Campbell-Walsh Urology, 11th Edition

PART VII

Renal Physiology and Pathophysiology

43

Physiology and Pharmacology of the Renal Pelvis and Ureter

Robert M. Weiss; Darryl T. Martin

Questions

  1. During development, the ureteral lumen is obliterated and then recanalizes. Which of the following substances appears to be involved in this recanalization process?
  2. Prostaglandin E2
  3. c-KIT
  4. Angiotensin
  5. Calcitonin gene-related peptide (CGRP)
  6. Acetylcholine
  7. Caspases are involved in:
  8. smooth muscle relaxation.
  9. smooth muscle contraction.
  10. hysteresis.
  11. apoptosis.
  12. calcium sequestration.
  13. The resting membrane potential is primarily determined by the distribution of which of the following ions across the cell membrane and the preferential permeability of the cell membrane to that ion?
  14. Potassium
  15. Sodium
  16. Calcium
  17. Chloride
  18. Barium
  19. With excitation of the ureteral muscle cell, an action potential is formed. Which of the following pairs of ions are primarily responsible for the upstroke of the action potential?
  20. Potassium and calcium
  21. Sodium and chloride
  22. Calcium and sodium
  23. Potassium and sodium
  24. Calcium and chloride
  25. Which of the following must be phosphorylated for smooth muscle contraction to occur?
  26. Actin
  27. Myosin
  28. Calmodulin
  29. Calcium
  30. Troponin
  31. The primary site for intracellular storage of calcium is:
  32. mitochondria.
  33. caveolae.
  34. the nucleolus.
  35. actin.
  36. the endoplasmic reticulum.
  37. The second messenger involved in β-adrenergic agonist-induced ureteral relaxation is:
  38. cyclic adenosine monophosphate (AMP).
  39. cyclic guanosine monophosphate (GMP).
  40. nitric oxide.
  41. inositol 1,4,5-triphosphate (IP3).
  42. diacylglycerol (DG).
  43. The enzyme that degrades cyclic GMP is:
  44. guanylyl cyclase.
  45. myosin light-chain kinase.
  46. phosphodiesterase.
  47. phospholipase C.
  48. nitric oxide synthase (NOS).
  49. The enzyme that degrades cyclic AMP is:
  50. adenylyl cyclase.
  51. myosin light-chain kinase.
  52. phosphodiesterase.
  53. phospholipase C.
  54. NOS.
  55. Nitric oxide causes smooth muscle relaxation. In doing so, it activates which of the following enzymes?
  56. Guanylyl cyclase
  57. Myosin light-chain kinase
  58. Phosphodiesterase
  59. Phospholipase C
  60. NOS
  61. The substrate for NOS is:
  62. cyclic AMP.
  63. cyclic GMP.
  64. GTP.
  65. l-Arginine.
  66. l-Citrulline.
  67. Inducible NOS (iNOS) is:
  68. nicotinamide adenine dinucleotide phosphate (NADPH) independent and calcium independent.
  69. NADPH independent and calcium dependent.
  70. NADPH dependent and calcium independent.
  71. NADPH dependent and calcium dependent.
  72. nitric oxide dependent and calcium dependent.
  73. The enzyme involved in the formation of DG is:
  74. adenylyl cyclase.
  75. guanylyl cyclase.
  76. phosphodiesterase.
  77. protein kinase C.
  78. phospholipase C.
  79. DG increases the activity of which enzyme?
  80. Adenylyl cyclase
  81. Guanylyl cyclase
  82. Phosphodiesterase
  83. Protein kinase C
  84. Phospholipase C
  85. An agent that prevents reuptake of norepinephrine in nerve terminals and thus potentiates and prolongs the activity of norepinephrine is:
  86. tyrosine.
  87. monoamine oxidase.
  88. imipramine.
  89. tetramethylammonium.
  90. tetraethylammonium.
  91. Norepinephrine is synthesized from:
  92. tyrosine.
  93. arginine.
  94. choline.
  95. cocaine.
  96. imipramine.
  97. Which of the following inhibits ureteral and renal pelvic contractile activity?
  98. Substance P
  99. Neurokinin A
  100. Neuropeptide K
  101. Neuropeptide Y
  102. CGRP
  103. Which of the following collagen types is associated with ureteral obstruction?
  104. Type I collagen
  105. Type II collagen
  106. Type III collagen
  107. Type IV collagen
  108. Type V collagen
  109. The enzyme involved in prostaglandin synthesis is:
  110. phospholipase C.
  111. cyclooxygenase.
  112. protein kinase C.
  113. phosphodiesterase.
  114. adenosine triphosphate.
  115. With ureteral obstruction, prostaglandins are involved in a process that aids in the preservation of renal function. What is this process?
  116. Afferent arteriole vasoconstriction
  117. Afferent arteriole vasodilatation
  118. Efferent arteriole vasoconstriction
  119. Efferent arteriole vasodilatation
  120. Glomerular vasoconstriction
  121. Which of the following agents could theoretically cause urinary retention?
  122. Bethanechol
  123. BAY K 8644
  124. Prostaglandin F
  125. Verapamil
  126. Substance P
  127. Which of the following is a β-adrenergic agonist?
  128. Cromakalim
  129. Physostigmine
  130. Propranolol
  131. Phenoxybenzamine
  132. Isoproterenol
  133. Which of the following conditions must be present for urine to pass efficiently from the ureter into the bladder?
  134. Intraluminal ureteral contractile pressure must be above 40 cm H2O.
  135. The ureterovesical junction must relax.
  136. Intraluminal ureteral contractile pressures must be greater than intravesical baseline pressures.
  137. Intravesical contractile pressures must be less than 40 cm H2O.
  138. The bladder must relax just before contraction of the ureter.
  139. What is normal baseline or resting ureteral pressure?
  140. 0 to 5 cm H2O
  141. 5 to 10 cm H2O
  142. 10 to 15 cm H2O
  143. 15 to 20 cm H2O
  144. 20 to 25 cm H2O
  145. The Laplace equation expresses the relationship between the variables that affect intraluminal pressure. Which of the following conforms to the Laplace relationship?
  146. Tension = (radius × wall thickness)/pressure
  147. Tension = (radius × pressure)/wall thickness
  148. Tension = (wall thickness × pressure)/radius
  149. Pressure = (radius × wall thickness)/tension
  150. Pressure = (radius × tension)/wall thickness
  151. Factors that facilitate ureteral stone passage include:
  152. increased hydrostatic pressures proximal to the calculus and relaxation of the ureter in the region of the stone.
  153. increased hydrostatic pressures proximal to the calculus and contraction of the ureter in the region of the stone.
  154. decreased hydrostatic pressures proximal to the calculus and relaxation of the ureter in the region of the stone.
  155. decreased hydrostatic pressures proximal to the calculus and contraction of the ureter in the region of the stone.
  156. decreased contractile pressures proximal to the calculus and contraction of the ureter in the region of the stone.
  157. Which of the following hormones inhibits ureteral contractility?
  158. Bombesin
  159. Thyroxine
  160. Estrogen
  161. Aldosterone
  162. Progesterone
  163. A drug that has efficacy in managing ureteral colic is:
  164. bethanechol.
  165. prostaglandin F.
  166. physostigmine.
  167. indomethacin.
  168. ephedrine.
  169. Which of the following is a calcium-binding protein that plays a role in smooth muscle contraction?
  170. Connexin 43
  171. Calmodulin
  172. Cromakalim
  173. Survivin
  174. Myosin
  175. In the ureter, the resting or the contractile force developed at any given length depends on the direction in which the change in length is occurring. This is referred to as:
  176. viscoelasticity.
  177. creep.
  178. hysteresis.
  179. stress relaxation.
  180. compensatory relaxation.
  181. Which of the following is noted to be expressed before initiation of ureteral peristaltic activity?
  182. Prostanoids
  183. Nitric oxide
  184. c-KIT
  185. Myosin light chain
  186. Phosphodiesterase
  187. Ureteral pacemaker activity is amplified by:
  188. prostanoids.
  189. norepinephrine.
  190. CGRP.
  191. cyclic GMP.
  192. potassium channel openers.
  193. Which cells are the primary pacemaker cells for ureteral peristalsis?
  194. Interstitial cells of Cajal-like cells (ICC-like cells)
  195. c-KIT-positive mast cells
  196. c-KIT-negative typical smooth muscle cells
  197. Atypical smooth muscle cells
  198. Caveolae-containing smooth muscle cells

Answers

  1. c. Angiotensin.At a point during development, the ureteral lumen is obliterated and then recanalizes. It appears that angiotensin, acting through the AT2 receptor, is involved in the recanalization process. Knockout mice for the ATR2 gene have congenital anomalies of the kidney and urinary tract, which include multicystic dysplastic kidneys, megaureters, and ureteropelvic junction obstructions.
  2. d. Apoptosis.Programmed cell death, or apoptosis, is involved in branching of the ureteric bud and subsequent nephrogenesis, and inhibitors of caspases, which are factors in the signaling pathway of apoptosis, inhibit ureteral bud branching.
  3. a. Potassium.When a ureteral muscle cell is in a nonexcited or resting state, the electrical potential difference across the cell membrane, the transmembrane potential, is referred to as the resting membrane potential (RMP). The RMP is determined primarily by the distribution of potassium ions (K+) across the cell membrane and by the permeability of the membrane to potassium ions.
  4. c. Calcium and sodium.When the ureteral cell is excited, its membrane loses its preferential permeability to K+ and becomes more permeable to calcium ions (Ca2 +) that move inward across the cell membrane, primarily through L-type Ca2 + channels, and give rise to the upstroke of the action potential.
  5. b. Myosin.The most widely accepted theory suggests that phosphorylation of myosin is involved in the contractile process.
  6. e. The endoplasmic reticulum.Calcium release from tightly bound storage sites (i.e., the endoplasmic or sarcoplasmic reticulum) increases the Ca2 + concentration in the sarcoplasm.
  7. a. Cyclic AMP.Cyclic AMP is believed to mediate the relaxing effects of β-adrenergic agonists in a variety of smooth muscles.
  8. c. Phosphodiesterase.Another cyclic nucleotide, cyclic GMP, also can cause smooth muscle relaxation. Cyclic GMP is synthesized from GTP by the enzyme guanylyl cyclase and is degraded to 5′-GMP by a phosphodiesterase.
  9. c. Phosphodiesterase.Phosphodiesterase activity that can degrade both cyclic AMP and cyclic GMP has been demonstrated in the canine ureter, and various inhibitors can preferentially inhibit the breakdown of one or the other cyclic nucleotide.
  10. a. Guanylyl cyclase.Nitric oxide released from the nerve activates the enzyme guanylyl cyclase in the smooth muscle cell, with the resultant conversion of guanosine triphosphate to cyclic GMP, with resultant smooth muscle relaxation.
  11. d. l-Arginine.NOS converts l-arginine to nitric oxide and l-citrulline in a reaction that requires nicotinamide adenine dinucleotide phosphate (NADPH).
  12. c. NADPH dependent and calcium independent.An inducible NOS isoform, iNOS, is NADPH dependent but Ca2 + independent and has been identified in ureteral smooth muscle.
  13. e. Phospholipase C.Some actions of α1-adrenergic and muscarinic cholinergic agonists and a number of other hormones, neurotransmitters, and biologic substances are associated with an increase in intracellular Ca2 + and are related to changes in inositol lipid metabolism. These agonists combine with a receptor on the cell membrane, and the agonist-receptor complex, in turn, activates an enzyme, phospholipase C, that leads to the hydrolysis of polyphosphatidylinositol 4,5-bisphosphate, with the formation of two second messengers: IP3 and DG.
  14. d. Protein kinase C.DG binds to an enzyme, protein kinase C, causes its translocation to the cell membrane, and, by reducing the concentration of Ca2 + required for protein kinase C activation, results in an increase in this enzyme's activity.
  15. c. Imipramine.The greatest percentage of the norepinephrine is actively taken up (reuptake or neuronal uptake) into the neuron. Neuronal reuptake regulates the duration for which norepinephrine is in contact with the innervated tissue and thus regulates the magnitude and duration of the catecholamine-induced response. Agents such as cocaine and imipramine (Tofranil, Mallinckrodt, Inc., Hazelwood, MO), which inhibit neuronal uptake, potentiate the physiologic response to norepinephrine.
  16. a. Tyrosine.Norepinephrine, the chemical mediator responsible for adrenergic transmission, is synthesized in the neuron from tyrosine.
  17. e. CGRP.Tachykinins and CGRP are neurotransmitters released from peripheral endings of sensory nerves. Tachykinins stimulate contractile activity, and CGRP inhibits contractile activity.
  18. c. Type III collagen.Increased amounts of type III collagen are seen in a variety of obstructed ureteral states.
  19. b. Cyclooxygenase.The "primary" prostaglandins, PGE1, PGE2, and PGF, are synthesized from the fatty acid arachidonic acid by enzymatic reactions involving two cyclooxygenase (COX) isoforms, COX-1 and COX-2.
  20. b. Afferent arteriole vasodilatation.Indomethacin has been used in the management of ureteral colic. The beneficial effects are probably due to indomethacin's inhibition of the prostaglandin-mediated vasodilatation that occurs subsequent to obstruction. The vasodilatation theoretically would result in an increase in glomerular capillary pressure and subsequent increase in pelviureteral pressure.
  21. d. Verapamil.The calcium channel blockers verapamil, D-600 (a methoxy derivative of verapamil), diltiazem, and nifedipine have been shown to inhibit ureteral activity. These inhibitory effects are accompanied by decreases in action potential duration, number of oscillations on the plateau of the guinea pig action potential, excitability, and rate of rise and amplitude of the action potential. High concentrations of verapamil and D-600 cause a complete cessation of electrical and mechanical activity. Similar inhibition of bladder activity can occur.
  22. e. Isoproterenol.Isoproterenol, a β-adrenergic agonist, depresses contractility.
  23. c. Intraluminal ureteral contractile pressures must be greater than intravesical baseline pressures.The theoretical aspects of the mechanics of urine transport within the ureter were described in detail by Griffiths and Notschaele in 1983.* At normal flow rates, while the renal pelvis fills, a rise in renal pelvic pressure occurs, and urine is extruded into the upper ureter, which is initially in a collapsed state. The contraction wave originates in the most proximal portion of the ureter and moves the urine in front of it in a distal direction. The urine that had previously entered the ureter is formed into a bolus. To propel the bolus of urine efficiently, the contraction wave must completely coapt the ureteral walls, and the pressure generated by this contraction wave provides the primary component of what is recorded by intraluminal pressure measurements. The bolus that is pushed in front of the contraction wave lies almost entirely in a passive, noncontracting part of the ureter.
  24. a. 0 to 5 cm H2O.Baseline or resting ureteral pressure is approximately 0 to 5 cm H2O.
  25. b. Tension = (radius × pressure)/wall thickness.The Laplace equation expresses the relationship between the variables that affect intraluminal pressure: pressure = (tension × wall thickness)/radius. The Laplace law: T = PR, where T is tension, P is pressure and R is radius.
  26. a. Increased hydrostatic pressures proximal to the calculus and relaxation of the ureter in the region of the stone. Two factors that appear to be most useful in facilitating stone passage are an increase in hydrostatic pressure proximal to a calculus and relaxation of the ureter in the region of the stone.
  27. e. Progesterone. Several studies have shown an inhibitory effect of progesterone on ureteral function. Progesterone has been noted to increase the degree of ureteral dilatation during pregnancy and to retard the rate of disappearance of hydroureter in postpartum women.
  28. d. Indomethacin.Indomethacin, by reducing pelviureteral pressure and thus pelviureteral wall tension, might eliminate some of the pain of renal colic that is dependent on distention of the upper urinary tract.
  29. b. Calmodulin.With excitation, there is a transient increase in the sarcoplasmic Ca2 + concentration from its steady-state concentration of 10− 8 to 10− 7 M to a concentration of 10− 6 M or higher. At this higher concentration, Ca2 + forms an active complex with the calcium-binding protein calmodulin. Calmodulin without Ca2 + is inactive. The calcium-calmodulin complex activates a calmodulin-dependent enzyme, myosin light-chain kinase. The activated myosin light-chain kinase, in turn, catalyzes the phosphorylation of the 20,000-dalton light chain of myosin. Phosphorylation of the myosin light chain allows activation by actin of myosin Mg2 +-ATPase activity, leading to hydrolysis of ATP and the development of smooth muscle tension or shortening.
  30. c. Hysteresis.Because the ureter is a viscoelastic structure, the resting or contractile force developed at any given length depends on the direction in which change in length is occurring and on the rate of length change. This is referred to as hysteresis; for the ureter, at any given length, the resting force is less and contractile force is greater when the ureter is allowed to shorten than when the ureter is being stretched.
  31. c. c-KIT.This tyrosine kinase receptor is important in the development of pacemaker activity and peristalsis of the gut (Der-Silaphet et al, 1998). Pezzone and colleagues (2003) identified c-KIT-positive cells in the mouse ureter. The expression of c-KIT was noted to be upregulated in the embryonic murine ureter before its development of unidirectional peristaltic contractions (David et al, 2005). Incubation of isolated cultured embryonic murine ureters with antibodies that neutralize c-KIT activity alters ureteral morphology and inhibits unidirectional peristalsis. c-KIT-positive cells have been identified in the human ureter (Metzger et al, 2004).
  32. a. Prostanoids.The ionic conduction underlying pacemaker activity in the upper urinary tract is due to the opening and slow closure of voltage-activated L-type Ca2 + channels, which are amplified by prostanoids (Santicioli et al, 1995a). This is opposed by the opening and closure of voltage and Ca2 +-dependent K+ channels. It has been suggested that prostaglandins and excitatory tachykinins, released from sensory nerves, help maintain autorhythmicity in the upper urinary tract through maintenance of Ca2 + mobilization. Tetrodotoxin and blockers of the autonomic nervous system, both parasympathetic and sympathetic, have little effect on peristalsis, suggesting that autonomic neurotransmitters play little role in maintaining pyeloureteral motility.
  33. d. Atypical smooth muscle cells.Atypical smooth muscle cells give rise to pacemaker activity in the rat and guinea pig ureter. In contrast to typical smooth muscle cells, they have less than 40% of their cellular area occupied by contractile elements and demonstrate sparse immunoreactivity for smooth muscle actin (Klemm et al, 1999; Lang et al, 2001). ICC-like cells in the upper urinary tract do not appear to be primary pacemaker cells but rather may provide for preferential conduction of electrical signals from pacemaker cells to typical smooth muscle cells of the renal pelvis and ureter (Klemm et al, 1999). In the mouse ureteropelvic junction, c-KIT-positive ICC-like cells have been identified that showed high-frequency, spontaneous, transient inward currents that often occurred in bursts to sum and produce long-lasting large inward currents (Lang et al, 2007b). It is postulated that in the absence of a proximal pacemaker drive, these ICC-like cells could act as pacemaker cells and trigger contractions in adjacent smooth muscle cells in the ureteropelvic junction. Thus atypical smooth muscle cells and ICC-like cells both may play a pacemaker role in the initiation and propagation of pyeloureteric peristalsis (Lang et al, 2006, 2007a).

Chapter review

  1. Efficient propulsion of the urinary bolus depends on the ability of the walls of the ureter to coapt.
  2. Autonomic neurotransmitters play little role in maintaining pyeloureteral motility even though the ureter is supplied by sympathetic and parasympathetic neurons.
  3. Ureteral muscle fibers are arranged in a longitudinal, circumferential, and spiral configuration.
  4. The ureter is a syncytial type of smooth muscle without discrete neuromuscular junctions.
  5. Ureteral peristalsis can occur without innervation; however, the nervous system does play at least a modulating role in ureteral peristalsis, particularly the sympathetic nervous system.
  6. Alpha-adrenergic stimulation increases ureteral activity. Beta-adrenergic stimulation inhibits ureteral and renal pelvic activity.
  7. Ureteral pressures can be as high as 20 to 80 cm of water during a contraction.
  8. Pressure within the bladder during the storage phase is of paramount importance in determining the efficiency of urine transport across the ureterovesical junction (UVJ).
  9. Ureteral obstruction causes a gradual increase in ureteral length and diameter.
  10. Infection impairs urine transport by reducing ureteral contractions; it also reduces compliance at the UVJ, which may permit reflux.
  11. Progesterone has an inhibitory effect on ureteral function. Progesterone has been noted to increase the degree of ureteral dilatation during pregnancy and to retard the rate of disappearance of hydroureter in postpartum women. The obstruction of pregnancy is primarily due, however, to mechanical factors and secondarily due to the hormonal effects of progesterone.
  12. Pacemaker cells have resting potentials less negative than non-pacemaker cells and are located near the pelvicalyceal border.
  13. Phosphodiesterase inhibitors and alpha 1A antagonists cause ureteral smooth muscle relaxation.
  14. UPJ obstruction may be mechanical or due to a disordered propagation of peristaltic activity. Some have suggested that the latter is due to an alteration in the configuration of the muscle fibers at the UPJ.
  15. Ureteral decompensation will occur when there are sustained intravesicular pressures that exceed 40 cm H2O.

* Sources referenced can be found in Campbell-Walsh Urology, 11th Edition, on the Expert Consult website.