UROPHARMACOLOGY
LOWER URINARY TRACT PHARMACOLOGY I. Anatomic Considerations NABIL K. BISSADA,
M.D.
ALEX E. FINKBEINER, LARRY T. WELCH,
M.D.
PH.D.
From the Departments of Urology and Pharmacology, University of Arkansas College of Medicine, Little Rock, Arkansas
ABSTRACT -With this issue Dr. Bissada, Dr. Finkbeiner, and Dr. Welch introduce a series on uropharmacology, starting with the lower urinary tract. Since an understanding of the anatomy, neurophysiology, and basic pharmacology is necessary, Part I is a description of the functional anatomy of the lower urinary tract and the mechanisms of continence and voiding. Part ZZis a review of the differences between somatic and autonomic reflexes; the afferent and efferent innervation of lower urinary tract; the organization of pelvic ganglionic cells and the spinal and supraspinal control of lower urinary tract function. Subsequent articles will be on basic pharmacology of lower urinary tract and individual drug classes.
The anatomy of the lower urinary tract, especially that of the bladder outlet, is an area of extreme controversy. The following review is an attempt to analyze the available literature and to supply a unifying concept of the morphology and function of this region. Although this presentation is intended as an introduction to the series of pharmacology of the lower urinary tract, we hope that it will also serve as a convenient review of the functional morphology of this area.
The urinary bladder is a hollow musculomembranous organ lined by transitional epithelium. Functionally, it may be described as consisting of the body and base regions.
As early as 1891, Griffiths’ denied the separate strata in the urinary bladder, observing that muscular bundles run from plane to plane and become circular and oblique in the regions of the bladder neck. Huntel-2 also noted this decussation. Woodburne3 and Winkler4 described the muscular wall of the bladder as a meshwork. Wesson5 believed that he could follow anterior fascicles from the bladder wall which circled behind the urethral orifice and fascicles from the posterior wall of the bladder which circled in front of it. It may be concluded that in the region of the body of the urinary bladder, muscle fibers from all layers are intermingled, and the muscular wall of the bladder is to be considered as a continuum of smooth musculature, the vesical detrusor.3
Bladder body
Bladder base and bladder neck
The smooth muscle fibers of the bladder body were described as being composed of three layers, the external and internal longitudinal layers, and the middle layer, which is the thickest and is composed of circularly running muscle fibers.
In the following discussion, the bladder base is considered to include the trigonal structures as well as the other smooth muscle fibers in the distal one inch of the bladder just above the bladder neck (Fig. 1). As the detrusor muscle bundles converge on the internal orifice of the
Anatomy of the Bladder
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cle rings, arranged concentrically around the bladder neck, and incorporated into the base of the bladder. The most caudal of these fibers form the true bladder neck. The ring is complete anteriorly while posteriorly it fuses with the trigone. This structure was first described by Heiss in 19157 (Heiss ring) and then by Uhlenhath, Hunter, and Loechel in 19558 as the “fundus ring.” In 1965 Hutchs~g~lo demonstrated that anatomically and functionally the “fundus ring” or “Heiss ring” fuses with the deep trigone to form a structure which he called the “base plate.” The base plate is divided into two parts, the anterior part is made up of the anterior bladder wall from the bladder neck to a point 2 to 2.5 cm. above the bladder neck. The posterior part is the deep trigone.
Outer longitudinal layer. The outer longitudinal layer contains many muscle bundles that are prominent along the anterior and posterior walls of the bladder but are thin on its lateral aspects. As the fibers representing this group converge on the narrow bladder neck, they coalesce into distinct muscle groups:g
FIGURE 1. Schematic knidsagittal section of bladder base and male proximal urethra: (1) mucosa and inner longitudinal muscle layer; (2) middle circular layer; (3) outer longitudinal layer; (4) fundus (Heiss) ring of middle longitudinal layer; (5) deep trigone; (5A and 5B) circular layer of urethra; (6) median lobe of prostate; (7) posterior lobe of prostate; (8) external urethral sphincter; (9) periurethral striated muscle; (10) transverse precervical arc; (11) detrusor loop; and (12) smooth muscle sling from precervical arc to urethral inner longitudinal layer.
ANTEFUOR PORTION. This group is arranged in a wide band extending from the bladder neck to the vertex of the bladder along its anterior wall. Superiorly, many of these fibers can be seen to loop around the urachus. Inferiorly, this group narrows and thickens as it approaches the bladder neck and makes a major insertion just ventral to the vesical neck into a fibromuscular structure which Gil-Vernetl’ calls the transverse precervical arc.
bladder, they tend to become oriented into three layers.” Znner longitudinal layer. Through the bladder the fibers of the inner longitudinal layer are widely separated and run in different directions. As they approach the bladder neck they become organized on a longitudinal axis and pass through the bladder neck to become the inner longitudinal layer of the urethra. This layer is interrupted in the trigonal region where it fuses with the superficial trigone. Middle circular layer. The middle circular layer terminates at the bladder neck and does not go into the urethra. In the base of the bladder it is thickened and its fibers are prominent. Thickening is caused by a marked increase in the number of circularly oriented smooth mus-
POSTERIOR PORTION. This concentration of longitudinal fibers is even longer and stronger than the anterior group. The fibers also run from the vertex of the bladder to the bladder neck, and some of them also loop around the urachus. As they approach the bladder neck they form a medial group and right and left lateral groups. The medial group forms a flat wide muscle which inserts into the posterior surface of the apex of the trigone at the bladder neck. It lies against the posterior surface of the deep trigone but is not attached to it except at the apex. The lateral groups encompass the remaining outer posterior longitudinal fibers which pass downward and forward, actually leaving the bladder to pass into the groove formed by the junction of the bladder and urethra in females or bladder and prostate in males. These muscle bundles then leave the vesicourethral groove to form the superior part of the anterior wall of the urethra just distal to the anterior part of the
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or continence and will not be discussed further. The female urethra and the posterior urethra in the male consist of a mucosa and two smooth muscle layers: (1) the inner longitudinal layer, which is a direct continuation of the inner layer of the bladder, and (2’ the middle circular layer, which is a direct continuation of the deep trigone. This layer is present throughout the entire urethra in the female and the posterior urethra in the male, except where it is replaced by the detrusor loop. It is partially surrounded by the paraurethral striated muscle in both sexes. Considerable quantity of smooth muscle tissue extends from the proximal bulbous urethra to the verumontanum.‘3-‘7 This is surrounded by the striated external sphincter.
base plate. They then loop back to the opposite vesicourethral groove and then to the posterior outer longitudinal layer on the side of the bladder opposite their origin. This is the detrusor loop first described by Heiss7 and emphasized b Y Gil-Vernet.” This horseshoe-shaped structure forms most of the anterior and lateral portions of the bladder neck. Its prongs are directed dorsally and continue into the posterior bladder wall in the same manner as the right and left lateral posterior outer longitudinal muscles described. Its concave surface, into which the apex of the trigone fits, is directed dorsally. Ventrally, its convex surface is fused with the transverse precervical arc. The transverse precervical arcg*rl is a tough fibrous point of insertion for the anterior outer longitudinal layer and the detrusor 10op.~*” It lies at the anterior bladder neck, just anterior to the detrusor loop and just below the anterior part of the base plate. It surrounds the anterior third of the bladder neck. Trigonal
Striated
structures
The trigonal structures include the deep trigone which lies in the floor of the bladder in the triangular area between the two ureteral orifices and bladder neck and at a depth corresponding to the middle circular layer. It lies between the superficial trigone internally and the outer longitudinal layer externally. Laterally, it fuses imperceptibly into the middle circular layer, the smooth muscle rings of which form the fundus ring. Tanagho and PughI demonstrated that at each craniolateral border, the deep trigone is rolled into a tube - Waldeyer’s sheath and that the ureter left the bladder through this sheath. Caudally the deep trigone continues directly across the bladder neck into the urethra. It is this continuity between the deep trigone and the wall of the urethra that keeps the urethra firmly attached to the bladder. The deep trigone fuses with the fundus ring of the middle circular layer. The superficial trigone lies on top of the deep trigone and directly under the bladder mucosa. It fuses with the inner longitudinal layer of the detrusor and continues upward as the ureter, leaving the bladder through Waldeyer’s sheath. Its superior border forms Mercier’s bar while its lateral borders form Bell’s muscle. Urethral
core structure
The anterior urethra in the male acts merely as a conduit and normally has no role in voiding
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muscle
component
The true external sphincter consists of circularly oriented striated muscle lying between the superior and inferior layers of the urogenital diaphragm. The paraurethral striated muscle originates from the striated muscle of the true sphincter and climbs sharply upward along the outer surface of the urethra. It inserts into the connective tissue and smooth muscle rings of the urethral core structures at a point about halfway between the urogenital diaphragm and the bladder neck. In both sexes the striated muscle occupies the inferior one half of the anterior urethral wall and is less prominent along the posterior wall of the urethra. In male subjects it is limited to the small area between the urogenital diaphragm and the apex of the prostate. In female subjects striated muscle is sparse along the inferior half of the posterior wall of the urethra, but is abundant in the superior half of the posterior wall. Urinary
Continence
Three sphincteric mechanisms continence in normal individuals Bladder
neck sphincteric
contribute (Fig. 2):
to
mechanism
The importance of the bladder neck continence mechanism has been a controversial subject. While some investigators have denied its importance, 1,18-22 others have emphasized its ro1e.5,6,g,23-26 The anatomic findings of Hunter,2 22 and of Tanagho and Clegg, 27 Woodburne Smith2’ have failed to ‘demonstrate an anatomic sphincter at this area. Instead, they found that the detrusor muscle and the urethra form one continuous sheet of muscle. Accordingly, sev-
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The bladder neck sphincteric mechanism is also important to prevent retrograde ejaculation. When the bladder function is impaired, problems of urination, ejaculation, or both may occur.21 Urethral
Schematic FIGURE 2. mechanisms.
representation
of sphincter
era1 investigators maintain that, with increasing vesical distention, tension is transmitted to the urethral wall resulting in a more effective closure.2g-31 On the other hand, several other investigators have been able to demonstrate a functional sphincteric mechanism at the bladder neck.32-35 Hutch6 reviewed his work and the extensive literature on the subject and described the bladder neck sphincter as a double loop. This consists of the base plate forming the top loop and the detrusor loop forming the bottom Hutch’s description offers an explanaloop. 7*g~11 tion as to why the bladder neck remains closed at rest and is open during voiding. It is also in accord with changes that are seen during void34 The tone of the base ing cystourethrography. plate is constantly forcing the apex of the trigone forward. The detrusor loop, located in the very top of the urethra, forms most of the anterior and lateral walls of the urethra near the bladder neck. The loop is so positioned that the apex of the trigone fits snugly into its concave surface. Its force is constantly directed backward or dorsally in direct opposition to the apex of the trigone which, as previously discussed, is being continuously forced forward. Since the detrusor loop is stretched around the posterior wall of the bladder from the anterior bladder neck to the urachus, it is pulled tighter and tighter as the bladder fills. Also with bladder filling, the base plate remains flat and the rings of circular smooth muscle exert their force in an inward direction, thus keeping the bladder neck closed constantly. At the same time, the right and left lateral posterior outer longitudinal layers pull the detrusor loop backward in direct opposition to the base plate.
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sphincter
The urethral sphincter consists of the musculature and connective tissue in the proximal 3 cm. of the urethra. 2g,36*37Its role in continence is by the pressure or resistance it creates. This resistance is determined by the caliber of the urethral lumen, the. tension exerted by the wall of the urethra against its lumen, and by the length of the urethra. The elastic element of the connective tissue may aid in keeping the urethra closed.37*38 Most of the elastic tissue is situated at the bladder neck and first part of the urethra,39 and some have denied its contribution to urethral pressure.13 However, there is general agreement that the urethral smooth muscle plays an important role in normal 13-17,21,26,37,38,40-42 continence D uring the collecting phase, there is a gradual increase in the urethral pressure which is higher than the rise of the intravesical pressure.30 This was more pronounced in the distal segment of the urethra. External
sphincter
mechanism
The anatomy of the striated component of the sphincter (external urethral sphincter and periurethral striated muscle) has been discussed previously. The striated muscles of the pelvic floor, especially the levator ani muscle, further contribute to this sphincteric function. The external sphincter can maintain continence during sudden rises in intravesical pressure. While the internal sphincter can stand an intravesical pressure of 30 to 40 mm. Hg without opening, the external sphincter usually takes 70 to 100 mm. Hg to open it forcefully, and under some circumstances these figures may be doubled or triof the external sphincpled. 2* The contribution ter mechanism to normal continence has been debated. 13*21,30.37,40*43-47 Whatever the contribution of the striated muscle to the resting urethral pressure may be, there is agreement that it does appear to have an important role in preventing leakage during stress. 21,37*44 This may be accomplished by a twofold action of the striated pelvic and periurethral muscles. The external urethral sphincter and the pubococcygeus fibers of the levator ani muscles compress the urethra circumferentially as well as elongate it by pulling it upward and cephalad. In pathologic condi-
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tions of hyperreflexia, due to central nervous lesions, a spastic contraction of this sphincter may constitute an effective hindrance to bladder emptying.48*4Q Surgically, these sphincter mechanisms may be considered to consist of proximal and distal sphincteric mechanisms, either of which is capable of preserving continence. The proximal sphincters are the bladder neck and uppermost part of the proximal urethra.50 The distal sphincters consist of the skeletal muscle component and the circular smooth muscle of the membranous and proximal bulbous urethra 17,51,52 Mechanics of Voiding Urine is retained in the bladder as long as the closure pressure, that is, the difference between the maximal intraurethral pressure and simultaneously existing bladder pressure, remains above zerouS For micturition to start, this closure pressure must first drop and become negative. There are several diverging concepts regarding the mechanisms involved in the process of initiation of voiding. During normal voiding, the bladder neck opens, the urethral pressure is lowered, and the striated muscle of the external sphincter and the pelvic floor relaxes. contends that contraction of inner Lapides longitudinal muscles of the bladder and urethra results in shortening of the urethra, widening of its lumen, and reduction of its resistance to flow. Hutch6 agrees that the inner longitudinal layer can exert an active opening action on the urethra. A group of smooth muscle bundles that originates from the precervical arc and are inserted in the inner longitudinal layer (Fig. 1) tend actively to pull open the top part of the anterior wall of the urethral sphincter. Muellner55 postulated that in man voluntary relaxation of the pelvic floor permits the descent of the vesical neck and that this descent is the stimulus for the detrusor to contract initiating voiding. Tanagho and Miller56 also reported that prior to voiding there is a drop of the intraurethral pressure as a result of relaxation of the pelvic floor and the striated external sphincter. Ghoneim et ~~1.~~3~~ demonstrated that during the expulsion phase there is a reduction in urethral pressure which involved both the smooth and striated muscle elements. The mechanism of opening of the bladder neck is even more controversial. Lapides contends that the bladder body contracts down on
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the bolus of urine pulling open the bladder neck. Bro-Rasmussen et ~1.~~postulated that the bladder neck is pulled open by contraction of the trigonal muscle, a muscle similar to the latter situated in front of the internal orifice and the detrusor muscle, and that opening is further aided by concurrent shortening of the urethra brought about by contraction of its longitudinal fibers. A similar view is also held by Hutch.34 He drew conclusions from cinefluoroscopic observations. He noted on lateral voiding cystourethrograms, that during bladder filling and at rest, the base plate is flat and that the urethra enters slightly forward to the center of the flat area. During voiding the anterior and posterior halves of the base plate move sharply upward to form a funnel above the bladder neck, “the trigonal canal. “58 During the initiation of voiding, the bladder neck appears to remain in the same position and the urethra fills out with contrast medium, but does not change in length. Hutch’ postulated that during voiding, the transverse precervical arc is pulled upward and forward by the anterior outer longitudinal muscles and is pulled upward and backward by the detrusor loop. The result is a compromise in which the arc moves upward for about 1 to 2 cm. This breaks the anterior and lateral parts of the base plate. At the same time the contraction of the medial posterior outer longitudinal muscle breaks the posterior half of the base plate out of the flat position and extracts the apex of the trigone out of the detrusor loop. As a result of the base plate assuming the early funnel shape, continuous active contraction of the fundus ring now actively helps to break both the anterior and posterior halves of the base plate to form the trigonal canal. The net result of these changes is an open bladder neck.
References 1. GRIFFITHS, J.: Observations on the urinary bladder and urethra, J. Anat. Physiol. 25: 535 (1891). 2. HUNTER, D. T., JR.: A new concept of urinary bladder musculature, J. Urol. 71: 695 (1954). 3. WOODBURNE, R. T.: The sphincter mechanism of the urinary bladder and the urethra, Anat. Rec. 141: 11 (1961). 4. WINKLER, G.: Cartribucional estudeo de la inervacion de la visceras pelvianas, Arch. Esp. Urol. 20: 259 (1967). Anatomical, embryological and 5. WESSON, M. B.: physiological studies of the trigone and neck of the bladder, J. Urol. 4: 279 (1920).
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6. HUTCH,
7. 8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18. 19.
20. 21. 22. 23.
24. 25. 26.
27. 28.
29.
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J. A.: Anatomy and Physiology of the Trigone, Bladder and Urethra, New York, AppletonCentury Croft, 1972. HEISS, R.: Ueber den Sphincter vesicalis internus, Virchows Arch. Pathol. Anat. 220: 367 (1915). UHLENHUTH, E., HUNTER, D. T., and LOECHEL, W. E. : Problems in the Anatomy of the Pelvis, An Atlas, Philadelphia, J. B. Lippincott Co., 1953. HUTCH, J. A.: The internal urinary sphincters: a double-loop system, J. Urol. 105: 375 (1971). IDEM: A new theory of the anatomy of the internal urinary sphincter and the physiology of micturition. II. The base plate, ibid. 96: 182 (1966). GIL-VERNET, S.: Morphology and function of vesico-prostato-urethral musculature, Treviso, Italy, Canova, 1968, p. 334. TANAGHO, E. A., and PUGH, R. C. B.: The anatomy and function of the ureterovesical junction, Br. J. Ural. 35: 151 (1963). DONKER, P. J., IVANOVICI, F., and NOACH, E. L.: Analysis of the urethral pressure profile by means of electromyography and the administration of drugs, ibid. 44: 180 (1972). ELLIOT, J. S., Postoperative urinary incontinence, a revised concept of the external sphincter, J. Urol. 71: 49 (1954). DRAHN, H. P., and MORALES, P. A.: The effect of pudendal nerve anesthesia on urinary continence after prostatectomy, ibid. 94: 282 (1965). NEMOY, M. J., and GOVAN, D. E.: Urinary continence in the absence of an intact external sphincter, ibid. 102: 200 (1969). COLAPINTO, V., and MCCALLUM, R. W.: Urinary continence after repair of membranous urethral stricture in prostatectomized patients, ibid. 115: 392 (1976). BOYARSKY, S.: The Neurogenic Bladder, Baltimore, The Williams and Wilkins, Co., 1967. GOSLING, J. A., and DIXON, J, S.: The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra, Br. J. Urol. 47: 549 (1975). of the prostate HUNTER, D. T., JR.: Musculature gland, ibid. 40: 278 (1968). KLEEMAN, F. J.: The physiology of the internal urinary sphincter, J. Urol. 104: 549 (1970). WOODBURNE, R. T.: Structure and function of the urinary bladder, ibid. 84: 79 (1960). HOMSY, G. E.: The dynamics of the ureterovesical and vesicourethral junctions, Invest. Urol. 4: 408 (1967). HINMAN, F.: Male incontinence: relationship of physiology to surgery, J. Urol. 115: 274 (1976). PENNINGTON, L. T., and LUND, H. Z.: An elastic ring of tissue in the male urethra, ibid. 84: 481 (1960). TURNER-WARWICK, R., et al. : A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and transtrigonal posterior prostatectomy, Br. J. Urol. 45: 44 (1973). CLEGG, E. J.: The musculature of the human prostatic urethra, J. Anat. 91: 345 (1957). TANAGHO, E. A., and SMITH, D. R.: The anatomy and function of the bladder neck, Br. J. Urol. 38: 54 (1966). LAPIDES, J.: Structure and function of the internal
vesical sphincter, J. Ural. 80: 341 (1958). 30. GHONEIM, M. A., FRETIN, J. A., GAGNON, D. J., and SUSSET, J. G.: The influence of vesical distension on urethral resistance to flow: the collecting phase, Br. J. Urol. 47: 657 (1975). 31. TANAGHO, E. A., MILLER, E. R., MEYERS, F. H., and CORBETT, R. K.: Observations on the dynamics of the bladder neck, ibid. 38: 72 (1966). 32. EDVARDSEN, P.: Nervous control of urinary bladder in cats. A survey of recent experimental results and their relation to clinical problems, Acta Neurol. Stand. 43: 543 (1967). 33. BRO-RASMUSSEN, F., et al. : The structure and function of the urinary bladder, Urol. Int. 19: 280 (1965). 34. HUTCH, J. A.: A new theory of the anatomy of the internal urinary sphincter and the physiology of micturition. II. The base plate, J, Urol. 96: 182 (1966). 35. FRANKSSON, C., and PETERSEN, I. : Electromyographic recording from the normal human urinary bladder, internal urethral sphincter and ureter, Acta Physiol. Stand. (Suppl.) 29: I50 (1953). 36. LAPIDES, J.: Observations on normal and abnormal bladder physiology, J. Urol. 70: 74 (1953). 37. LAPIDES, J., et al. : Further observations on the kinetics of the urethrovesical sphincter, ibid. 84: 86 (1960). 38. WHITFIELD, H. N., DOYLE, P. T., MAYS, M. E., and POOPALASINGHAM, N. : The effect of adrenergic blocking drugs on outflow resistance, Br. J. Urol. 47: 823 (1975). 39. WOODBURNE, R. T.: Anatomy of the bladder, in Boyarsky, S., Ed. : Neurogenic Bladder, Baltimore, The Williams and Wilkins Company, 1967, p. 3. 40. LAPIDES, J., SWEET, R. B., and LEWIS, L. W.: Role of striated muscle in urination, J. Urol. 77: 247 (1957). 41. TANAGHO, E. A., MEYERS, F. H., and SMITH, D. . Urethral resistance: the components and implicaEons, Invest. Urol. 7: 135 (1969). 42. RAEZER, D. M., et al. : Innervation of trigonal area of canine urinary bladder, Urology 7: 369 (1976). 43. CASS, A. S., and HINMAN, F., JR.: Constant urethral flow in female dogs. I. Normal vesical and urethral pressures and effect of muscle relaxant, J. Urol. 99: 442 (1968). 44. TANAGHO, E. A., MEYERS, F. H., and SMITH, D. R.: Urethral resistance: its components and implications, II. Striated muscle component, Invest. Urol. 7: 195 (1969). 45. DORTENMANN, S., and BAUER, K. M.: Untersuchungen iiber den Einfluss der guergestreiften Muskulatur auf die Blasenfunktionen mit Hilfe eines muskelrelaxans, Medizinische 15: 528 (1955). 46. SCULTETY, S., and ABRANDI, E.: The effect of muscle relaxants on bladder function, Z. Urol. 53: 103 (1960). 47. PETERSEN, I., KOLLBERG, S., and DHUNER, K. G.: The effect of the intravenous injection of succinylcholine on micturition: an electromyographic study, Br. J. Urol. 33: 392 (1961). 48. HARDY, A. G.: Neurological interventions in the treatment of the spastic bladder, ibid. 33: 370 (1961). 49. RAZ, S., and SMITH, R. B.: External sphincter spasticity syndrome in female patients, J. Urol. 115: 443 (1976). 50. TURNER-WARWICK, R.: The repair of urethral strictures in the region of the membranous urethra, ibid. 100: 303 (1968)”
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51. CALDWELL, K. P. S., COOK, P. J., FLACK, F. C., and JAMES, D. : Treatment of post-prostatectomy incontinence by electronic implant, Br. J. Ural. 40: 183 (1968). 52. RAZ, S., and KAUFMAN, J. J.: Pathophysiology of the ureteral compression operation: the use of silicone gel prosthesis, J. Urol. 115: 435 (1976). 53. ENHORNING, G.: Simultaneous recording of intravesical and intraurethral pressure, Acta Chir. Stand. (Suppl.) 276: 1 (1961). 54. LAPIDES, J.: Physiology of the urinary sphincter and
55. 56. 57.
58.
its relation to operations for incontinence, Br. J. Ural. 33: 284 (1961). MUELLNER, S. R.: The voluntary control of micturition in man, J. Urol. 80: 473 (1958). TANAGHO, E. A., and MILLER, E. R.: Initiation of voiding, Br. J. Urol. 42: 175 (1970). GHONEIM, M. A., FRETIN, J. A., GAGNON, D. J.. and SUSSET, J. G.: The influence of vesical distension on urethral resistance to flow, ibid. 47: 663 (1975). SHOPFNER, C. E., and HUTCH, J. A.: The trigonal canal, Radiology 88: 269 (1967).
II. Review of Neurology
A clear understanding of the anatomy and physiology of the nervous control of the lower urinary tract is essential for the study of its pharmacology. Although this review is intended for that purpose, it may also serve as a convenient review of the neurology of that area. Since the lower urinary tract is influenced by somatic and autonomic systems, a brief review of the general organization of somatic and autonomic reflexes follows. Responses to peripheral nervous stimulation that occur independently of volition are called reflexes if their operation requires the presence of part of the central nervous system. The simplest example is the reflex arc which consists of a chain of neurons with a minimum of two, a8erent (receptor) and efferent (effector). Except for a few spinal reflexes, such as the stretch reflex, there is generally one or more connecting or internuncial neurons (interneurons) intervening between the afferent and efferent neurons. The afferent neuron leads from an organ via a dorsal nerve root into the central nervous system with its nutrient cell in the dorsal root ganglion. There are no important physiologic differences between visceral and somatic afferent fibers, and their responses to drugs does not differ significantly. ’ In somatic reflexes the internuncial or connector neuron is situated in the dorsal horn of gray matter which by means of its axon transmits the impulse to the ventral horn. The excitor or efferent neuron is situated in the ventral horn of gray matter (ventral horn cells), and its axon passes out in the ventral root to the skeletal muscle (such as the urethral striated external sphincter muscle).
In the case of visceral reflexes, the interneurons and efferent neurons have a more comThe interneuron is not plex arrangement. situated in the dorsal horn but in the adjacent gray matter such as the lateral (intermediolateral) horn. This neuron connects the afferent neuron with the excitor neuron which actually supplies the viscus. The excitor cells are not found within the central nervous system; they have migrated outward to form masses of cells situated peripherally. The connector fibers are called preganglionic fibers. The excitor cells (ganglionic cells) lie peripherally either as ganglia or as isolated groups of cells. Fibers arising from the ganglionic cells reach the various organs which they innervate. These are the postganglionic fibers. Autonomic nerves form extensive peripheral plexuses, whereas such networks are absent from the somatic system. From a functional standpoint the efferent or motor side of the autonomic nervous system consists of two large divisions: (1) the sympathetic or thoracolumbar outflow, and (2) the parasympathetic or craniosacral outflow. When stimulated the sympathetic and parasympathetic nerves generally produce antagonistic effects on the visceral organs supplied by them. Under natural conditions, however, the two systems act synergistically with each other as well as with the somatic system.
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Neurology
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Large gaps in our understanding of the innervation and pathophysiology of the detrusor muscle and urethra remain. During infancy, the sacral segments of the spinal cord are the only link between &erent
LOWER URINARY TRACT PHARMACOLOGY I. Anatomic Considerations NABIL K. BISSADA,
M.D.
ALEX E. FINKBEINER, LARRY T. WELCH,
M.D.
PH.D.
From the Departments of Urology and Pharmacology, University of Arkansas College of Medicine, Little Rock, Arkansas
ABSTRACT -With this issue Dr. Bissada, Dr. Finkbeiner, and Dr. Welch introduce a series on uropharmacology, starting with the lower urinary tract. Since an understanding of the anatomy, neurophysiology, and basic pharmacology is necessary, Part I is a description of the functional anatomy of the lower urinary tract and the mechanisms of continence and voiding. Part ZZis a review of the differences between somatic and autonomic reflexes; the afferent and efferent innervation of lower urinary tract; the organization of pelvic ganglionic cells and the spinal and supraspinal control of lower urinary tract function. Subsequent articles will be on basic pharmacology of lower urinary tract and individual drug classes.
The anatomy of the lower urinary tract, especially that of the bladder outlet, is an area of extreme controversy. The following review is an attempt to analyze the available literature and to supply a unifying concept of the morphology and function of this region. Although this presentation is intended as an introduction to the series of pharmacology of the lower urinary tract, we hope that it will also serve as a convenient review of the functional morphology of this area.
The urinary bladder is a hollow musculomembranous organ lined by transitional epithelium. Functionally, it may be described as consisting of the body and base regions.
As early as 1891, Griffiths’ denied the separate strata in the urinary bladder, observing that muscular bundles run from plane to plane and become circular and oblique in the regions of the bladder neck. Huntel-2 also noted this decussation. Woodburne3 and Winkler4 described the muscular wall of the bladder as a meshwork. Wesson5 believed that he could follow anterior fascicles from the bladder wall which circled behind the urethral orifice and fascicles from the posterior wall of the bladder which circled in front of it. It may be concluded that in the region of the body of the urinary bladder, muscle fibers from all layers are intermingled, and the muscular wall of the bladder is to be considered as a continuum of smooth musculature, the vesical detrusor.3
Bladder body
Bladder base and bladder neck
The smooth muscle fibers of the bladder body were described as being composed of three layers, the external and internal longitudinal layers, and the middle layer, which is the thickest and is composed of circularly running muscle fibers.
In the following discussion, the bladder base is considered to include the trigonal structures as well as the other smooth muscle fibers in the distal one inch of the bladder just above the bladder neck (Fig. 1). As the detrusor muscle bundles converge on the internal orifice of the
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cle rings, arranged concentrically around the bladder neck, and incorporated into the base of the bladder. The most caudal of these fibers form the true bladder neck. The ring is complete anteriorly while posteriorly it fuses with the trigone. This structure was first described by Heiss in 19157 (Heiss ring) and then by Uhlenhath, Hunter, and Loechel in 19558 as the “fundus ring.” In 1965 Hutchs~g~lo demonstrated that anatomically and functionally the “fundus ring” or “Heiss ring” fuses with the deep trigone to form a structure which he called the “base plate.” The base plate is divided into two parts, the anterior part is made up of the anterior bladder wall from the bladder neck to a point 2 to 2.5 cm. above the bladder neck. The posterior part is the deep trigone.
Outer longitudinal layer. The outer longitudinal layer contains many muscle bundles that are prominent along the anterior and posterior walls of the bladder but are thin on its lateral aspects. As the fibers representing this group converge on the narrow bladder neck, they coalesce into distinct muscle groups:g
FIGURE 1. Schematic knidsagittal section of bladder base and male proximal urethra: (1) mucosa and inner longitudinal muscle layer; (2) middle circular layer; (3) outer longitudinal layer; (4) fundus (Heiss) ring of middle longitudinal layer; (5) deep trigone; (5A and 5B) circular layer of urethra; (6) median lobe of prostate; (7) posterior lobe of prostate; (8) external urethral sphincter; (9) periurethral striated muscle; (10) transverse precervical arc; (11) detrusor loop; and (12) smooth muscle sling from precervical arc to urethral inner longitudinal layer.
ANTEFUOR PORTION. This group is arranged in a wide band extending from the bladder neck to the vertex of the bladder along its anterior wall. Superiorly, many of these fibers can be seen to loop around the urachus. Inferiorly, this group narrows and thickens as it approaches the bladder neck and makes a major insertion just ventral to the vesical neck into a fibromuscular structure which Gil-Vernetl’ calls the transverse precervical arc.
bladder, they tend to become oriented into three layers.” Znner longitudinal layer. Through the bladder the fibers of the inner longitudinal layer are widely separated and run in different directions. As they approach the bladder neck they become organized on a longitudinal axis and pass through the bladder neck to become the inner longitudinal layer of the urethra. This layer is interrupted in the trigonal region where it fuses with the superficial trigone. Middle circular layer. The middle circular layer terminates at the bladder neck and does not go into the urethra. In the base of the bladder it is thickened and its fibers are prominent. Thickening is caused by a marked increase in the number of circularly oriented smooth mus-
POSTERIOR PORTION. This concentration of longitudinal fibers is even longer and stronger than the anterior group. The fibers also run from the vertex of the bladder to the bladder neck, and some of them also loop around the urachus. As they approach the bladder neck they form a medial group and right and left lateral groups. The medial group forms a flat wide muscle which inserts into the posterior surface of the apex of the trigone at the bladder neck. It lies against the posterior surface of the deep trigone but is not attached to it except at the apex. The lateral groups encompass the remaining outer posterior longitudinal fibers which pass downward and forward, actually leaving the bladder to pass into the groove formed by the junction of the bladder and urethra in females or bladder and prostate in males. These muscle bundles then leave the vesicourethral groove to form the superior part of the anterior wall of the urethra just distal to the anterior part of the
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or continence and will not be discussed further. The female urethra and the posterior urethra in the male consist of a mucosa and two smooth muscle layers: (1) the inner longitudinal layer, which is a direct continuation of the inner layer of the bladder, and (2’ the middle circular layer, which is a direct continuation of the deep trigone. This layer is present throughout the entire urethra in the female and the posterior urethra in the male, except where it is replaced by the detrusor loop. It is partially surrounded by the paraurethral striated muscle in both sexes. Considerable quantity of smooth muscle tissue extends from the proximal bulbous urethra to the verumontanum.‘3-‘7 This is surrounded by the striated external sphincter.
base plate. They then loop back to the opposite vesicourethral groove and then to the posterior outer longitudinal layer on the side of the bladder opposite their origin. This is the detrusor loop first described by Heiss7 and emphasized b Y Gil-Vernet.” This horseshoe-shaped structure forms most of the anterior and lateral portions of the bladder neck. Its prongs are directed dorsally and continue into the posterior bladder wall in the same manner as the right and left lateral posterior outer longitudinal muscles described. Its concave surface, into which the apex of the trigone fits, is directed dorsally. Ventrally, its convex surface is fused with the transverse precervical arc. The transverse precervical arcg*rl is a tough fibrous point of insertion for the anterior outer longitudinal layer and the detrusor 10op.~*” It lies at the anterior bladder neck, just anterior to the detrusor loop and just below the anterior part of the base plate. It surrounds the anterior third of the bladder neck. Trigonal
Striated
structures
The trigonal structures include the deep trigone which lies in the floor of the bladder in the triangular area between the two ureteral orifices and bladder neck and at a depth corresponding to the middle circular layer. It lies between the superficial trigone internally and the outer longitudinal layer externally. Laterally, it fuses imperceptibly into the middle circular layer, the smooth muscle rings of which form the fundus ring. Tanagho and PughI demonstrated that at each craniolateral border, the deep trigone is rolled into a tube - Waldeyer’s sheath and that the ureter left the bladder through this sheath. Caudally the deep trigone continues directly across the bladder neck into the urethra. It is this continuity between the deep trigone and the wall of the urethra that keeps the urethra firmly attached to the bladder. The deep trigone fuses with the fundus ring of the middle circular layer. The superficial trigone lies on top of the deep trigone and directly under the bladder mucosa. It fuses with the inner longitudinal layer of the detrusor and continues upward as the ureter, leaving the bladder through Waldeyer’s sheath. Its superior border forms Mercier’s bar while its lateral borders form Bell’s muscle. Urethral
core structure
The anterior urethra in the male acts merely as a conduit and normally has no role in voiding
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muscle
component
The true external sphincter consists of circularly oriented striated muscle lying between the superior and inferior layers of the urogenital diaphragm. The paraurethral striated muscle originates from the striated muscle of the true sphincter and climbs sharply upward along the outer surface of the urethra. It inserts into the connective tissue and smooth muscle rings of the urethral core structures at a point about halfway between the urogenital diaphragm and the bladder neck. In both sexes the striated muscle occupies the inferior one half of the anterior urethral wall and is less prominent along the posterior wall of the urethra. In male subjects it is limited to the small area between the urogenital diaphragm and the apex of the prostate. In female subjects striated muscle is sparse along the inferior half of the posterior wall of the urethra, but is abundant in the superior half of the posterior wall. Urinary
Continence
Three sphincteric mechanisms continence in normal individuals Bladder
neck sphincteric
contribute (Fig. 2):
to
mechanism
The importance of the bladder neck continence mechanism has been a controversial subject. While some investigators have denied its importance, 1,18-22 others have emphasized its ro1e.5,6,g,23-26 The anatomic findings of Hunter,2 22 and of Tanagho and Clegg, 27 Woodburne Smith2’ have failed to ‘demonstrate an anatomic sphincter at this area. Instead, they found that the detrusor muscle and the urethra form one continuous sheet of muscle. Accordingly, sev-
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The bladder neck sphincteric mechanism is also important to prevent retrograde ejaculation. When the bladder function is impaired, problems of urination, ejaculation, or both may occur.21 Urethral
Schematic FIGURE 2. mechanisms.
representation
of sphincter
era1 investigators maintain that, with increasing vesical distention, tension is transmitted to the urethral wall resulting in a more effective closure.2g-31 On the other hand, several other investigators have been able to demonstrate a functional sphincteric mechanism at the bladder neck.32-35 Hutch6 reviewed his work and the extensive literature on the subject and described the bladder neck sphincter as a double loop. This consists of the base plate forming the top loop and the detrusor loop forming the bottom Hutch’s description offers an explanaloop. 7*g~11 tion as to why the bladder neck remains closed at rest and is open during voiding. It is also in accord with changes that are seen during void34 The tone of the base ing cystourethrography. plate is constantly forcing the apex of the trigone forward. The detrusor loop, located in the very top of the urethra, forms most of the anterior and lateral walls of the urethra near the bladder neck. The loop is so positioned that the apex of the trigone fits snugly into its concave surface. Its force is constantly directed backward or dorsally in direct opposition to the apex of the trigone which, as previously discussed, is being continuously forced forward. Since the detrusor loop is stretched around the posterior wall of the bladder from the anterior bladder neck to the urachus, it is pulled tighter and tighter as the bladder fills. Also with bladder filling, the base plate remains flat and the rings of circular smooth muscle exert their force in an inward direction, thus keeping the bladder neck closed constantly. At the same time, the right and left lateral posterior outer longitudinal layers pull the detrusor loop backward in direct opposition to the base plate.
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sphincter
The urethral sphincter consists of the musculature and connective tissue in the proximal 3 cm. of the urethra. 2g,36*37Its role in continence is by the pressure or resistance it creates. This resistance is determined by the caliber of the urethral lumen, the. tension exerted by the wall of the urethra against its lumen, and by the length of the urethra. The elastic element of the connective tissue may aid in keeping the urethra closed.37*38 Most of the elastic tissue is situated at the bladder neck and first part of the urethra,39 and some have denied its contribution to urethral pressure.13 However, there is general agreement that the urethral smooth muscle plays an important role in normal 13-17,21,26,37,38,40-42 continence D uring the collecting phase, there is a gradual increase in the urethral pressure which is higher than the rise of the intravesical pressure.30 This was more pronounced in the distal segment of the urethra. External
sphincter
mechanism
The anatomy of the striated component of the sphincter (external urethral sphincter and periurethral striated muscle) has been discussed previously. The striated muscles of the pelvic floor, especially the levator ani muscle, further contribute to this sphincteric function. The external sphincter can maintain continence during sudden rises in intravesical pressure. While the internal sphincter can stand an intravesical pressure of 30 to 40 mm. Hg without opening, the external sphincter usually takes 70 to 100 mm. Hg to open it forcefully, and under some circumstances these figures may be doubled or triof the external sphincpled. 2* The contribution ter mechanism to normal continence has been debated. 13*21,30.37,40*43-47 Whatever the contribution of the striated muscle to the resting urethral pressure may be, there is agreement that it does appear to have an important role in preventing leakage during stress. 21,37*44 This may be accomplished by a twofold action of the striated pelvic and periurethral muscles. The external urethral sphincter and the pubococcygeus fibers of the levator ani muscles compress the urethra circumferentially as well as elongate it by pulling it upward and cephalad. In pathologic condi-
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tions of hyperreflexia, due to central nervous lesions, a spastic contraction of this sphincter may constitute an effective hindrance to bladder emptying.48*4Q Surgically, these sphincter mechanisms may be considered to consist of proximal and distal sphincteric mechanisms, either of which is capable of preserving continence. The proximal sphincters are the bladder neck and uppermost part of the proximal urethra.50 The distal sphincters consist of the skeletal muscle component and the circular smooth muscle of the membranous and proximal bulbous urethra 17,51,52 Mechanics of Voiding Urine is retained in the bladder as long as the closure pressure, that is, the difference between the maximal intraurethral pressure and simultaneously existing bladder pressure, remains above zerouS For micturition to start, this closure pressure must first drop and become negative. There are several diverging concepts regarding the mechanisms involved in the process of initiation of voiding. During normal voiding, the bladder neck opens, the urethral pressure is lowered, and the striated muscle of the external sphincter and the pelvic floor relaxes. contends that contraction of inner Lapides longitudinal muscles of the bladder and urethra results in shortening of the urethra, widening of its lumen, and reduction of its resistance to flow. Hutch6 agrees that the inner longitudinal layer can exert an active opening action on the urethra. A group of smooth muscle bundles that originates from the precervical arc and are inserted in the inner longitudinal layer (Fig. 1) tend actively to pull open the top part of the anterior wall of the urethral sphincter. Muellner55 postulated that in man voluntary relaxation of the pelvic floor permits the descent of the vesical neck and that this descent is the stimulus for the detrusor to contract initiating voiding. Tanagho and Miller56 also reported that prior to voiding there is a drop of the intraurethral pressure as a result of relaxation of the pelvic floor and the striated external sphincter. Ghoneim et ~~1.~~3~~ demonstrated that during the expulsion phase there is a reduction in urethral pressure which involved both the smooth and striated muscle elements. The mechanism of opening of the bladder neck is even more controversial. Lapides contends that the bladder body contracts down on
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the bolus of urine pulling open the bladder neck. Bro-Rasmussen et ~1.~~postulated that the bladder neck is pulled open by contraction of the trigonal muscle, a muscle similar to the latter situated in front of the internal orifice and the detrusor muscle, and that opening is further aided by concurrent shortening of the urethra brought about by contraction of its longitudinal fibers. A similar view is also held by Hutch.34 He drew conclusions from cinefluoroscopic observations. He noted on lateral voiding cystourethrograms, that during bladder filling and at rest, the base plate is flat and that the urethra enters slightly forward to the center of the flat area. During voiding the anterior and posterior halves of the base plate move sharply upward to form a funnel above the bladder neck, “the trigonal canal. “58 During the initiation of voiding, the bladder neck appears to remain in the same position and the urethra fills out with contrast medium, but does not change in length. Hutch’ postulated that during voiding, the transverse precervical arc is pulled upward and forward by the anterior outer longitudinal muscles and is pulled upward and backward by the detrusor loop. The result is a compromise in which the arc moves upward for about 1 to 2 cm. This breaks the anterior and lateral parts of the base plate. At the same time the contraction of the medial posterior outer longitudinal muscle breaks the posterior half of the base plate out of the flat position and extracts the apex of the trigone out of the detrusor loop. As a result of the base plate assuming the early funnel shape, continuous active contraction of the fundus ring now actively helps to break both the anterior and posterior halves of the base plate to form the trigonal canal. The net result of these changes is an open bladder neck.
References 1. GRIFFITHS, J.: Observations on the urinary bladder and urethra, J. Anat. Physiol. 25: 535 (1891). 2. HUNTER, D. T., JR.: A new concept of urinary bladder musculature, J. Urol. 71: 695 (1954). 3. WOODBURNE, R. T.: The sphincter mechanism of the urinary bladder and the urethra, Anat. Rec. 141: 11 (1961). 4. WINKLER, G.: Cartribucional estudeo de la inervacion de la visceras pelvianas, Arch. Esp. Urol. 20: 259 (1967). Anatomical, embryological and 5. WESSON, M. B.: physiological studies of the trigone and neck of the bladder, J. Urol. 4: 279 (1920).
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6. HUTCH,
7. 8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18. 19.
20. 21. 22. 23.
24. 25. 26.
27. 28.
29.
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J. A.: Anatomy and Physiology of the Trigone, Bladder and Urethra, New York, AppletonCentury Croft, 1972. HEISS, R.: Ueber den Sphincter vesicalis internus, Virchows Arch. Pathol. Anat. 220: 367 (1915). UHLENHUTH, E., HUNTER, D. T., and LOECHEL, W. E. : Problems in the Anatomy of the Pelvis, An Atlas, Philadelphia, J. B. Lippincott Co., 1953. HUTCH, J. A.: The internal urinary sphincters: a double-loop system, J. Urol. 105: 375 (1971). IDEM: A new theory of the anatomy of the internal urinary sphincter and the physiology of micturition. II. The base plate, ibid. 96: 182 (1966). GIL-VERNET, S.: Morphology and function of vesico-prostato-urethral musculature, Treviso, Italy, Canova, 1968, p. 334. TANAGHO, E. A., and PUGH, R. C. B.: The anatomy and function of the ureterovesical junction, Br. J. Ural. 35: 151 (1963). DONKER, P. J., IVANOVICI, F., and NOACH, E. L.: Analysis of the urethral pressure profile by means of electromyography and the administration of drugs, ibid. 44: 180 (1972). ELLIOT, J. S., Postoperative urinary incontinence, a revised concept of the external sphincter, J. Urol. 71: 49 (1954). DRAHN, H. P., and MORALES, P. A.: The effect of pudendal nerve anesthesia on urinary continence after prostatectomy, ibid. 94: 282 (1965). NEMOY, M. J., and GOVAN, D. E.: Urinary continence in the absence of an intact external sphincter, ibid. 102: 200 (1969). COLAPINTO, V., and MCCALLUM, R. W.: Urinary continence after repair of membranous urethral stricture in prostatectomized patients, ibid. 115: 392 (1976). BOYARSKY, S.: The Neurogenic Bladder, Baltimore, The Williams and Wilkins, Co., 1967. GOSLING, J. A., and DIXON, J, S.: The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra, Br. J. Urol. 47: 549 (1975). of the prostate HUNTER, D. T., JR.: Musculature gland, ibid. 40: 278 (1968). KLEEMAN, F. J.: The physiology of the internal urinary sphincter, J. Urol. 104: 549 (1970). WOODBURNE, R. T.: Structure and function of the urinary bladder, ibid. 84: 79 (1960). HOMSY, G. E.: The dynamics of the ureterovesical and vesicourethral junctions, Invest. Urol. 4: 408 (1967). HINMAN, F.: Male incontinence: relationship of physiology to surgery, J. Urol. 115: 274 (1976). PENNINGTON, L. T., and LUND, H. Z.: An elastic ring of tissue in the male urethra, ibid. 84: 481 (1960). TURNER-WARWICK, R., et al. : A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and transtrigonal posterior prostatectomy, Br. J. Urol. 45: 44 (1973). CLEGG, E. J.: The musculature of the human prostatic urethra, J. Anat. 91: 345 (1957). TANAGHO, E. A., and SMITH, D. R.: The anatomy and function of the bladder neck, Br. J. Urol. 38: 54 (1966). LAPIDES, J.: Structure and function of the internal
vesical sphincter, J. Ural. 80: 341 (1958). 30. GHONEIM, M. A., FRETIN, J. A., GAGNON, D. J., and SUSSET, J. G.: The influence of vesical distension on urethral resistance to flow: the collecting phase, Br. J. Urol. 47: 657 (1975). 31. TANAGHO, E. A., MILLER, E. R., MEYERS, F. H., and CORBETT, R. K.: Observations on the dynamics of the bladder neck, ibid. 38: 72 (1966). 32. EDVARDSEN, P.: Nervous control of urinary bladder in cats. A survey of recent experimental results and their relation to clinical problems, Acta Neurol. Stand. 43: 543 (1967). 33. BRO-RASMUSSEN, F., et al. : The structure and function of the urinary bladder, Urol. Int. 19: 280 (1965). 34. HUTCH, J. A.: A new theory of the anatomy of the internal urinary sphincter and the physiology of micturition. II. The base plate, J, Urol. 96: 182 (1966). 35. FRANKSSON, C., and PETERSEN, I. : Electromyographic recording from the normal human urinary bladder, internal urethral sphincter and ureter, Acta Physiol. Stand. (Suppl.) 29: I50 (1953). 36. LAPIDES, J.: Observations on normal and abnormal bladder physiology, J. Urol. 70: 74 (1953). 37. LAPIDES, J., et al. : Further observations on the kinetics of the urethrovesical sphincter, ibid. 84: 86 (1960). 38. WHITFIELD, H. N., DOYLE, P. T., MAYS, M. E., and POOPALASINGHAM, N. : The effect of adrenergic blocking drugs on outflow resistance, Br. J. Urol. 47: 823 (1975). 39. WOODBURNE, R. T.: Anatomy of the bladder, in Boyarsky, S., Ed. : Neurogenic Bladder, Baltimore, The Williams and Wilkins Company, 1967, p. 3. 40. LAPIDES, J., SWEET, R. B., and LEWIS, L. W.: Role of striated muscle in urination, J. Urol. 77: 247 (1957). 41. TANAGHO, E. A., MEYERS, F. H., and SMITH, D. . Urethral resistance: the components and implicaEons, Invest. Urol. 7: 135 (1969). 42. RAEZER, D. M., et al. : Innervation of trigonal area of canine urinary bladder, Urology 7: 369 (1976). 43. CASS, A. S., and HINMAN, F., JR.: Constant urethral flow in female dogs. I. Normal vesical and urethral pressures and effect of muscle relaxant, J. Urol. 99: 442 (1968). 44. TANAGHO, E. A., MEYERS, F. H., and SMITH, D. R.: Urethral resistance: its components and implications, II. Striated muscle component, Invest. Urol. 7: 195 (1969). 45. DORTENMANN, S., and BAUER, K. M.: Untersuchungen iiber den Einfluss der guergestreiften Muskulatur auf die Blasenfunktionen mit Hilfe eines muskelrelaxans, Medizinische 15: 528 (1955). 46. SCULTETY, S., and ABRANDI, E.: The effect of muscle relaxants on bladder function, Z. Urol. 53: 103 (1960). 47. PETERSEN, I., KOLLBERG, S., and DHUNER, K. G.: The effect of the intravenous injection of succinylcholine on micturition: an electromyographic study, Br. J. Urol. 33: 392 (1961). 48. HARDY, A. G.: Neurological interventions in the treatment of the spastic bladder, ibid. 33: 370 (1961). 49. RAZ, S., and SMITH, R. B.: External sphincter spasticity syndrome in female patients, J. Urol. 115: 443 (1976). 50. TURNER-WARWICK, R.: The repair of urethral strictures in the region of the membranous urethra, ibid. 100: 303 (1968)”
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51. CALDWELL, K. P. S., COOK, P. J., FLACK, F. C., and JAMES, D. : Treatment of post-prostatectomy incontinence by electronic implant, Br. J. Ural. 40: 183 (1968). 52. RAZ, S., and KAUFMAN, J. J.: Pathophysiology of the ureteral compression operation: the use of silicone gel prosthesis, J. Urol. 115: 435 (1976). 53. ENHORNING, G.: Simultaneous recording of intravesical and intraurethral pressure, Acta Chir. Stand. (Suppl.) 276: 1 (1961). 54. LAPIDES, J.: Physiology of the urinary sphincter and
55. 56. 57.
58.
its relation to operations for incontinence, Br. J. Ural. 33: 284 (1961). MUELLNER, S. R.: The voluntary control of micturition in man, J. Urol. 80: 473 (1958). TANAGHO, E. A., and MILLER, E. R.: Initiation of voiding, Br. J. Urol. 42: 175 (1970). GHONEIM, M. A., FRETIN, J. A., GAGNON, D. J.. and SUSSET, J. G.: The influence of vesical distension on urethral resistance to flow, ibid. 47: 663 (1975). SHOPFNER, C. E., and HUTCH, J. A.: The trigonal canal, Radiology 88: 269 (1967).
II. Review of Neurology
A clear understanding of the anatomy and physiology of the nervous control of the lower urinary tract is essential for the study of its pharmacology. Although this review is intended for that purpose, it may also serve as a convenient review of the neurology of that area. Since the lower urinary tract is influenced by somatic and autonomic systems, a brief review of the general organization of somatic and autonomic reflexes follows. Responses to peripheral nervous stimulation that occur independently of volition are called reflexes if their operation requires the presence of part of the central nervous system. The simplest example is the reflex arc which consists of a chain of neurons with a minimum of two, a8erent (receptor) and efferent (effector). Except for a few spinal reflexes, such as the stretch reflex, there is generally one or more connecting or internuncial neurons (interneurons) intervening between the afferent and efferent neurons. The afferent neuron leads from an organ via a dorsal nerve root into the central nervous system with its nutrient cell in the dorsal root ganglion. There are no important physiologic differences between visceral and somatic afferent fibers, and their responses to drugs does not differ significantly. ’ In somatic reflexes the internuncial or connector neuron is situated in the dorsal horn of gray matter which by means of its axon transmits the impulse to the ventral horn. The excitor or efferent neuron is situated in the ventral horn of gray matter (ventral horn cells), and its axon passes out in the ventral root to the skeletal muscle (such as the urethral striated external sphincter muscle).
In the case of visceral reflexes, the interneurons and efferent neurons have a more comThe interneuron is not plex arrangement. situated in the dorsal horn but in the adjacent gray matter such as the lateral (intermediolateral) horn. This neuron connects the afferent neuron with the excitor neuron which actually supplies the viscus. The excitor cells are not found within the central nervous system; they have migrated outward to form masses of cells situated peripherally. The connector fibers are called preganglionic fibers. The excitor cells (ganglionic cells) lie peripherally either as ganglia or as isolated groups of cells. Fibers arising from the ganglionic cells reach the various organs which they innervate. These are the postganglionic fibers. Autonomic nerves form extensive peripheral plexuses, whereas such networks are absent from the somatic system. From a functional standpoint the efferent or motor side of the autonomic nervous system consists of two large divisions: (1) the sympathetic or thoracolumbar outflow, and (2) the parasympathetic or craniosacral outflow. When stimulated the sympathetic and parasympathetic nerves generally produce antagonistic effects on the visceral organs supplied by them. Under natural conditions, however, the two systems act synergistically with each other as well as with the somatic system.
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Tract
Large gaps in our understanding of the innervation and pathophysiology of the detrusor muscle and urethra remain. During infancy, the sacral segments of the spinal cord are the only link between &erent
