Jason Lee 9th Edition Notes

Chapter #55 – Physiology and Pharmacology of the

Renal Pelvis and Ureter
(Robert M. Weiss)

CELLULAR ANATOMY

What are the main components of the smooth muscle cell of the ureter?
 nucleus } DNA + nucleolus
 cytoplasm/sarcoplasm } mitochondria (energy)
} endoplasmic reticulum and sarcoplasmic reticulum (Ca2+ storage)
} actin and myosin (contractile proteins)

DEVELOPMENT OF THE URETER

What is the embryologic origin of the ureter?

- arises as an outpouching from mesonephric duct
- formation of ureteric bud and its subsequent branching is induced by several factors derived
from the adjacent metanephrogenic mesenchyme
 GDNF, TGF-β, HGF, FGF, heparin sulfate proteoglycans, laminins, integrins, MMPs
- ureteral bud branching is controlled by apoptotic pathways
 caspase inhibitors can inhibit ureteral bud branching
- ureteral lumen obliterates at one point during development, then recanalizes again
 angiotensin II, acting through AT2 receptors, are involved in recanalization of ureter
- calcineurin is also important in development of renal pelvis, ureter, & ureteral smooth muscle

ELECTRICAL ACTIVITY

What are the basics of cell resting potential and depolarization?

- resting membrane potential } determined mainly by K+ but Na also plays a role
(RMP)  [K] is higher inside the cell & [Na] is higher outside the cell
} NA-K-ATPase maintains K and Na gradient
} ureteral smooth muscle cell RMP is –33 to –70mV
 inside of cell membrane is more –ve than outside
- action potential } stimulus strong enough to decrease transmembrane potential to the threshold
potential results in an action potential
 action potential is related to rise in intracellular Ca2+
& decreased membrane permeability to K+
 depolarization results in inside of cell membrane becoming less
- ve than RMP
} once peak of action potential is reached, membrane maintains depolarized state
(action potential plateau) for a period of time before repolarization occurs
 action potential plateau is related to persistent influx of Ca2+ and
Na+ influx
 repolarization is related to renewed ↑ in permeability to K+
} action potential can act as stimulus for excitation of adjacent resting cells
 propagation of ureteral contraction
 Jason Lee 9th Edition Notes

What is the origin of ureteral peristalsis?

- originates with electrical activity at pacemaker sites located at pelvicalyceal border
 minor calyx serves as site of primary pacemaker cells
 C-kit is important in development of pacemaker activity
- electrical activity is propagated distally } peristalsis – ureteral contraction
- efficient propulsion of urine depends on the ureter’s ability to coapt its walls completely
- latent pacemakers are found in all regions of ureter
 peristalsis still occurs after transection of ureter

How do pacemaker cells differ from other cells?

- RMP is less –ve & does not remain constant } undergoes slow spontaneous depolarization
- action potentials have a slower rate of rise and a lower amplitude
 in upper urinary tract, related to opening and slow closure of voltage-activated L-type
Ca2+ channels

CONTRACTILE ACTIVITY

What are the main steps involved in smooth muscle contraction responsible for ureteral contraction?
 increased free sarcoplasmic Ca2+ causes actin and myosin to contract
- higher concentration of Ca2+ results in formation of Ca2+-calmodulin complex
- Ca2+-calmodulin activates myosin light-chain kinase
- activated myosin light-chain kinase catalyzes phosphorylation of myosin light chain
- phosphorylated myosin light chain allows actin to activate myosin Mg2+-ATPase
- activated myosin Mg2+-ATPase leads to smooth muscle contraction
 different from skeletal muscle which involves increased Ca2+ that binds to troponin, thereby
displacing tropomyosin, thus allowing actin and myosin to interact and contract
 Ca2+-independent contraction is possible

What are the 2 sources of the increased Ca2+ responsible for ureteral smooth muscle contraction?
1) influx of extracellular Ca2+ through L-type Ca channels (major source of Ca2+)
2) intracellular Ca2+ release from endoplasmic or sarcoplasmic reticulum

What are the 2nd messengers involved in Ca2+-related ureteral smooth muscle contraction?
- phospholipase C (PLC)
- inositol 1,4,5 trisphosphate (IP3)
- protein kinase C (PKC)
- diacylglycerol (DG)

What are the factors important in ureteral relaxation?

- in response to β-agonists, Gs protein + Mg + GTP + adenylyl cyclase converts ATP to cAMP
 cAMP responsible for smooth muscle relaxation
- increased Ca2+ leads to synthesis of NO, which activates guanylyl cyclase resulting in conversion of
GTP to cGMP
 involves nNOS, eNOS, and iNOS
 cGMP responsible for smooth muscle relaxation
- adenosine also involved in relaxation of ureteral smooth muscle
 Jason Lee 9th Edition Notes

MECHANICAL PROPERTIES

What are the mechanical factors involved in ureteral contraction?

1) force-length relations } depends on number of linkages between contractile proteins
 actin and myosin
2) force-velocity relations } depends on rate of formation & breakdown of linkages b/w actin & myosin
3) pressure-length-diameter relations } result of longitudinal, circumferential, and spiral configuration
of ureteral smooth muscle fibers

ROLE OF THE NERVOUS SYSTEM IN URETERAL FUNCTION

How is the ureteric smooth muscles innervated?

- syncytial type of smooth muscle } no discrete NMJ for each fiber
- depends on diffuse release of NT from a bundle of nerves with subsequent spread of excitation from
one muscle cell to the next
- sympathetic & parasympathetic neurons involved
 ureteral peristalsis can occur without innervation (latent pacemakers all throughout)
 nervous system plays a modulating role in ureteral peristalsis

What is the effect of the parasympathetics on ureteral smooth muscle?

 cholinergics have excitatory effect } ↑’d frequency & force of peristalsis
- ACh
- methacholine
- carbamylcholine
- bethanechol

What are the precursors to acetylcholine?

- acetyl CoA + choline ------------------------------------- Ach
choline acetyltransferase

What is the effect of anticholinesterases on the ureter?

 eg physostigmine, neostigmine
- increases duration and intensity of Ach action
- increased peristalsis

What is the effect of parasympatholytics on the ureter?

 eg atropine
- does NOT significantly decrease ureteral peristalsis } no benefit in ureteral colic

What is the effect of the sympathetics on ureteral smooth muscle?

- activation of α-adrenergics results in ureteral peristalsis } NE, phenylephrine
- activation of β-adrenergics tend to inhibit peristalsis } isoproterenol, orciprenaline

What is the effect of sympatholytics on the ureter?

- α-blockers decrease ureteral peristalsis } ++ benefit in ureteral colic
- β-blockers block inhibitory effects of β-adrenergics on ureteral peristalsis

What is the role of sensory nerves in ureteral contraction?

- tachykinins stimulate ureteral contraction } eg substance P, neurokinin A, neuropeptide K
 more prominent in renal pelvis
- calcitonin gene-related peptide (CGRP) inhibits ureteral contraction
 more prominent in ureter
 Jason Lee 9th Edition Notes

URINE TRANSPORT

How is urine transported out of the renal pelvis?

- N urine flows } calyceal & renal pelvic contractions >> upper ureteral contractions
} ureteral contractile pressures >> renal pelvic pressures
} relative block of electrical activity at UPJ
 renal pelvis fills and pressure rises until urine extrudes into upper ureter
 closed UPJ may protect kidney in dissipating backpressure from ureter
- high flow rates } block at UPJ ceases and calyceal & pelvic ctxs = ureteral ctxs

How is urine transported down the ureter?

- N urine flows } contraction wave proximal to urine bolus propels urine down to bladder
} efficient transport of urine requires complete coaptation of ureteral walls
- high flow rates } ureteral walls don’t coapt
} continuous column of fluid transported, NOT boluses of urine
 increases in urine flow result in increased in frequency of peristalsis

What is ureteral pressure during urine transport?

- resting baseline pressure } 0-5cm H2O
- ureteral contractions } 20-80cm H2O  occurs at 2-6 times per minute
 normal renal pelvic pressure is ~6.5 mmHg

How does intravesical pressure affect urine transport in the upper tracts?
- N urine flow } ureteral contractile pressure must exceed bladder pressure
- high flow rates } baseline pressure in column of urine within ureter must exceed intravesical pressure
 intravesical pressures ≥40 cm H2O leads to ureteral decompensation & chronically
can lead to upper tract deterioration

What are the 3 potential impediments of efficient urine bolus transfer across the UVJ into the bladder?
1) UVJ obstruction
2) excessively high intravesical pressure
3) high urine flow rates that exceed transport capacity of normal UVJ

PATHOLOGIC PROCESSES AFFECTING URETERAL FUNCTION

What are the effects of obstruction on ureteral function?

 depends on degree & duration of obstruction, rate of urine flow, and presence of infection
 obstructed ureter can’t coapt ureteral wall & can’t generate N active intraluminal pressures
- increased resting ureteral intraluminal pressure initially
 ureteral pressure reaches maximum ~3hrs
 declines afterwards to a little above baseline and then plateaus } remains ↑’d longer in BUO
- due to reduced RBF, GFR, pyelovenous reabsorption, etc
- resting ureteral pressures can’t differentiate obstruction from non-obstructive dilation
- gradual increase in ureteral length and diameter
 occurs even once ureteral pressure plateaus } “creep” seen in viscoelastic structures
 Laplace’s law } increased diameter related to decreased pressure
- also get a transient increase in amplitude & frequency of peristaltic contractions
 as urine fills ureter, however, contractions become smaller and coaptation does not occur
 urine transport then becomes dependent on hydrostatic forces generated by kidney
- ureteral smooth muscle hypertrophy occurs over time
 potential for increased contractility } this is offset by dilation & thinning of muscle though
 N ureteral peristalsis can occur after relief of obstruction <2wks
- presence of infection impairs urine transport by decreasing ureteral contractions
 Jason Lee 9th Edition Notes

How does obstruction affect the upper tract on the cellular level?
- increase in type 1 & type 3 collagen
- increased ratio of collagen:smooth muscle
- alters coordinated pacemaker cells in renal pelvis

What are the 3 main factors implicated in the development of VUR?

1) anatomical and functional abN’ities of UVJ (primary)
2) significantly high intravesical pressures (secondary)
3) impaired ureteral function

What are the 5 main factors that affect spontaneous stone passage?
1) size & shape of stone
2) intrinsic areas of narrowing within ureter (eg UVJ, pelvic brim, UPJ)
3) ureteral peristalsis
4) hydrostatic pressure of column of urine proximal to stone
5) edema, inflammation, spasm of ureter at site of stone impaction

What are the 2 most important factors in facilitating stone passage?

1) increase in hydrostatic pressure proximal to stone
2) relaxation of ureter in region of stone

EFFECT OF AGE ON URETERAL FUNCTION

How does age affect ureteral function?

 neonates & children } more significant degree of ureteral dilation in response to obstruction
} increased force of ureteral contractions between 3wks and 3 months
- no increase in rate of peristalsis during this period
 older age } decrease in ureteral relaxation in response to β-agonists (less cAMP with age)

EFFECT OF PREGNANCY ON URETERAL FUNCTION

What are the effects of pregnancy on ureteral function?

- hydroureteronephrosis } starts in T2 and subsides by first month after parturition
} mainly mechanical (uterus) … ?? hormonal also (progesterone)

What findings support a mechanical cause of hydroureteronephrosis of pregnancy?

1) worse on R side
2) elevated resting ureteral pressures above pelvic brim that improves when positional changes
allow the uterus to fall away from the ureters
3) normal ureteral contractile pressures
4) no hydro of pregnancy in those with conduits or pelvic kidneys
5) no hydro of pregnancy in quadrupeds (uterus hangs away from ureters)
 Jason Lee 9th Edition Notes

EFFECT OF DRUGS ON THE URETER

Which drugs stimulate ureteral activity (INCREASED CONTRACTIONS)?

1) narcotics } if anything, they stimulate ureteral contractions
 use in renal colic is related to decreased CNS pain perception
 not a local effect
2) angiotensin } increases ureteral contractions
3) endothelins } increases contractions (potent vasoconstrictor)
4) histamines } mostly increases peristalsis (mediated by H1 receptors)
} can also cause ureteral relaxation (mediated by H2 receptors)
5) kinins } increases frequency of ureteral contractions
6) ABx } most cause ureteral relaxation but a few cause contraction
 tetracycline
7) cholinergics (eg bethanecol)
8) anticholinesterases (eg neostigmine) } perpetuates cholinergic effects
9) β-blockers

Which drugs inhibit ureteral activity (DECREASED CONTRACTIONS)?

 “Not Action PACK”
1) NSAIDs } decreases PG-mediated ureteral contractions
 good for renal colic
} prevents PG-mediated vasodilation
 decreases RBF & urine production, leading to lower intra-ureteral pressures
2) α-blockers
3) Progesterone
4) ABx } most decrease ureteral contractions
 eg ampicillin, gentamicin
5) CCB } decrease ureteral contractions
6) K+ channel openers } inhibits renal pelvic and ureteral contractions
 eg TCAs (amitriptyline)

What are the effects of 5-HT and cardiac glycosides on ureteral function?
 serotonin } can stimulate, inhibit, or have no effect on ureteral contractions
 cardiac glycosides } depends on species, but can cause increased & decreased contractions