PATPHYSYOLOGY OF HYPERTENSION

Some of the causes of hypertension are known (e.g., renal or hormonal abnormalities; !B2,3), but these
forms make up only about 5–10% of all cases. In all others the diagnosis by exclusion is primary or essential
hypertension (!B1). Apart from a genetic component, more women than men and more urbanites than country
dwellers are affected by primary H. In addition, chronic psychological stress, be it job-related (pilot, bus driver) or
personality-based (e.g., “frustrated fighter” type), can induce hypertension. Especially in “salt-sensitive” people
(ca. 1⁄3 of patients with primary H.; increased incidence when there is a family history) the high NaCl intake (ca.
10–15 g/d = 170–250 mmol/d) in the western industrialized countries might play an important role. While the
organism is well protected against Na+ loss (or diminished extracellular volume) through an increase in
aldosterone, those with an increased salt sensitivity are apparently relatively unprotected against a high NaCl
intake. In these patients, aldosterone release is so strongly inhibited even at “normal” Na+ intake (> 100mmol/d)
that it cannot be lowered any further. A diet with low NaCl intake would in this case bring NaCl balance into the
aldosterone regulatory range. The actual connection between NaCl sensitivity and primary H. has not been fully
elucidated, but the possibility is being considered that responsiveness to catecholamines is raised in people
sensitive to NaCl. This results, for example, on psychological stress, in a greater than normal rise in blood pressure,
on the one hand, due directly to the effect of increased cardiac stimulation ( !B, upper right) and, on the other
hand, indirectly as a result of increased renal absorption and thus retention of Na+ (rise in extracellular volume
leads to hyperdynamic H.). The increased blood pressure leads to pressure diuresis with increased Na+ excretion,
restoring Na+ balance (Guyton). This mechanism also exists in healthy people, but the pressure increase required
for excretion of large amounts of NaCl is much lower (!C, a ! b). In primary H. (as in disorders of renal function) the
NaCl-dependent increase in blood pressure is greater than normal (!C, c ! d). A diet that is low in Na+ can thus
lower (not yet fixed) H. in these cases (C, c ! e). A simultaneously elevated K+ supply accentuates this effect for
unknown reasons. The cellular mechanism of salt sensitivity still awaits clarification. It is possible that changes in
cellular Na+ transport are important. In fact cellular Na+ concentration is raised in primary H., which decreases the
driving force for the 3 Na+/Ca2+ exchange carrier in the cell membrane, as a result of which the intracellular Ca2+
concentration rises, which in turn increases the tone of the vasoconstrictor muscles (Blaustein). It is possible that
digitalislike inhibitors of Na+-K+-ATPase are involved (ouabain?). They may be present in larger amounts, or there
may be a special sensitivity to them in primary H. Atriopeptin (= atrial natriuretic peptide [ANP]), which has
vasodilator and natriuretic effects, is probably not involved in the development of primary H. Although the
concentration of renin is not elevated in primary H., blood pressure can be reduced even in primary H. by inhibiting
the angiotensin-converting enzyme (ACE inhibitors;
Neurogenic hypertension. Encephalitis, cerebral edemas or hemorrhage, and brain tumors may lead to a
massive rise in blood pressure via central nervous stimulation of the sympathetic nervous system. An abnormally
high central stimulation of cardiac action as part of the hyperkinetic heart syndrome may also cause H.
The consequences of hypertension (!E) most importantly result from atherosclerotic damage in arterial
vessels (!p. 236ff.), which can be observed well by means of fundoscopy. Because of the resulting increase in flow
resistance, every form of hypertension ultimately creates a vicious circle. Vascular damage finally leads to ischemia
of various organs and tissues (myocardium, brain, kidneys, mesenteric vessels, legs), renal ischemia accelerating
the vicious circle. Damage to the vascular walls together with hypertension can, for example, lead to brain
hemorrhage (stroke) and in the large arteries (e.g., aorta) to the formation of aneurysms and ultimately their
rupture (!p. 238). Life expectancy is therefore markedly reduced.
 A number of renal diseases can ultimately lead to the destruction of renal tissue ( !p.102ff., 114). If the
residual renal tissue is not in a position to adequately fulfill its tasks, the picture of renal failure evolves. Reduced
renal excretion is particularly significant. The decreased GFR leads to an inversely proportional rise in the plasma
level of creatinine (!A, top; see also p. 94). The plasma concentration of reabsorbed substances also rises, but less
markedly, because Renal tubular reabsorption is impaired in renal failure. The reabsorption of Na+ and water is
inhibited in renal failure by a variety of factors, such as natriuretic hormone, PTH, and vanadate ( !p.112). The
reduced reabsorption of Na+ in the proximal tubules also directly or indirectly decreases the reabsorption of other
substances, such as phosphate, uric acid, HCO3 –, Ca2+, urea, glucose, and amino acids. The reabsorption of
phosphate is also inhibited by PTH. Reduced NaCl reabsorption in the ascending limb compromises the
concentrating mechanism (!p.100). The large supply of volume and NaCl from parts of the proximal nephron
promotes the reabsorption of Na+ distally and aids in the secretion of K+ and H+ in the distal nephron and in the
collecting duct. As a result, the plasma concentration of electrolytes can remain practically normal even if GFR is
markedly reduced (compensated renal insufficiency). Disorders occur only once GFR has fallen to less than a
quarter of the normal level. However, this compensation is carried out at the cost of the regulatory range, in that
the damaged kidney is unable adequately to increase the excretion of water, Na+, K+, H+, phosphate, etc. (e.g., if
oral intake is increased). It is probably the disruption in renal water and electrolyte excretion that is responsible, at
least partially, for the development of most of symptoms of chronic renal failure. Excess volume and the changed
electrolyte concentrations lead to edemas, hypertension, osteomalacia, acidosis, pruritus, and arthritis, either
directly or via the activation of hormones (!p.112). Also, abnormalities of the excitatory cells (polyneuropathy,
confusion, coma, seizures, cerebral edemas), of gastrointestinal function (nausea, peptic ulcer, diarrhea), and of
blood cells (hemolysis, abnormal leukocyte function, abnormal blood clotting) are due to this. While uric acid can
be precipitated at high concentrations, especially in the joints, and thus cause gout (!p. 250), sufficiently high
concentrations of uric acid are only rarely achieved in renal failure. The role of reduced elimination of so-called
uremia toxins (e.g., acetone, 2,3-butyleneglycol, guanidinosuccinic acid, methylguanidine, indoles, phenols,
aliphatic and aromatic amines, etc.) as well as of so-called middle molecules (lipids or peptides with a molecular
weight of 300–2000 Da) in producing the symptoms of renal failure remains the subject of considerable debate.
High concentrations of urea can destabilize proteins and bring about cell shrinkage. But its effect is partly canceled
by the cellular uptake of stabilizing osmolytes (especially betaine, glycerophosphorylcholine). The impaired renal
production of erythropoietin leads to the development of renal anemia (!p. 30ff.), while the reduced formation of
calcitriol contributes to abnormalities of mineral metabolism (!p.112). Depending on the cause and course of the
disease, the intrarenal formation of renin and of prostaglandins can be raised (!p.114) or reduced (death of renin-
or prostaglandin-producing cells). Increased formation of renin promotes, while its reduced formation inhibits, the
development of hypertension, a frequent occurrence in renal failure (!p.112ff.). Prostaglandins, on the other hand,
are more likely to cause vasodilation and a fall in blood pressure (!p. 296). The loss of renal inactivation of
hormones (!p. 92) may slow down hormonal regulatory cycles. It is not clear, however, what the role of these
changes is in the development of symptoms. The reduced consumption of fatty acids by the kidney contributes to
hyperlipidemia, while reduced gluconeogenesis favors the developmentof hypoglycemia.
Reduced renal elimination of water and electrolytes is particularly important in the development of
symptoms of renal failure (see also p.110). The extracellular volume expands if there is an excess of NaCl and water
(!A), and hypervolemia as well as edemas develop (!p.122); pulmonary edema being the most dangerous
complication (!p. 80). If it is predominantly water which is in excess, the osmotically driven entry of water increases
the intracellular volume (!A) and there is a danger of cerebral edema (!p. 358). The hypervolemia results in the
release of atrial natriuretic factor (ANF) and probably also of ouabain. The latter inhibits Na+/K+- ATPase (!A1).
Vanadate (VNO4), which is largely excreted by the kidney, has a similar effect. Its clearance is about the same as
GFR and its plasma level is markedly raised in renal failure. Inhibition of Na+/K+-ATPase causes reduced
Na+reabsorption in the kidney. Additionally, the intracellular K+ concentration falls in cells from diverse tissues and
the cells depolarize. The intracellular concentration of Na+ rises. This impairs 3Na+/Ca2+ exchange ( !A2), and thus
the intracellular concentration of Ca2+ also increases. The consequences of depolarization are abnormal
neuromuscular excitability, cellular accumulation of Cl–, and cell swelling (!A; see also p.10). The increased Ca2+
concentration causes vasoconstriction as well as increased release of hormones (e.g., gastrin, insulin) and
increased hormonal effects (e.g., epinephrine). Abnormalities of mineral metabolism also contribute greatly to the
symptoms of renal failure (!B). If the GFR is reduced to less than 20% of normal rate, less phosphate is filtered than
is absorbed through the gut. Even if the entire amount of filtered phosphate is eliminated, i.e., there is no
reabsorption, renal elimination cannot keep up with intestinal absorption, and the plasma concentration of
phosphate rises. When the solubility is exceeded, phosphate combines with Ca2+ to form poorly soluble calcium
phosphate. The precipitated calcium phosphate is deposited in the joints and skin (causing joint pains or pruritus,
respectively).
When Ca2+ forms a complex with phosphate, the concentration of Ca2+ is lowered. The hypocalcemia
stimulates the release of PTH from the parathyroid gland, mobilizing calciumphosphate from bone (!B). The result
is demineralization of bone (osteomalacia). Normally PTH makes it possible, by simultaneous inhibition of renal
reabsorption of phosphate, for the plasma concentration of phosphate to fall so that, despite mobilization of
calcium phosphate from bone, the solubility product in plasma is not exceeded and Ca2+ concentration can
increase. In renal insufficiency, however, renal excretion cannot be enhanced, plasma phosphate concentration
increases, CaHPO4 is precipitated, and plasma Ca2+ concentration remains low. The stimulus for PTH release
therefore continues. Under this persisting secretory stimulus the parathyroid glands hypertrophy and, in a vicious
circle, release ever larger amounts of PTH. As the receptors for PTH are, in addition to those in the kidney and
bones, in many other organs (nervous system, stomach, blood cells, gonads) it is assumed that PTH plays a role in
the development of abnormalities in these organs. In fact, removal of the parathyroid glands is thought to
significantly improve numerous symptoms of renal failure. The formation of calcitriol is reduced in renal failure,
which also plays a part in causing the abnormalities of mineral metabolism. Normally this hormone stimulates the
absorption of calcium and phosphate in the gut (!B). Although calcitriol deficiency reduces the intestinal absorption
of phosphate, it aggravates the hypocalcemia. There are receptors for calcitriol in various organs. Calcitriol
substitution does not necessarily improve the symptoms and endangers the patient with renal failure by
stimulating the intestinal absorption of phosphate.

Silbernagl, Stefan & Florian Lang. 2000. Color Atlas of Patophysiology. New York: Thieme p. 110-114