Campbell-Walsh Urology, 11th Edition

PART XII

Urine Transport, Storage, and Emptying

69

Physiology and Pharmacology of the Bladder and Urethra

Toby C. Chai; Lori A. Birder

Questions

  1. The lower urinary tract is innervated by three sets of peripheral nerves. Which of the following is correct?
  2. Pelvic parasympathetic nerves arise at the sacral spinal cord level and excite the bladder and urethra.
  3. Sympathetic nerves inhibit the bladder body and excite the bladder neck and urethra
  4. Pudendal (somatic) nerves excite the bladder body and the external urethral sphincter.
  5. All of the above are true.
  6. None of the above are true.
  7. “Sensing” bladder volume is relevant during bladder storage. Which of the following is correct?
  8. It has been speculated the sense of imminent micturition arises in the urethra.
  9. Bladder filling has been shown to correlate with episodic bursts of sensation and afferent discharge.
  10. Nathan first described sensations of awareness during bladder filling.
  11. Sensations of awareness during bladder distension can be mapped to the urinary bladder.
  12. All are correct.
  13. Bladder afferents can be:
  14. characterized by responses to receptive field stimulation.
  15. classified according to ability to respond to a diverse range of chemical mediators.
  16. silent initially but sensitized during inflammatory processes.
  17. variable in both morphology and function depending upon species.
  18. All of the above.
  19. Sensitization of afferents in bladder pathology can:
  20. open ion channels in the nerve terminals.
  21. release a number of inflammatory mediators.
  22. develop rapidly and be relatively short lived.
  23. be resolved easily.
  24. a-c only.
  25. Patients with irritable bowel syndrome (IBS) often report changes in bladder function. Which of the following statements is correct?
  26. This is an example of cross-organ sensitization.
  27. In animal models colonic inflammation rarely leads to bladder dysfunction.
  28. Cross-organ sensitization only occurs between the gastrointestinal tract and the urinary bladder.
  29. The mediators, which are responsible for these conditions, have been well described.
  30. None are true.
  31. In terms of nerves innervating the detrusor:
  32. the majority express acetylcholinesterase enzyme.
  33. acetylcholine and adenosine triphosphate (ATP) appear to provide the majority of the excitatory input.
  34. release of both acetylcholine and ATP result in smooth muscle contraction.
  35. additional substances released from efferent nerves include nitric oxide and vasoactive intestinal polypeptide.
  36. all are correct.
  37. In terms of adrenergic influences:
  38. reflex bladder activity can be modulated by alpha-1 adrenergic mechanisms.
  39. alpha-1 adrenergic mechanisms control blood pressure and tissue blood flow.
  40. the beta-3 adrenergic receptors are present at a number of sites (both peripherally and centrally).
  41. beta-3 receptor agonists, via effects on a number of sites, are a promising treatment for overactive bladder.
  42. all are correct.
  43. Which of the following is TRUE about ATP?
  44. It is the main excitatory neurotransmitter for bladder contraction in humans.
  45. It can activate two main families of purinergic receptors: P2X and P2Y
  46. Purinergic neurotransmission plays an important role in bladder overactivity and bladder pain
  47. b and c are true
  48. All are correct
  49. During bladder storage:
  50. bladder accommodation is dependent upon activation of sympathetic pathways.
  51. bladder accommodation is dependent upon quiescence of parasympathetic efferent pathways.
  52. intravesical pressure measurements are low when below the voiding threshold.
  53. the sympathetic reflex provides negative feedback.
  54. all are true.
  55. During storage phase of the bladder:
  56. the urothelium plays an important role in accommodating urine storage.
  57. the urothelium is only a barrier and exhibits no other functions.
  58. increase of urothelial-mediators during bladder filling can influence smooth muscle tone.
  59. the urothelial surface cells change shape during bladder filling.
  60. a, c, and d are correct.
  61. The guarding reflex is a mechanism for maintaining continence and is characterized by:
  62. activation of pudendal motoneurons.
  63. increased outlet resistance.
  64. activation of external urethral sphincter motoneurons.
  65. activation of afferent input from the urethra or pelvic floor that leads to closure of the urethral outlet.
  66. all of the above.
  67. Electrical stimulation of the sacral nerve roots is known to be:
  68. an effective treatment for refractory overactive bladder
  69. an effective treatment for non-obstructive urinary retention
  70. effective by modulation of central nervous system pathways
  71. a better treatment compared with posterior tibial nerve stimulation.
  72. a-c are correct.
  73. In terms of bladder emptying:
  74. switching between bladder storage and emptying can occur involuntarily (reflex emptying) or voluntarily.
  75. reflex voiding only occurs in the normal adult.
  76. initial expulsion of urine consists of initial contraction of the urethral sphincter.
  77. relaxation of the urethral smooth muscle during micturition is achieved by release of acetylcholine.
  78. none are true.
  79. The facilitatory urethra to bladder reflex was characterized by:
  80. Barrington
  81. Delancey
  82. de Groat
  83. increased urethral afferent activation promoting bladder emptying.
  84. a and d are correct
  85. An essential control center for micturition in healthy individuals is:
  86. the dorsal pontine tegmentum.
  87. Barrington nucleus.
  88. the pontine micturition center.
  89. the M region.
  90. all of the above.
  91. In terms of cerebral control of voiding in humans:
  92. coordinated relaxation and contraction of urethra and bladder is driven by a long-loop spinobulbospinal reflex.
  93. afferents activated during bladder filling synapse in the central PAG and PMC regions.
  94. spinobulbospinal voiding-reflex pathway functions as a “switch.”
  95. absence of the “switch” would lead to incontinence.
  96. all of the above.
  97. In terms of continence and brain-bladder control:
  98. it involves limbic areas associated with basic emotion and safety.
  99. it involves cortical circuits concerned with social propriety.
  100. the PAG and PMC form the main brainstem “switch.”
  101. all of the above.
  102. The contraction of detrusor by cholinergic muscarinic receptor agonists is characterized by:
  103. IP3 hydrolysis and release of intracellular calcium.
  104. decreased calcium flux through nifedipine-sensitive calcium channels.
  105. involvement of the muscarinic M1 subtype only.
  106. stimulation of the Rho-kinase pathway.
  107. none of the above.
  108. Stimulation of beta-adrenergic receptors in human detrusor is characterized by:
  109. relaxation of detrusor smooth muscle.
  110. involvement of beta 2 and beta 3 subtype receptors.
  111. accumulation of cyclic adenosine monophosphate (cAMP).
  112. all of the above.
  113. Urethral tone and intraurethral pressure are influenced by:
  114. alpha adrenergic receptors.
  115. sympathetic innervation.
  116. number of intramural ganglia.
  117. parasympathetic innervation.
  118. a and b are correct
  119. Which transgenic animal models has (have) been published showing detrusor overactivity?
  120. Increased M3
  121. Decreased P2X3/P2X2
  122. Decreased BK
  123. Decreased β1-integrin
  124. c and d are correct
  125. The lamina propria (LP) of the bladder is thought to be the critical compartment because of which cell(s) that can mediate interaction between urothelium and nerves within the LP?
  126. Fibroblasts
  127. Ganglion cells
  128. Myofibroblasts
  129. Interstitial cells
  130. c and d are correct
  131. The primary mechanism of action of onabotulinumtoxinA is:
  132. blockade of intracellular vesicle fusion in presynaptic nerves.
  133. suppression of afferent nerves in the lamina propria.
  134. blockade of M3 receptor on detrusor myocyte.
  135. opening of BK channel on detrusor myocyte.
  136. blockade of voltage dependent calcium channels on detrusor myocyte.
  137. What distinguishing feature(s) in the bladder urothelium distinguish(es) it from the lamina propria, detrusor and serosal compartments?
  138. Presence of connexin-43 (Cx43)
  139. Presence of purinergic receptors
  140. Presence of tight junction proteins
  141. Presence of uroplakins
  142. c and d are correct
  143. During acute bacterial cystitis, uropathogenic bacteria induce a host immune response due to their interaction with which of the following receptors on the urothelial cell?
  144. TRPV1
  145. M2
  146. NK-A
  147. TLR4
  148. P2X3
  149. Maintenance of normal bladder compliance during urinary storage is (are) due to:
  150. passive viscoelastic properties.
  151. active neural signaling.
  152. modulation of filling rate.
  153. all of the above.
  154. a and b are correct.
  155. Connexin-43 (Cx43) is important in regulating detrusor contractility because:
  156. it regulates acetylcholine release by efferent nerves.
  157. it breaks down acetylcholine in the neuromuscular junction.
  158. it allows for passage of ions between adjoining detrusor myocytes.
  159. it has a circadian rhythm of expression.
  160. c and d are correct.
  161. Which urethral mechanisms are involved in maintenance of continence in the female?
  162. Network of submucosal vascularity
  163. Guarding reflex
  164. Hammock hypothesis
  165. Sympathetic tone
  166. All are correct
  167. G-coupled proteins:
  168. mediate many different receptor functions.
  169. enzymatically cleave ATP to adenosine monophosphate (ADP).
  170. regulate protein folding in the endoplasmic reticulum (ER).
  171. help regulate intracellular calcium concentrations.
  172. a and d are correct.
  173. Urothelial barrier function is maintained by which of the following?
  174. Gap junctions
  175. Uroplakins
  176. TLR4 receptor
  177. Aquaporin channels
  178. Mucinous layer
  179. In supraspinal SCI (spinal cord injury), the mechanisms mediating neurogenic detrusor overactivity include that it:
  180. is mediated by C-fiber afferent fibers.
  181. involves NGF in pathophysiology.
  182. can be blocked by?-blockers.
  183. is associated with external sphincter contractions.
  184. all are correct.
  185. Membrane potential of a cell:
  186. requires energy to maintain, even at rest.
  187. at rest, is maintained by low intracellular potassium and high extracellular potassium.
  188. at rest, is maintained by low intracellular sodium and high intracellular chloride.
  189. becomes electrically more negative during an action potential in a neuron.
  190. changes during an action potential due to influx of anions into the detrusor myocyte.
  191. Which of the following mechanisms is unique to M2 muscarinic receptor activation when compared to M3 muscarinic receptor activation?
  192. Mediates rise in intracellular calcium when activated
  193. Uses G-coupled proteins
  194. Involves cAMP downstream
  195. Causes detrusor contraction
  196. Causes detrusor relaxation
  197. Isolated nocturia complaints are due to:
  198. nocturnal polyuria.
  199. sleep apnea.
  200. detrusor overactivity.
  201. peripheral edema.
  202. a, b, and d are correct.
  203. Which of the following declines with aging?
  204. Bladder sensation
  205. ATP content of bladder
  206. Detrusor contractile responses to α-adrenergic stimulation
  207. Detrusor contractile responses to cholinergic or electrical stimulation
  208. Bladder capacity
  209. Urine from BPS/IC patients has been found to contain:
  210. a protein that inhibits urothelial cell growth in culture.
  211. a virus that induces T-cell mediated inflammation.
  212. a protozoan that invades the urothelial cell.
  213. an increased level of ATP.
  214. a and d are correct.
  215. The "motor-sensory" hypothesis is used to explain mechanism of action in treating:
  216. bladder underactivity with a muscarinic agonist.
  217. neurogenic detrusor overactivity with TRPV1 blocker.
  218. idiopathic detrusor overactivity with onabotulinumtoxin A.
  219. urinary urgency with antimuscarinics.
  220. urinary frequency with α-blockers.
  221. The reason that some women void without measureable increase in Pdet is because:
  222. the detrusor does not need to contract during voiding in women.
  223. the urethra contains smooth, in addition to striated, muscle fibers.
  224. there is a reduced parasympathetic innervation to the female bladder.
  225. Pdet is not the only measure of the bladder's mechanical work ability.
  226. the female bladder has increased viscoelastic properties.
  227. Differences between smooth and striated muscles include:
  228. actinomyosin cross-bridge cycling in smooth muscle only.
  229. visible striations in striated muscle only.
  230. release of acetylcholine by pre-junctional motor neurons in smooth muscle only.
  231. lack of intermediate filaments in skeletal muscles only.
  232. b and d are correct.
  233. Bladder outlet obstruction results in:
  234. change in collagen subtype proportions.
  235. afferent and efferent neuronal hypertrophy.
  236. urothelial hyperplasia.
  237. C-fiber mediated micturition reflex.
  238. a, b, and d are correct.
  239. The principle behind neuromodulation in treating overactive bladder is:
  240. inhibition of detrusor interstitial cell activity.
  241. block of release of postganglionic neuronal acetylcholine.
  242. activation of C-fiber afferents.
  243. inhibition of somatic afferent processing in spinal cord.
  244. excitation of sacral sympathetic nerve fibers.
  245. Which of the following animal models best mimics human BPS/IC?
  246. Social stress model
  247. Water avoidance stress model
  248. Acetic acid infusion into bladder
  249. Cyclophosphamide intraperitoneal injection
  250. Bowel radiation model
  251. Etiologic causes for stress urinary incontinence may include:
  252. decreased urethral support.
  253. loss of urothelial seal.
  254. decreased serotonin in sacral spinal cord.
  255. shortened urethra.
  256. a, b, and c are correct.
  257. The neurotransmitter released by sympathetic preganglionic neurons at the ganglia is:
  258. acetylcholine.
  259. norepinephrine.
  260. adenosine triphosphate.
  261. epinephrine.
  262. nitric oxide.
  263. The action potential in either an afferent or efferent neuron is due to:
  264. influx of Na.
  265. influx of K.
  266. influx of Cl.
  267. influx of Ca.
  268. efflux of Ca.

Answers

  1. b. Sympathetic nerves inhibit the bladder body and excite the bladder neck and urethra.
  2. e. All are correct.
  3. e. All are correct.
  4. e. a-c only.
  5. a. This is an example of cross-organ sensitization.
  6. e. All are correct.
  7. e. All are correct.
  8. d. b and c are true.
  9. e. All are true.
  10. e. a, c, and d are correct.
  11. e. All of the above.
  12. e. a-c are correct.
  13. a. Switching between bladder storage and emptying can occur involuntarily (reflex emptying) or voluntarily.
  14. e. a and d are correct.
  15. e. All of the above.
  16. e. All of the above.
  17. d. All of the above.
  18. a. IP3 hydrolysis and release of intracellular calcium.
  19. d. All of the above.
  20. e. a and b are correct.
  21. e. c and d are correct.
  22. e. c and d are correct.
  23. a. Blockade of intracellular vesicle fusion in presynaptic nerves.
  24. e. c and d are correct.
  25. d. TLR4
  26. e. a and b are correct.
  27. e. c and d are correct.
  28. e. All are correct.
  29. e. a and d are correct.
  30. b. Uroplakins.
  31. e. All are correct.
  32. a. Requires energy to maintain, even at rest.
  33. c. Involves cAMP downstream.
  34. e. a, b, and d are correct.
  35. a. Bladder sensation.
  36. e. a and d are correct.
  37. d. Urinary urgency with antimuscarinics.
  38. d. Pdet is not the only measure of bladder's mechanical work ability.
  39. e. b and d are correct.
  40. e. a, b, and d are correct.
  41. d. Inhibition of somatic afferent processing in spinal cord.
  42. b. Water avoidance stress model.
  43. e. a, b, and c are correct.
  44. a. Acetylcholine.
  45. a. Influx of Na.

Chapter review

  1. The bladder has two parts: the body, which lies above the ureteral orifices, and the base, consisting of the trigone and bladder neck.
  2. Smooth muscle is able to adjust its length over a much wider range than skeletal muscle. Thus, an empty bladder has a small intravesical space despite the amount of smooth muscle it contains.
  3. There is a complete, competent ring of smooth muscle around the bladder neck in the male. This does not occur in the female.
  4. In women the density of adrenergic innervation in the bladder neck is less than in men.
  5. Myofibroblasts in the lamina propria modulate physiologic interactions between the urothelium and detrusor.
  6. Bladder wall blood flow is reduced by distention; in patients with decreased compliance, this effect is pronounced.
  7. In the female, the external urethral sphincter covers the ventral surface of the urethra in a horseshoe configuration.
  8. The levator ani pelvic floor muscle does not surround the ventral aspect of the urethra in either the male or the female.
  9. The external urethral sphincter is composed of (1) periurethral striated muscle of the pelvic floor and (2) striated muscle within the urethra.
  10. The bladder urothelium serves a barrier function but is permeable to water to a limited degree and can actively transport sodium.
  11. There is no definite evidence that the GAG layer acts as a primary epithelial barrier.
  12. Urothelial cells release chemical mediators such as NO, ATP, acetylcholine, and substance P that have excitatory and inhibitory actions on afferent nerves in the bladder wall.
  13. Prostaglandins are released from the urothelium.
  14. Uroplakin and tight junction proteins are important in maintaining the urothelial barrier function.
  15. The normal bladder at rest may be spontaneously active.
  16. A low voiding pressure in women does not equate with impaired detrusor contractility.
  17. The parasympathetic nerves from S2-4 excite the bladder and relax the urethra. They have afferent fibers. The lumbar sympathetic nerves inhibit the bladder body and excite the bladder base and urethra. They also have afferent fibers. The pudendal nerves (S2-4) excite the external urethral sphincter. Afferent nerve fibers travel with the pudendal nerve as well.
  18. There may be parasympathetic afferent and efferent nerve interconnections at the level of the intramural ganglia.
  19. Pelvic nerve afferents monitor bladder volume and amplitude of the bladder contraction.
  20. The bladder neck and proximal urethra contain the largest density of bladder nerves.
  21. Decreased afferent sensitivity or excitability in certain pathologic conditions as well as aging may be an important cause of impaired voiding.
  22. Activation of the parasympathetic pathway during voiding triggers the release of NO, which is a major inhibitor of urethral smooth muscle.
  23. Cross organization may occur between bladder and bowel, uterus, pelvic urethra, vagina, and prostate. This may contribute to the chronic pelvic pain syndrome.
  24. A substantial proportion of the C-fiber afferent population is silent; pathologic conditions may recruit mechanosensitive C-fibers to form a new functional afferent pathway.
  25. Activation of the central serotonergic system can suppress voiding by inhibiting the parasympathetic excitatory input to the urinary bladder.
  26. The bladder sympathetic reflex promotes closure of the urethral outlet and inhibits neurally mediated contractions of the bladder.
  27. While the bladder fills, the external sphincter activity increases (guarding reflex)—that is, pudendal motor neurons are activated by bladder afferent input.
  28. The dorsal pontine tegmentum is the control center for micturition.
  29. Stimulation of beta 2 and beta 3 receptors relaxes the detrusor.
  30. Sex steroids modulate receptors and influence growth of bladder tissues.
  31. After spinal cord injury, a C-fiber–mediated spinal reflex develops and may play a role in the development of detrusor overactivity.
  32. Alterations of neural networks occur in the central nervous system following obstruction of the lower urinary tract.
  33. Obstruction-induced detrusor overactivity may be due to denervation supersensitivity.
  34. With aging detrusor contractility, bladder sensation and urethral pressure decline.
  35. Sacral neuromodulation is thought to have its beneficial effect by somatic inhibition of sensory processing in the spinal cord.
  36. The hammock hypothesis of urinary continence suggests that the urethra has a fixed dorsal surface due to its attachments to the pubis, pelvic muscles, and fascia, which allows ventral wall compression of the urethra against the fixed dorsal wall.