Pittsburgh Med-
ical Center Children’s Hospital of Pittsburgh, University of Pittsburgh School
of Medicine, Pittsburgh, PA, USA
xxiv Contributors

Xamayta Negroni-Balasquide Department of Pediatrics, University of

Puerto Rico Medical Science Campus, San Juan, PR, USA

Angeliki Ntineri Third Department of Medicine, Sotiria Hospital, School of

Medicine, Hypertension Center STRIDE-7, National and Kapodistrian Uni-
versity of Athens, Athens, Greece

Josep Redon CIBER Fisiopatología Obesidad y Nutrición (CB06/03),

Instituto de Salud Carlos III, Madrid, Spain
Cardiovascular and Renal Research Group, INCLIVA Research Institute,
University of Valencia, Valencia, Spain

Amee Revana Department of Pediatrics, Pulmonary and Sleep Medicine

Section, Baylor College of Medicine/Texas Children’s Hospital, Houston,
TX, USA

Sandeep K. Riar Pediatric Nephrology, Children’s Mercy Hospital, Univer-

sity of Missouri, Kansas City, MO, USA

Matthew B. Rivara Division of Nephrology, Department of Medicine, Kid-

ney Research Institute, University of Washington, Seattle, WA, USA

Derek Roebuck Medical School, University of Western Australia, Perth,

WA, Australia
Department of Medical Imaging, Perth Children’s Hospital, Nedlands, WA,
Australia

Joyce P. Samuel Department of Pediatrics- Division of Pediatric Nephrology

& Hypertension, McGovern Medical School at University of Texas Health
Science Center, Houston, TX, USA

Joshua Samuels Department of Pediatrics, University of Puerto Rico Med-

ical Science Campus, San Juan, PR, USA

Franz Schaefer Division of Pediatric Nephrology, Center for Pediatrics and

Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

Tomáš Seeman Department of Pediatrics, Charles University Prague, 2nd

Medical Faculty, Prague, Czech Republic
Department of Pediatrics, Dr. von Hauner Children’s Hospital, LMU Munich,
Munich, Germany

Manish D. Sinha Department of Paediatric Nephrology, Evelina London

Children’s Hospital, Guys & St Thomas’ NHS Foundation Trust, London, UK
Kings College London British Heart Foundation Centre, London, UK

Andrew M. South Department of Pediatrics, Section of Nephrology, Brenner

Children’s, Wake Forest University School of Medicine, Winston Salem, NC,
USA

Stella Stabouli Department of Pediatrics, Aristotle University of

Thessaloniki, Hippocratio Hospital, Thessaloniki, Greece
Contributors xxv

Deborah R. Stein Division of Nephrology, Boston Children’s Hospital,

Harvard Medical School, Boston, MA, USA
George S. Stergiou Third Department of Medicine, Sotiria Hospital, School
of Medicine, Hypertension Center STRIDE-7, National and Kapodistrian
University of Athens, Athens, Greece
Jelena Stojanovic Great Ormond Street Hospital for Children, London, UK
Vidhu Thaker Divisions of Molecular Genetics, and Pediatric Endocrinol-
ogy, Department of Pediatrics, Columbia University Medical Center, New
York, NY, USA
Division of Endocrinology, Boston Childrens Hospital, Harvard Medical
School, Boston, MA, USA
Elizabeth J. Thompson Department of Pediatrics, Duke Clinical Research
Institute, Durham, NC, USA
Rachel D. Torok Department of Pediatrics, University of Pittsburgh Medical
Center, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
Avram Z. Traum Division of Nephrology, Boston Children’s Hospital,
Boston, MA, USA
Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Takeshi Tsuda Nemours Cardiac Center, Nemours Children’s Hospital,
Wilmington, DE, USA
Kjell Tullus Great Ormond Street Hospital for Children, London, UK
Elaine M. Urbina Preventive Cardiology, Cincinnati Children’s Hospital
Medical Center, University of Cincinnati, Cincinnati, OH, USA
Donald J. Weaver Jr. Department of Pediatrics, Division of Nephrology and
Hypertension, Atrium Health Levine Children’s, Charlotte, NC, USA
Perrin C. White Division of Pediatric Endocrinology, Department of Pedi-
atrics, UT Southwestern Medical Center and Children’s Medical Center,
Dallas, TX, USA
Dawn K. Wilson Department of Psychology, Barnwell College, University
of South Carolina, Columbia, SC, USA
Elke Wühl Center for Pediatrics and Adolescent Medicine, University Hos-
pital Heidelberg, Heidelberg, Germany
Ihor V. Yosypiv Department of Pediatrics, Tulane University, New Orleans,
LA, USA
 Part I
Regulation of Blood Pressure and
Pathophysiological Mechanisms of
Hypertension
 Neurohumoral and Autonomic Regulation
of Blood Pressure 1
Empar Lurbe and Josep Redon

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Neural Components of BP Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Autonomic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Sympathetic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Parasympathetic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Baro- and Chemoreflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Humoral Components of BP Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Renin-Angiotensin-Aldosterone System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Atrial Natriuretic Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
The Apelin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Kidney, Fluid Volume, and Salt Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Vasculature and Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

E. Lurbe (*)
Pediatric Department, Consorcio Hospital General,
University of Valencia, Valencia, Spain
CIBER Fisiopatología Obesidad y Nutrición (CB06/03),
Instituto de Salud Carlos III, Madrid, Spain
e-mail: empar.lurbe@uv.es
J. Redon
CIBER Fisiopatología Obesidad y Nutrición (CB06/03),
Instituto de Salud Carlos III, Madrid, Spain
Cardiovascular and Renal Research Group, INCLIVA
Research Institute, University of Valencia, Valencia, Spain
e-mail: josep.redon@uv.es

© Springer Nature Switzerland AG 2023 3

J. T. Flynn et al. (eds.), Pediatric Hypertension,
https://doi.org/10.1007/978-3-031-06231-5_1
4 E. Lurbe and J. Redon

Circadian Variation of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Abstract Keywords

Maintenance of BP requires the coordinated Angiotensin II · Atrial natriuretic peptides ·

regulation of many components that interact Baroreflex · Blood pressure · Circadian
in an interdependent network that ultimately rhythm · Endothelin · Nitric oxide ·
controls the main determinants of BP, cardiac Sympathetic activity · Parasympathetic ·
output, peripheral resistance, and blood vol- Vasoconstriction · Vasopressin
ume. Neurohumoral and autonomic mecha-
nisms are key components of a complex Abbreviations
network. The central nervous system, orga-
nized into multiple levels of integrative cen- ACE1 Angiotensin-converting enzyme 1
ters, regulates sympathetic activity and ACE2 Angiotensin-converting enzyme 2
vasopressin release in response to nervous ACh Acetylcholine
and humoral input. The autonomic system, by ADMA Asymmetric dimethylarginine
means of the efferent sympathetic and para- ALD Aldosterone
sympathetic pathways, regulates heart rate, Ang I Angiotensin I
vasoconstriction, and activation of the renin- Ang I–7 Angiotensin 1–7
angiotensin-aldosterone system. Humoral Ang II Angiotensin II
components, angiotensin II, aldosterone, and Ang III Angiotensin III
atrial natriuretic peptides regulate vasocon- Ang IV Angiotensin IV
striction and sodium excretion. Short-term reg- AngIVr Angiotensin IV receptor
ulation of cardiac output and peripheral ANGN Angiotensinogen
resistance is interconnected by autonomic ner- ANP Atrial natriuretic peptide
vous system reflexes with the intervention of ANS Autonomic nervous system
baroreceptors. Mid-term control is achieved by Apr Apelin receptor
the interplay between sympathetic nervous AS Apelinergic system
traffic, humoral systems, and the kidney, con- AT1r AT1-receptor
trolling vascular peripheral resistance and AT2r AT2-receptor
blood volume. The kidney, through both BNP Brain natriuretic peptide
pressure-natriuresis and arteriolar mecha- BP Blood pressure
nisms, as well as by flow-mediated vasodilata- CNP C-type natriuretic peptide
tion and myogenic reactivity, participates CNS Central nervous system
broadly in the process. Finally, a circadian CV Circadian variability
rhythm of BP levels is regulated by a clock CVLM Caudal ventrolateral medulla
mechanism driven by the suprachiasmatic DMV Dorsal motor nucleus of the vagus
nucleus, which is stimulated directly by light. eNOS Nitric oxide synthase
Advances in molecular biology techniques and EP Epinephrine
genetic experimental models continue to pro- ErB Endothelin receptor B
vide more precise information about these GABA Gamma-aminobutyric acid
complex networks. ILM Intermediate lateral medulla
1 Neurohumoral and Autonomic Regulation of Blood Pressure 5

MCA4R Melanocortin neurological (central nervous and autonomic

MR Mineralocorticoid receptor systems), humoral (circulating peptides), barore-
NA Nucleus ambiguus ceptors and chemoreceptors, arteries, heart, and
NEP Norepinephrine kidneys, are crucial to maintain the equilibrium
NO Nitric oxide of the system. In the short-term, cardiac output
NOX NADPH oxidase and peripheral resistance are interconnected by
NPRA Natriuretic peptide receptor A autonomic nervous system reflexes. In the
NPRB Natriuretic peptide receptor B mid-term, vascular peripheral resistance and
NTS Nucleus of tractus solitarius blood volume control are achieved through the
OVLT Organum vasculosum of the lamina interplay between sympathetic nervous system
terminalis activity (SNA), humoral systems, and the kidney.
PRR Prorenin receptor The mission of each of these components men-
PSN Parasympathetic nucleus tioned above, as a sensor or as an effector, is
PVN Paraventricular nucleus regulated and/or modulated by complex organ-
RAAS Renin-angiotensin-aldosterone specific mechanisms (Fig. 2).
system Dysregulation in one or more BP determi-
RGS Regulator of G protein signaling nants produces a response by the system to
RVLM Rostral ventrolateral medulla restore BP values, returning to equilibrium.
SNA Sympathetic nervous activity However, if the dysregulation persists, the feed-
back set point will need to be reset; if it is ele-
vated, a hypertensive state develops. The
Introduction complexity of the interactions among the differ-
ent systems in hypertensive patients or animal
Intravascular pressure, known as blood pressure models is well represented in Page’s mosaic
(BP), is necessary in order to create blood flow concept, which reflects the many interactions of
that transports oxygen and nutrients to body the mechanisms involved in hypertension (Page
organs. Required to achieve this crucial function, 1949). The mosaic theory has been continuously
many components are orchestrated in an updated since Page created it with the addition of
interdependent network. The determinants of new elements due to advances in the knowledge
BP are cardiac output, peripheral resistance, of the physiopathology of BP regulation (Page
and blood volume (Fig. 1). Diverse elements, 1974; Harrison et al. 2021).

Fig. 1 Basic scheme of

main factors controlling BP
and their interactions
6 E. Lurbe and J. Redon
Fig. 2 Determinants,
effectors – sensors and
modulators of BP
regulation
In the 1970s, Guyton and Coleman published
a model of BP regulation that attempted to pro-
vide concepts to explain the mechanism for long-
term BP control, based on the link between blood
pressure and sodium balance (Guyton et al.
1972), and subsequent updates have refined the
model. In it, nevertheless, the role of the nervous
system was specifically lacking (Guyton 1990).
Currently, it is recognized that integrated neuro-
humoral and autonomic mechanisms are the cen-
tral components that coordinate the control
process even when their activity is modulated
by other relevant physiological and pathological
processes (Pluznick 2017; Raizada et al. 2017;
Carnagarin et al. 2019; Yang et al. 2020; Madhur
et al. 2021).
This chapter reviews the most relevant mecha-
nisms involved in determining BP levels – effec-
tors and sensors. The anatomy and function of
each of the elements requires an individual
description, and the present chapter emphasizes
their interplay in driving BP regulation.
Neural Components of BP Regulation
Both the central nervous system (CNS) and auto-
nomic nervous system (ANS) play key roles in BP
regulation (Johnson et al. 2015). Generally, while
they integrate multiple afferent and efferent ele-
ments, the CNS predominantly commands the
level of activation and the ANS predominantly
executes the orders.
Central Nervous System
Several structures of the CNS are involved in BP
control, organized as multiple levels of integrative
centers (Ghali 2017a). Usually, these centers
respond to signals received through neurogenic
afferent connexons or circulating humoral pep-
tides from the blood. The integration of all these
elements results in SNA and vasopressin release
(Fig. 3).
1 Neurohumoral and Autonomic Regulation of Blood Pressure
Fig. 3 Main central and autonomic neural pathways in BP
regulation. Elements controlling the role of the CNS
receiving signals from forebrain structures, baroreceptors,
chemoreceptors, homeostatic parameters, and organs,
through autonomic fibers, cranial nerves, as well as from
humoral factors in areas with an absent blood-brain barrier.
In response, sympathetic and parasympathetic systems
are activated or blunted. Sympathetic activity is exerted
7
by the interaction of neurons from the lamina terminalis,
PVN, RVLM, CVLM, and NTS transmitting signals to the
preganglionic fibers of the ILM and then to the ganglionic
ones that innervate vessels and organs. Parasympathetic
activity is exerted by the NTS which recruits neurons in the
NA and DNV innervating sinus node and the heart-lungs,
respectively. Sympathetic activity and humoral peptides
interact both in CNS and in systemic actions (see text).
8 E. Lurbe and J. Redon
Sympathetic Activity
Activation of the sympathetic nervous system
produces not only an increase in the heart rate
and vasoconstriction of the arterioles, but it also
increases renin production in the juxtaglomerular
apparatus of the kidney. The most relevant nodes
and pathways of the SNS include the nucleus of
tractus solitarius (NTS), the rostral (RVLM) and
caudal ventrolateral medulla (CVLM), and the
intermedium lateral medulla (ILM). Furthermore,
elements present in the lamina terminalis of the
third ventricle (circumventricular organ) and
dorsomedial hypothalamus are also involved in
SNA (Briant et al. 2016).
Although the above nodes and pathways have
direct functions in establishing SNA, the NTS and
the RVLM play the key roles. The NTS, located in
the dorsomedial medulla, contains different neu-
ronal clusters that receive the diverse afferent
sensory signals (Martinez and Kline 2021). The
NTS is the first relay station for general visceral
afferents, and it has a critical position in the initi-
ation and integration of a wide variety of reflexes
controlling cardiovascular and respiratory func-
tions, matching the process of tissue perfusion
and pulmonary ventilation. From the NTS, effer-
ent sympathetic fibers go to the RVLM and effer-
ent parasympathetic (PSN) fibers projected in the
dorsal motor nucleus of the vagus (DMV) and
nucleus ambiguus (NA) from which fibers emerge
to innervate the heart and vessels (Cutsforth-
Gregory and Benarroch 2017; Zanutto et al.
2010). The RVLM integrate information from
PVN, NTS, and baroreflexes (Ghali 2017b).
The lamina terminalis of the third ventricle,
formed by the subfornical organ and the organum
vasculosum of the lamina terminalis (OVLT),
is a small structure juxtaposed to the third
ventricle that has connections to the hypothala-
mus, limbic system, thalamus, and cerebral cortex
Fig. 3 (continued) Green arrows show afferent pathways,
and black arrows show efferent pathways. CVLM caudal
ventrolateral medulla, DNV dorsal nucleus of the vagus,
GN ganglionic, ILM intermediolateral medulla, NA
(Fry and Ferguson 2021), and with a practically
nonexistent blood-brain barrier. Consequently,
this lack of a blood-brain barrier exposes the neu-
rons to humoral factors – angiotensin II among
others (Leenen 2014) – facilitating their detection
of signals from the circulating blood. Beginning at
the lamina terminalis, the downstream SNA path-
ways involve the PNV, upper cervical spinal cord,
and the RVLM. In addition, the SNA pathways
also impact other processes that, in part, contrib-
ute to BP regulation, such as thirst, secretion of
antidiuretic hormone, and vascular reactivity in
the skin vessels.
SNA is generated through different neurotrans-
mitters. Fast SNA is transmitted by mechanisms
in which glutamate or gamma-aminobutyric acid
(GABA) binds to ligand-gated ionotropic recep-
tors, opening the ion channels of the neurons to
initiate membrane depolarization and generate the
potential action in the relevant axon. The response
depends on the quantity of presynaptic neuro-
transmitter, postsynaptic receptors, and the level
of activity in the intraneuronal signaling path-
ways. In the mid-term SNA, angiotensinogen
(ANGN) neurons play an important role. In
them, angiotensin II (Ang II) is released in the
synaptic cleft and binds to the AT1-receptor
(AT1r). This receptor stimulates a G protein sig-
naling pathway with activation of NADPH-
oxidases (NOX) increasing intracellular reactive
oxygen species (ROS). The final result is the
activation of several mechanisms and gene
expressions in the neurons transmitting the signals
(Leenen et al. 2017). Evidence of the relevance of
a more slowly acting pathway which maintains
the stimulation elicited by Ang II is available
nowadays. This slow-acting pathway involves
aldosterone (ALD) and the mineralocorticoid
receptor (MR), elements co-localized in the
ANGN neurons.
nucleus ambiguus, NTS, PVN paraventricular nucleus,
PSNA parasympathetic nervous activity, RVLM rostral
ventrolateral medulla, SNA sympathetic nervous system
activity
1 Neurohumoral and Autonomic Regulation of Blood Pressure
Vasopressin
Vasopressin, a potent antidiuretic and vasoconstric-
tor hormone, intervenes in the control of plasma
volume. It is produced in the PVN and the supra-
optic nucleus that contain magnocells and
parvocells (Pittman 2021). The magnocells project
to the neurohypophysis which secretes vasopressin
when a reduction in blood volume or changes in
natremia are detected. The parvocells of the PVN
project to the lower brainstem and spinal cord in
two separate ways. One is the RVLM excitatory
pathway, and the other is the CVLM modulatory
pathway of SNA (Koba et al. 2018; Brown et al.
2020). In addition to the above mechanisms, stim-
ulation of neuronal vasopressin-receptors by
hyperosmolarity and stress is implicated in SNA
(Carmichael and Wainford 2015).
Melanocortin
The melanocortin system, MC4R, also appears to
modulate SNS activity in response to various
stimuli that are accompanied by sympathetic over-
activity. The regions with the greatest abundance
of MC4R are all important sites for the regulation
of autonomic function: PVN, lateral hypothala-
mus, amygdala, NTS, DMV, and preganglionic
sympathetic neurons of the intermediolateral
medulla (ILM) (do Carmo et al. 2017). The
MC4R, induced by leptin in the presence of obe-
sity, has been implicated in SNA (da Silva et al.
2019).
Autonomic Nervous System
The autonomic nervous system, previously
defined functions, integrates visceral afferent
inputs with descending influences from forebrain
areas. The ANS is involved in homeostasis, emo-
tions, and responses to survival, and its relevance
on BP regulation has been acknowledged based
on multiple experimental, pharmacologic, and
clinical studies (Dampney 2016).
The autonomic system is composed of the
efferent sympathetic and parasympathetic, the vis-
ceral afferents, and the enteric nervous system.
Both sympathetic and parasympathetic go
through preganglionic neurons and autonomic
9
ganglions. While preganglionic neurons use ace-
tylcholine (ACh) as their neurotransmitter, the
autonomic ganglionic fiber uses ACh or norepi-
nephrine (NEP) (Benarroch 2020).
Sympathetic Activity
The sympathetic preganglionic neurons are
located in the ILM in the spinal column from
thoracic 1 to lumbar 3 segments. With the poten-
tial of being activated by the segmental visceral or
somatic afferents, they work in different ways to
mediate sympathetic responses driven by inputs
coming from the hypothalamus and the upper part
of the medulla. The preganglionic sympathetic
axons arrive at paravertebral, prevertebral, termi-
nal ganglia, and adrenal medulla. Paravertebral
and prevertebral ganglia innervate tissues and
organs releasing NEP. The adrenal medulla
releases epinephrine (EP) into the blood (Coote
and Spyer 2018).
Norepinephrine and EP stimulate specific recep-
tors (Farzam et al. 2021), the adrenoreceptors α1,2
and β1,2,3 in the heart, vessels, bronchus, bladder,
and uterus. Activation of the postsynaptic α1 recep-
tor by NEP and EP produces vasoconstriction and
changes in renal hemodynamics, while the α2 pre-
sents pre- and postsynaptically, reducing the liber-
ation of NEP and decreasing SNA. Activation of β1
by EP, which binds with greater affinity than does
NE, increases heart rate, cardiac contractibility, and
drives renin release. Therefore, the effects of SNA
are the increment of peripheral resistance, cardiac
output, and renin-angiotensin-aldosterone system
(RAAS) activity. In contrast, the β2 receptor, acti-
vated by epinephrine, produces mild smooth mus-
cle relaxation. Although the β3 receptor plays a role
in metabolic components, it has none in BP control.
The SNA is of special relevance to BP control
in the innervation of the kidney. The sympathetic
fibers in the kidney, both efferent and afferent with
a proportion of approximately 90% and 10%,
respectively, penetrate along the renal artery
wall. In the kidney ilium, they branch out and
penetrate the cortex and the juxtaglomerular area
(Ana Lusch et al. 2014). Renal SNA efferent
increases tubular reabsorption of water and
10
sodium, renin release, renal vascular resistance,
and it reduces glomerular filtration. The afferent
signal travels to the CNS boosting SNA. The
relevance of renal SNA in BP regulation is
emphasized by the use of renal denervation to
reduce BP values in patients with hypertension
that is difficult to control (Azizi 2021), even in
the absence of an antihypertensive drug regimen
(Mahfoud et al. 2021).
Parasympathetic Activity
In contrast to the widely spread SNS, the PSN has
the preganglionic neurons in the visceral efferent
part of the brainstem and in the sacral spinal
region (Garamendi-Ruiz and Gómez-Esteban
2019). The ganglia are outside or within the wall
of the target organs in which ACh exerts the
function through the muscarinic receptors, μ1,2,3.
The structure of the PSN results in organ-specific
reflexes. Relevant for BP regulation are those
driven by the vagus nerve which provides pregan-
glionic innervation to autonomous ganglia in the
thorax. Fibers emerging from the DMV innervate
ganglia of the heart and lungs, whereas neurons of
the NA innervate ganglia of the sinus node in the
heart with a reduction in heart rate (Standish et al.
1994).
Baro- and Chemoreflexes
The principal mechanism for the short-term con-
trol of BP is the baroreflex, providing continuous
buffering of acute changes in BP by sympathetic
vasomotor and cardiovagal outputs (Lauder et al.
2020). The arterial baroreceptors are located in the
wall of the carotid sinus and the aortic arch, inner-
vated by the glossopharyngeal and the vagus
nerves, respectively. Under normal resting condi-
tions, heart rate is regulated by the NA, providing
a tonic vagal activity controlling beat-to-beat in
the sinus node of the heart, and the SNA influ-
ences the peripheral resistance. An increment in
stretch by pulse pressure stimulates the afferent
synapse on neurons of the NTS initiating a
response which inhibits the SNA, producing
E. Lurbe and J. Redon
vasodilatation. In parallel, cardiovagal neurons
of the NA produce bradycardia. In response to a
decrease in pulsatile blood pressure, the afferent
input of the baroreceptor decreases with an incre-
ment in SNA, which results in vasoconstriction
and tachycardia due to a reduction in vagal tone.
In addition, as a result of the relationship between
cardiovagal output and respiration, heart rate
decreases during inspiration and increases during
expiration.
A second task integrated with breathing is the
regulation of tissue perfusion. Cardiac output, BP,
and SNA can be modified according to necessity
in response to signals coming from the arterial
chemoreceptors (Iturriaga et al. 2021). These che-
moreceptors, located in the carotid body and in the
aortic wall, respond mainly to PO2 in the blood
and less to PCO2 and pH. The generated output
signals travel through the glossopharyngeal and
vagus nerves to the NTS and the dorsal respira-
tory group, composed of inspiratory neurons
located in the medulla. The response, controlled
by the RVLM, differentially regulates cardiac out-
put, BP, and the perfusion of organs (Guyenet
et al. 2010). Furthermore, the signals of the carotid
body and aortic chemoreceptors interact with sig-
nals from the pCO2 neuron-sensitive in the CNS,
contributing to the modification of the SNA.
Humoral Components of BP
Regulation
Besides the activity of the nervous system,
humoral factors also play a key role in BP regula-
tion. Neural and humoral mechanisms continu-
ously interact; both become either activated or
downregulated (Fig. 4). This interaction results
in mid-term control of peripheral resistance and
blood volume.
Renin-Angiotensin-Aldosterone
System
The renin-angiotensin-aldosterone system (RAAS)
regulates many vital body functions, making it one
of the key mechanisms in BP regulation. Although
1 Neurohumoral and Autonomic Regulation of Blood Pressure
Fig. 4 Main humoral system in BP regulation. Peptides
stimulate or decrease diverse mechanisms in the vessels
(vasoconstriction/vasodilatation) and in the kidney (diure-
sis and sodium reabsorption). Angiotensin II activates the
SNA which in turn contributes to the activity of systemic
the relevance to BP regulation was the first to be
recognized, its role in many other physiological
processes extends its importance. Continuous
research has identified both the components of the
system, peptides and receptors, as well as the intra-
cellular mechanisms its activation triggers (see
▶ Chap. 3, “Vasoactive Factors and Blood Pressure
in Children”).
Precursors and enzymes for the formation
and degradation of biologically active peptides
form a complex network ubiquitous in the body.
11
peptides. Shaded blue promotes BP reduction, and shaded
white promotes BP increment. GN ganglionic, ILM
intermediolateral medulla, NTS, PVN paraventricular
nucleus, RVLM rostral ventrolateral medulla, SNA sympa-
thetic nervous activity
The peptides of the system not only produce sys-
temic action as an endocrine achievement but also
work locally in a paracrine/intracrine manner
(Leenen et al. 2017).
The initial RAAS components are prorenin and
renin (RN), produced mainly in the juxtaglomerular
apparatus in response to a low sodium concentration
in the distal tubule or reduction in the renal perfusion
pressure or increased activity of the SNS. There is a
circulating RAAS and local tissue RAASs. In the
circulating RAAS, once secreted in its inactive
12
form, prorenin, binds to the prorenin receptor
(PRR), activating renin, which then cleaves the
peptide angiotensin I (Ang I) from angiotensinogen,
which is synthesized in the liver. Subsequently,
angiotensin-converting enzyme (ACE1), present in
the endothelial pulmonary cells and within multiple
tissues, cleaves two amino acids from the
C-terminus of Ang I resulting in angiotensin II
(Ang II), the most active peptide of the RAAS. Of
note, ACE1 also reduces bradykinin concentration.
Ang II is further cleaved into other peptides –
(i) angiotensin 1–7 (Ang I–7) by the action of the
angiotensin-converting enzyme 2 (ACE2), which
cleaves one amino acid from the C-terminus of
Ang II; (ii) angiotensin III (Ang III) by the enzyme
aminopeptidase A in the CNS; and (iii) angiotensin
IV (Ang IV) a peptide converted from angiotensin
III by the angiotensin IV receptor (AngIVr) (Fig. 5)
(Carey 2013; Shu et al. 2021).
The actions elicited by the peptides described
above originate in three G protein-coupled recep-
tors: the angiotensin II type 1 receptor (AT1r), the
Fig. 5 Renin-angiotensin-aldosterone system: active pep-
tides, enzymes, receptors, and non-active peptides. Pro-
renin binds to the prorenin receptor (PRR), activating
renin, which then cleaves angiotensinogen to produce
angiotensin I, which is then cleaved to angiotensin II by
ACE1. Subsequently, ACE2 cleaves angiotensin II to pro-
duce angiotensin 1–7, aminopeptidase A produces angio-
tensin III, which through the receptor ATIVr is converted in
E. Lurbe and J. Redon
angiotensin II type 2 receptor (AT2r), and the
MAS receptor. Also present is one Ang IV bind-
ing site, a type II transmembrane zinc protein
(Karnik et al. 2015). The distribution of these
receptors in the CNS is variable. The AT1-recep-
tors are present not only in areas poorly protected
by the blood-brain barrier, the circumventricular
organs, but also in other areas, such as the supra-
optic, preoptic, and ventral medial nuclei, indicat-
ing the relevance of the neuronal synthesis of the
RAAS elements. The AT2r are located in areas
distinct from those of the AT1r (Guimond and
Gallo-Payet 2012). Moreover, the AngIVr,
although similarly distributed as the AT2r, are
also present in the hippocampus, a location at
which no other AT-receptors exist.
The principal effects of RAAS peptides in BP
regulation are the following:
• Angiotensin II exerts its action mainly by stim-
ulating the AT1r. This increases intracellular
MAP kinase inducing gene expression,
angiotensin IV. These four peptides then are able to bind to
three G protein-coupled receptors, AT1r, AT2r, and MASr,
and a type II transmembrane zinc protein ATIVr. Angio-
tensin II binding to AT1r stimulates aldosterone synthesis
and secretion. Active peptides (black square), enzymes
(light blue square), receptors (dark blue square), and non-
active peptides (red)
1 Neurohumoral and Autonomic Regulation of Blood Pressure
producing vasoconstriction and aldosterone
secretion in the cortical layer of the adrenal
glands. It regulates water and electrolyte bal-
ance, peripheral resistance, and BP levels.
Besides vasoconstriction, Ang II induces
cellular growth and cell migration, inflamma-
tion, and oxidative stress by activating other
intracellular mechanisms. Activation of the
AT2r partly reduces the contraction induced
by the AT1r by inhibiting cell proliferation
and releasing nitric oxide (NO). Besides its
systemic action, Ang II is secreted in the CNS
at synaptic clefts, contributing to stimulation of
the postsynaptic AT1r and consequently boosts
SNA (Hussain and Awan 2018).
• Angiotensin 1–7, in contrast to Ang II, through
coupling with the MAS-receptor and AT2r, can
restore endothelial function by increasing
endothelial nitric oxide synthase (eNOS) and
inhibiting NOX. Additionally, as a partial
antagonist of AT1r, Ang 1–7 also contributes
to the final effect of vasodilation. Furthermore,
Ang 1–7 may be a regenerative agent in the
cardiovascular system, since it stimulates
endothelial and endothelial-progenitor cells
(Roks et al. 2011; Diz et al. 2011).
• Angiotensin III, through AT1r and AT2r,
increases SNA and vasopressin release, and is
more potent than Ang II in the brain (Huber et al.
2017).
• Angiotensin IV is critical for dopamine and
acetylcholine release, and appears relevant for
enhancing memory, but not BP regulation
(Gard 2008).
The RAAS, as the key humoral component of
BP regulation, exerts its impact by increasing
peripheral resistance through vasoconstriction
and by controlling blood volume through actions
in the kidney and in stimulating aldosterone secre-
tion (Ames et al. 2019). In the CNS, components
of the RAAS exert both systemic and local
actions. Systemic actions of the RAAS are driven
by the concentration of Ang II in the blood and
within the CNS has greatest effect in those areas
of the brain in which there is a minimal or nonex-
istent blood-brain barrier. Further, a local tissue
RAAS exists in the CNS in which components are
13
synthesized de novo. Astrocytes are the main
angiotensinogen source in the brain, and neurons
have an intracellular RAAS with membrane-
bound receptors, as well as receptors in neuronal
mitochondria and nuclei (Sumners et al. 2020;
Cosarderelioglu et al. 2020).
Angiotensin II and Ang III in the adrenal
gland stimulate the synthesis and secretion of
aldosterone, which promotes transepithelial
sodium transport, chloride reabsorption, and
potassium/magnesium secretion in the kidney.
Aldosterone activity is mediated by the activa-
tion of the mineralocorticoid receptor (MR),
ubiquitous in many cellular systems (Bollag
2014). Due to its low selectivity, MRs bind not
only aldosterone but also cortisol in humans. The
distribution of this receptor in many organs
involved in cardiovascular homeostasis, such as
the brain, heart, kidney, and vessels, explains
why, in addition to modifying sodium re-
absorption, the MR mediates other relevant
physiological actions triggered by cortisol bind-
ing (Sztechman et al. 2018; please also see
▶ Chap. 2, “Cardiovascular Influences on
Blood Pressure”). Among these is a prolonged
response in presynaptic neurons of the ILM trig-
gered by binding of aldosterone to the MR
(Nakagaki et al. 2012).
Atrial Natriuretic Peptides
Atrial natriuretic peptides (ANPs) are a group of
hormones that contribute to BP regulation
throughout the vascular tree, kidney, and neural
tissues. After the description of the first ANP, two
other peptides, the brain natriuretic peptide (BNP)
and C-type natriuretic peptide (CNP), were iden-
tified. While ANP is mainly synthesized in the
cardiac atria, BNP is synthesized in cardiac ven-
tricles, and CNP is synthesized in the
endothelial vascular cells and the CNS. Once syn-
thesized, these peptides bind to plasma membrane
receptors, receptor A (NPRA) and B (NPRB).
While NPRA is activated by both ANP and
BNP, NPRB is only activated by CNP.
ANP increases the glomerular filtration rate
and inhibits sodium and water reabsorption in
14
the kidney, resulting in natriuresis and diuresis
(Goetze et al. 2020). Moreover, these natriuretic
peptides decrease renin secretion and aldosterone
synthesis in the adrenal gland, produce relaxation
of vascular smooth muscle cells, and increase
vascular permeability. Thus, they counteract the
actions of Ang II and vasopressin (Hodes and
Lichtstein 2014). Natriuretic peptide receptors
are broadly expressed in the CNS, and their pres-
ence in the area of the lamina terminalis of the
third ventricle suggests that the ANPs can be
synthetized by neurons or bound from the circu-
lation. Although no central relevant mission in BP
control has been identified, they seem to modulate
the activation of Ang II and vasopressin in the
CNS (dos Santos Moreira et al. 2017).
The Apelin System
Recently, a novel apelinergic system (AS) with a
putative role in water homeostasis and blood pres-
sure regulation has been described (Janssens et al.
2021; Chapman et al. 2021). This system, com-
posed of the two short-lived peptide ligands,
apelin and elabela, and a G protein-coupled apelin
receptor, appears to possess activity reciprocal to
that of the RAAS. Apelin receptors (Apr), identi-
fied in endothelial cells, vascular smooth muscle,
and cardiomyocytes, once stimulated, produce
arterial and venous vasodilatation (Gupta et al.
2016). In the kidney, they increase renal blood
flow and diuresis with mechanisms linked to NO
generation. Vasopressin, apelin, and the receptors
are co-localized in the hypothalamus; they also
interact in the CNS.
The Kidney, Fluid Volume, and Salt
Intake
The kidney is the main organ that modulates vol-
ume homeostasis, in close relation with neurohu-
moral factors. As discussed above, renin secretion
by the juxtaglomerular apparatus and sympathetic
activation by the efferent and afferent nerves con-
tribute to BP regulation. The other main contrib-
utor is the pressure-natriuresis curve.
E. Lurbe and J. Redon
The pressure-natriuresis curve is a mechanism
whereby BP elevation increases diuresis and natri-
uresis to restore equilibrium (O’Connor and Cow-
ley 2010). Changes in renal interstitial pressure
and in proximal tubular sodium transporters
largely control sodium reabsorption (Palmer and
Schnermann 2015). Renal medullary blood flow
is relatively poorly autoregulated, and when kid-
ney perfusion increases, glomerular efferent arte-
rioles of the juxtamedullary nephrons augment the
flow to the vasa recta. Consequently, capillary
hydrostatic pressure increases and is transmitted
to the renal interstitium (Sadowski and Bądzyńska
2020). This pressure increment produces a rapid
reduction in sodium reabsorption in the proximal
tubule by internalization of apical Na+/H+
exchanger isoform 3 and the sodium-phosphate
cotransporter along the microvilli of the proximal
tubule. Under normal conditions, the proximal
tubule reabsorbs two-thirds of the filtered sodium
(McDonough 2010). Concurrently, the RAAS and
SNA contribute to the dynamic intracellular trans-
position of the sodium transporters. Further,
washout of the medullary solute gradient contrib-
utes to the volume regulation in the distal neph-
rons (Franco and Oparil 2006).
Excess salt intake is rapidly eliminated by the
kidney, although when the capacity is reduced or
overload occurs, intravascular volume will
increase. Relatively reduced sodium excretion
capacity is present in about 25% of people, cate-
gorized as salt-sensitivity (Päivä et al. 2006). In
such persons, reduced flow-mediated vasodilation
is observed as a consequence of several elements –
enhanced vasoconstriction, decreased capacity to
modulate SNA, and increased asymmetric
dimethylarginine (ADMA), an endogenous nitric
oxide synthase inhibitor that reduces NO activity
(Päivä et al. 2006). Sodium accumulation in the
dermal and lymphatic interstitium and other tis-
sues, stored in hypertonic concentrations with pro-
teoglycans, may activate immune reactions (Wiig
et al. 2013). The putative role of sodium stored in
this manner is not yet well understood (Chachaj
and Szuba 2020).
Changes in body water/sodium balance are
also controlled by ANPs and the CNS. Atrial
natriuretic peptide induces natriuresis and diuresis
1 Neurohumoral and Autonomic Regulation of Blood Pressure
by increasing the glomerular filtration rate and
inhibiting sodium reabsorption, thereby
counteracting the activity of the RAAS (Bie and
Evans 2017). Through fibers from the lamina
terminalis and the VIIth, IXth, and Xth cranial
nerves, the CNS receives information about extra-
cellular fluid osmolarity, sodium concentration,
volume receptors, arterial/cardiopulmonary baro-
receptors, sense of taste, and BP. Once integrated
in the NTS, this information triggers appropriate
sympathetic, endocrine, and behavioral responses.
The Vasculature and Nitric Oxide
The vascular structure and function of arteries and
arteriolar vessels are key elements of BP regula-
tion. Peripheral resistance in the vasculature is
determined by the caliber, reactivity, and elasticity
of vessels. Autonomic activation, circulating
humoral factors, and mechanical forces generate
an environment in which endothelial and smooth
muscle cells establish the caliber of the vessels.
Additionally, changes in the muscular layer and
extracellular matrix of vessels form the basis of
vascular remodeling, which increases peripheral
resistance.
Beyond responses to various extravascular
stimuli, the endothelium modulates vascular tone
by synthesizing and releasing vasoactive factors
with vasodilatory capacity (NO, prostacyclin,
hyperpolarizing factor, low level endothelin-1) or
through vasoconstriction (thromboxane A2, high
level endothelin-1). Peripheral resistance increases
due to the action of circulating Ang II, catechol-
amines, vasopressin, high levels of endothelin-1,
and thromboxane A2. This is modulated by the
intracellular machinery present in the endothelial
and small muscle cells. In endothelial cells, the
small GTPase RhoA and the downstream target
Rho kinase reduces the bioavailability of NO,
favoring vasoconstriction. On the other hand, in
the smooth muscle cells, the G signaling proteins
(RGS) 1 and 2, and the RhoA increase vasocon-
striction. Furthermore, the activation of potassium
channels (Shvetsova et al. 2021) produces cellular
hyperpolarization, increasing vasorelaxation and
counteracting contraction induced by different
15
vasoconstrictors (Jackson 2017) and SNA (Martí-
nez et al. 2009).
Endothelin-1, produced and released by the
endothelial cells, in low levels stimulates the
endothelin receptor B (ErB), which in turn
increases the synthesis of vasodilatory NO and
prostacyclin PGI2, relevant to limiting the vaso-
constriction produced for the stimulation of endo-
thelin receptor A (Kostov 2021).
The vasodilatory capacity of arterial vessels
differs, depending on their structure: large arter-
ies, branched or arteriolar. While the large vessels
utilize preferent NO, the arteriolar ones use the
endothelium-dependent hyperpolarization factor,
which through the myoendothelial junctions is
transmitted to the smooth muscle cells (Lemmey
et al. 2020). Flow-mediated vasodilatation is an
endothelial mechanism which involves generation
of NO by eNOS, prostacyclin, and the opening of
calcium-sensitive potassium channels (Tomiyama
et al. 2017). Laminar flow elongates fibers in the
direction of flow and activates mechano-sensors,
G protein-coupled receptors, in the endothelial
surface (Hu et al. 2021). In contrast, turbulent
flow, which is generated in bifurcations, activates
inflammatory pathways (Amaya et al. 2015).
The vasodilatation induced by NO can be
blunted by the production of reactive oxygen
species (ROS) and by the presence of
asymmetric-dimethylarginine (ADMA) (Tsikas
2020). Activation of NOX by Ang II, in the vessels,
produces superoxide and other ROS, inactivating
NO and the cofactor for NO synthase, tetra-
hydrobiopterin, producing vasoconstriction (Pautz
et al. 2021). The impact of ROS from other sources
is not relevant for BP regulation. An endogenous
competitive inhibitor of NO synthase, the post-
translational modification of arginine, ADMA,
reduces the vasodilatory capacity (Jankovic et al.
2017; Poeggeler et al. 2021).
Beside the flow-induced vasodilatation,
smooth muscle cells are able to change the status
of vasoconstriction or vasodilatation in response
to intravascular pressure. In this myogenic reac-
tivity, several mechanisms have been implicated
(Kim and Hong 2021), among them the role of a
variety of transient receptor potential channels
(Liu et al. 2021) which are in charge of
16
maintaining the resting membrane potential and
the intracellular calcium dynamics in smooth
muscle cells.
Circadian Variation of Blood Pressure
Recent evidence supports the concept that cardio-
vascular and kidney function have variations
through the circadian clock. Under normal condi-
tions, BP rises during the morning, starting to
increase about 1 h prior to awakening, reaching
its highest level later, which is maintained until
late afternoon. Thereafter, BP decreases progres-
sively until its nadir, around 3:00 AM (Costello
and Gumz 2021). Circadian variation (CV) in the
brain, heart, kidney, and vessels prepares the tran-
sition from sleep to activity. This pattern seems
independent of an individual’s sleep/wake or
fasting/feeding patterns, although recent studies
have challenged the total independence of
CV. Physical activity impacts CV, increasing BP
during activity and decreasing it with night’s rest
(Bass and Lazar 2016). The presence of
hypertension-mediated organ damage, mainly in
the kidney, blunts the physiological BP nocturnal
fall (Redon and Lurbe 2008).
Circadian rhythm in the levels of peptides
(melatonin, plasma renin activity, ACE activity,
Ang II, aldosterone, ANP, NO, endothelin-1) with
activity on BP regulation around the clock has
been described (Zhang et al. 2021). Melatonin is
inhibited by light; plasma renin and ACE activity,
Ang II and aldosterone peak just before the usual
time of awakening; ANP is antiphase to BP; and
NO increases during wakefulness, the early stages
of sleep deprivation and the diurnal increment of
endothelin-1. If these changes are in response to
BP oscillation or play a relevant role in the circa-
dian variability it is not well established for some
of them.
In mammals, CV control is located in the supra-
chiasmatic nucleus (SCN) which is stimulated
directly by light through the retinal hypothalamic
tract (Dibner et al. 2010). Astrocytes of the SCN
generate a complex light-induced mechanism
involving glutamate as the neurotransmitter, which
E. Lurbe and J. Redon
induces a circadian secretion of neurotransmitters,
stimulates SNA, and reduces PSNA activity. The
gears of the clock are composed of activators,
CLOCK and BMAL1, that induce the expression
of their own repressors, PER and CRY, forming a
negative feedback loop (Allada and Bass 2021). The
duration of the stimulus is regulated post-
translationally, including phosphorylation by
kinases. Once astrocytes become activated, they
synchronize the peripheral clock genes located
mainly in the kidney, brain, heart, and vessels
resulting in rhythms of clock gene expression
(Patke et al. 2020). This system regulates the diurnal
rhythm of many biochemical pathways with the
rhythmic production/secretion of peptides and hor-
mones with cardiovascular and renal actions
(Lecarpentier et al. 2020).
Conclusion
Blood pressure control involves the interaction of
multiple systems with a close link between neu-
rohumoral and autonomic mechanisms to main-
tain in equilibrium the main BP determinants,
cardiac output, peripheral resistance, and blood
volume. Overall, the CNS paces the activity of
the different mechanisms implicated, processing
and responding to stimuli coming from both cor-
tical, subcortical, and visceral signals, as well as
from circulating humoral factors. Autonomic
functions, coupled with humoral peptides, exe-
cute the orders mainly in the vessels, kidney, and
heart, which themselves possess complex mecha-
nisms of autoregulation that modulate the
received inputs. Advances in molecular biology
techniques and genetic experimental models con-
tinue to provide more precise information about
the intracellular signals that regulate cellular com-
munication among these many systems.
Cross-References
▶ Cardiovascular Influences on Blood Pressure
▶ Vasoactive Factors and Blood Pressure in
Children
1 Neurohumoral and Autonomic Regulation of Blood Pressure
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 Cardiovascular Influences on Blood
Pressure 2
Manish D. Sinha and Phil Chowienczyk

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Relevance of BP Level During Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Hemodynamic Phenotypes of Primary Hypertension and Their Clinical
Relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Components of Blood Pressure: Static and Pulsatile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Pulsatile Components of Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Physiological Changes in CO, SVR, and HR During Childhood . . . . . . . . . . . . . . . . . . . . 26
Evidence for a “Hyperdynamic State” in Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Evidence of a Vascular Change in the Early Phase of Hypertension . . . . . . . . . . . . . . . 28
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Abstract

The study of hemodynamic mechanisms in

children and young people with primary hyper-
tension has been neglected historically. An
understanding of the abnormalities in the func-
M. D. Sinha (*) tion of the large arteries, the left ventricle, and
Department of Paediatric Nephrology, Evelina London
their interaction may be important to elucidate
Children’s Hospital, Guys & St Thomas’ NHS Foundation
Trust, London, UK the development and observed effects of
hypertension. In this chapter, we discuss car-
Kings College London British Heart Foundation Centre,
London, UK diovascular influences that determine blood
e-mail: manish.sinha@nhs.net pressure; highlighting the static and pulsatile
P. Chowienczyk components of blood pressure and review the
Kings College London British Heart Foundation Centre, published literature evaluating hemodynamics
London, UK in children with hypertension. We compare
e-mail: phil.chowienczyk@kcl.ac.uk

© Springer Nature Switzerland AG 2023 21

J. T. Flynn et al. (eds.), Pediatric Hypertension,
https://doi.org/10.1007/978-3-031-06231-5_3
22
findings in hypertensive children with those
with normotension. Increasing data support a
cardiac and large artery component in early
hypertension in children and young people.
Increase in cardiac output appears to be the
earliest identifiable abnormality in children
and young people (CYP) with increased sys-
temic vascular resistance (SVR) in hyperten-
sive young adults. Given the tracking of
hypertension from children to adults, the find-
ing of a cardiac/aortic rather than peripheral
vascular changes associated with primary
hypertension has implications for the etiology
of hypertension both in children and adults. It
also has implications for the best treatment in
children.
Introduction
Primary hypertension (PH) is a major health bur-
den globally and one of the main contributors to
excess morbidity and mortality, accounting for a
1/3rd of ischemic heart disease and 2/3rds of
strokes among adults (Egan et al. 2019). In chil-
dren and young people (CYP), there is an increas-
ing prevalence of PH, mirroring the childhood
obesity epidemic, with a steady increase over the
last two decades (Litwin and Kułaga 2021; Lurbe
et al. 2016; Song et al. 2019). Thus, although the
prevalence of PH is reported between 3% and 5%
in those aged <18 years, during adolescence prev-
alence rates are reported to increase to 10–11%,
similar to reports in young in young adults (Flynn
et al. 2017; Litwin and Kułaga 2021; McNiece
et al. 2007; Noubiap et al. 2017; Sharma et al.
2018; Symonides et al. 2010; Urbina et al. 2019a).
Relevance of BP Level During
Childhood
In childhood PH, despite only modestly elevated
blood pressure, hypertension-mediated organ
damage, including left ventricular hypertrophy
and arteriopathy, can be detected (Azukaitis
et al. 2021; Urbina et al. 2019b). Sustained hyper-
tension in childhood is also a strong predictor of
M. D. Sinha and P. Chowienczyk
hypertension in adulthood (Carrico et al. 2013;
Chen and Wang 2008; Tirosh et al. 2010). Recent
population-based data suggest that hypertension
during adulthood and its associated adverse car-
diovascular (CV) outcomes has its origin in ele-
vated BP during adolescence (Lurbe et al. 2016).
Similarly, a recent systematic review confirmed
that elevated BP in childhood or adolescence is
associated with several intermediate markers and
hard outcomes of cardiovascular disease in adult-
hood (Yang et al. 2020). Convincing evidence
regarding the consequences of childhood blood
pressure trajectories on adult outcomes was
recently demonstrated by the Bogalusa Heart
Study investigators, who observed that persis-
tently high BP particularly through adolescence
associated with higher risk for adult left ventricu-
lar hypertrophy (LVH) when compared with nor-
mal blood pressure (Zhang et al. 2018). The
authors reported that these associations remained
consistent across race and sex groups, with stron-
ger relationship of concentric LVH with adoles-
cent BP trajectories when compared with
eccentric LVH (Zhang et al. 2018). Overall, evi-
dence suggests an increasing prevalence of PH in
CYP, tracking of BP from childhood to adulthood,
and increased risk of adverse cardiovascular out-
comes as a result. These observations highlight
the need to improve our understanding of the
potential mechanisms underlying early increase
in blood pressure in children and adolescents.
Hemodynamic Phenotypes of Primary
Hypertension and Their Clinical
Relevance
Nearly two decades ago, Sorof and colleagues
reported that isolated systolic hypertension (ISH)
was the predominant hypertension phenotype in
12–16-year-old adolescents, affecting 88% of
youth with hypertension (Sorof et al. 2002). In
those with ISH, most were obese and had increased
heart rates and BP variability (Sorof et al. 2002;
Sorof 2002). Isolated diastolic hypertension (IDH),
in contrast, was less common (Sorof 2002).
Recent data from the United States evaluating the
National Health and Nutrition Examination Survey
2 Cardiovascular Influences on Blood Pressure
(NHANES, 1999–2016) including over 17,000 chil-
dren aged 8–18 reported the prevalence of ISH at
11.1%, but IDH nearly tenfold lower (1.9%)
(Alsaeed et al. 2021). Children with IDH were
more likely to be younger, female, white, and
leaner with lower rates of excess weight than
those with ISH (Alsaeed et al. 2021). In the
ENIGMA study of ~900 University students in
the United Kingdom, aged 20–27 years, ISH was
described in 8% and the combination of systolic
and diastolic hypertension (SDH) in 4%
(McEniery et al. 2005). In contrast, the phenotype
of hypertension, in adults, is strikingly different
with IDH predominating in young adults aged
<40 years and ISH predominating among
middle-aged and elderly hypertensive persons
(Franklin et al. 2001). The clinical relevance of
the hypertension phenotype was shown clearly by
the Chicago Heart Study Investigators (Yano et al.
2015). In their study, which included >35,000
persons, over a follow-up period of 31 years,
ISH was reported in 25% of men and 13% of
women, with a prevalence of ISH in younger
adults up to 50% (Yano et al. 2015). The relative
risk of mortality from cardiovascular and coro-
nary heart disease in adults with ISH was higher
than in those with normal BP (BP <130/85 mm
Hg) (Yano et al. 2015).
ISH in older adults is widely thought to result
from “stiffening” of the aorta and large arteries
secondary to an age-related degenerative process
(Franklin et al. 2001). This vascular change leads to
a widening of pulse pressure (PP, the difference
between systolic and diastolic BP) as discussed
below. Aging is associated with gradual physiolog-
ical changes in arterial structure and function with
arterial stiffening observed even in non-hyperten-
sive elderly persons (Najjar et al. 2005). Hyperten-
sion may also contribute to arterial stiffening as a
consequence of damage to the elastic component
of the artery following sustained elevated BP
leading to positive feedback in the relationship
between hypertension and stiffening (Cecelja and
Chowienczyk 2009). In CYP with ISH, an
age-related degenerative process leading to arterial
stiffness seems implausible, given the relatively
short duration of hypertension (Cecelja and
Chowienczyk 2010; Mitchell 2014).
23
It is likely, therefore, that there are different
hemodynamic mechanisms contributing to the
development of hypertension across the age spec-
trum with important differences in clinical out-
comes. An improved understanding of the
underlying mechanisms will help plan appropriate
intervention and follow-up of CYP with elevated
BP and prevent future adverse outcomes.
Components of Blood Pressure: Static
and Pulsatile
Typically, we measure blood pressure and express
it as “systolic BP,” which relates to the pressure in
the artery during ventricular contraction, and
“diastolic BP,” which relates to the pressure in
the artery during ventricular relaxation. A more
physiological description would be to express the
changes in the measured arterial pressure as
“static” and “pulsatile” components (Laosiripisan
et al. 2017; Roman and Devereux 2014; Tanaka
et al. 2016).
Thus, mean arterial pressure (MAP) represents
the steady-state or static BP. It can be regarded as
the perfusion pressure driving blood flow to the
organs and is dependent on cardiac output (CO)
and the total systemic peripheral vascular resis-
tance (SVR), a relationship, represented by the
familiar equation of MAP ¼ CO  SVR [31].
Accordingly, elevated MAP may be a result of
increase in CO, in SVR, or in both (Fig. 1).
Cardiac output, which represents pump func-
tion of the heart, is, in turn, the product of heart
rate (HR) and stroke volume (SV):
CO ¼ HR  SV:
Heart rate is determined by the relative influ-
ences of sympathetic vs. parasympathetic nerve
fibers at the sinoatrial node in the heart. Stroke
volume is determined by the contractile function
of the heart and by the “afterload” presented to the
heart by the arterial tree. The heart must generate a
force of contraction which exceeds the pressure in
the aorta to open the aortic valve and eject blood
into the systemic arterial circulation. Subsequent
ejection of blood depends on the afterload, and it
24 M. D. Sinha and P. Chowienczyk

P1 − P2: difference between MAP and CVP

CVP = 0 mmHg, so P1 − P2 is equivalent to MAP
Q = flow, equivalent to
CO

( 1 − 2) R = resistance,
Q= equivalent to SVR

= =

MAP, mean arterial pressure; CVP, central venous pressure; CO, cardiac output; SVR, total systemic peripheral
vascular resistance

Fig. 1 Schematic showing the equation of mean arterial pressure (MAP). MAP, mean arterial pressure; CVP, central
venous pressure; CO, cardiac output; SVR, total systemic peripheral vascular resistance

is important to appreciate that in a dynamic situ-
ation this is dependent on the stiffness of the aorta
and large arteries as well as the SVR.
Contractile energy is affected by the following:
(i) Preload, defined as the pressure in the atria at
the end of diastole, when the ventricles are at
their fullest, i.e., ventricular filling pressure.
Cardiac myocytes are unique in exhibiting
increased force of contraction with increased
stretch, which on a whole organ level trans-
lates to increased stroke volume as diastolic
volume increases. This phenomenon first
noted independently by Otto Frank and Ernest
Henry Starling in the early twentieth century
is known as the Frank-Starling mechanism.
(ii) Contractility, the strength of a contraction for
any given degree of stretch, which is regu-
lated by sympathetic activity. Arrival of an
action potential at the sympathetic postgan-
glionic terminal leads to release of epineph-
rine, which binds (predominantly) to β1
receptors on the cardiac myocyte. Sympa-
thetic actions are also by circulating adrena-
line released from the adrenal cortex. The
effects of sympathetic activity on the cardiac
action potential, contractility, and resultant
ventricular function are summarized in Fig. 2.
Thus, SV and CO can be modified by preload,
the contractile state of the heart, and afterload.
SVR (also known as total peripheral resistance,
TPR) is determined by the terminal arteries and
arterioles. Resistance to flow arises from internal
friction between the fluid and the walls of the
vessel and internally within the fluid. When the
flow in a vessel segment approximates fully
developed laminar flow, the resistance to flow is
given by the Hagen–Poiseuille relationship:
Resistance ðRÞ ¼ 8ηL=πr4
where η is blood viscosity, L the length of the
vessel, and r, the radius of the vessel. Flow
through the vessel is given by the pressure drop
ΔP across the tube (the vessel):
Q ¼ ΔP πr4 =8ηL:
Thus, flow through vessels is highly sensitive to
the radius of the resistance vessels, and halving the
lumen size will decrease flow by 93% for any given
perfusion pressure. When several vessels are joined
together in series (e.g., terminal artery and arteri-
ole), their total resistance is the sum of the individ-
ual resistances. When vessels are joined together in
parallel (e.g., a capillary bed), the total resistance is
the reciprocal of all their summed conductances
(conductance being the reciprocal of resistance).
Given this phenomenon, the terminal arteries and
arterioles contribute most towards SVR, whereas
resistance in the capillary beds is surprisingly low,
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