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
of the Lower
Urinary
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
signals from and efferent signals to the lower urinary tract. In early childhood the sacral cord reflex centers become the area for the transmission and modulation of descending and ascending impulses which flow between the higher centers and the lower urinary tract. The sacral segments provide the parasympathetic and somatic motor impulses while the thoracolumbar segments emit sympathetic motor impulses.* Afferent impulses reach the sacral and lumbar segments from the mucosal and muscular receptors via the pelvic, hypogastric, and pudendal nerves which also conduct the efferent signals.3 All parts of the bladder and its outlet are supplied with nerve fibers from the sympathetic and parasympathetic divisions of the autonomic nervous system although the distribution is not uniform.4-6 At present the most widely held theory of the function of the bladder nerves is that suggested by Learmonth’ who postulated a reciprocal innervation of the detrusor muscle and the internal vesical sphincter by both divisions of the autonomic nerves, that is, an over-all parasympathetic excitation of the detrusor muscle and inhibition of the sphincter, and an over-all sympathetic inhibition of the detrusor muscle and excitation of the sphincter.
The lumbar sensory pathways, unlike the sacral tierents, are most numerous in the trigone and bladder neck especially in the mucosa and submucosa, and are sparsely represented in the remainder of the detrusor muscle.16 They also innervate the contralateral as well as the ipsilatera1 detrusor. The sensory endings in the mucosa and submucosa are stimulated by exteroceptive modalities such as touch, pain, and temperature. Nathan” suggested that impulses from the bladder may reach the spinal cord rostral to the fourth thoracic segments by way of a.fYerent sympathetic fibers coursing in the sympathetic trunk. Patients with complete transverse lesions of the cord at midthoracic levels may have vague, nonspecific, and poorly localized sensation in lower abdomen indicating fullness of bladder. Furthermore, the sensory impulses from visceral structures adjacent to the bladder, such as small bowel, are conducted centrally on vagal and sympathetic pathways. Sensory muscle receptors (muscle spindles) in the striated external sphincter muscle generate impulses that travel in sensory fibers of the pudendal nerve to the sacral spinal cord.‘* Parasympathetic
efferents
Two types of sensory receptors have been identified in the bladder.‘-l2 These receptors are stimulated either by detrusor muscle contraction (tension receptors) or vesical distention (volume receptors). Complex sensory endings in the bladder muscle similar to those seen in the skin have been described; however, more recent reports suggest that what were thought to be complex sensory endings were instead artifacts of methylene blue fixation. Sacral afferents are uniformly distributed to all areas of the detrusor muscle and urethra.7J0J1,‘3 Approximately one third of the fibers cross to innervate the contralateral portion of the detrusor muscle. Proprioceptive impulses initiated by stimulation of the detrusor muscle nerve endings travel in the sensory portion of the pelvic nerve to the third and fourth sacral dorsal nerve roots and ultimately terminate in the posterior and lateral columns of the sacral spinal cord.14 Bradley et al. 13,15 believe that bladder sensory afferents do not synapse in the sacral spinal cord but, instead, long route to the detrusor nucleus in a specialized portion of the brain stem.
The preganglionic parasympathetic nerve fibers to the lower urinary tract are believed to arise from the intermediolateral nucleus of the sacral cord (second to fourth sacral in man, and first to third sacral in the cat).4,1g,20 Despite bilateral innervation to the bladder from the sacral roots, there may be functional ipsilateral dominance which awaits further elaboration.‘3,21 The motor fibers leave the cord primarily by way of the ventral root, but a few may exit through the posterior root.22 The fibers first travel within the pudendal plexus but leave it as the pelvic nerves on either side of the rectum and join the hypogastric (sympathetic) nerves to form the vesical (pelvic) plexus, best developed at the base of the bladder.20 Auxiliary pelvic nerves have been described. 23 Divergent opinions have been expressed regarding the extent of the parasympathetic innervation of the smooth muscle of the bladder.6p20*24*25Histochemical and electron microscopic studies in the cat, dog, rabbit, guinea pig, and rat bladder indicated that there is a rich and uniform distribution of acetylcholinesterase positive fibers in the smooth musculature of the bladder, bladder neck, and urethra.24~26-2g These nerve fibers have been reported to be intimately related to individual muscle cells.26,30-33
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The parasympathetic fibers mediate excitatory impulses leading to contraction of the detrusor muscle.34 Some authors also advocate a specific inhibitory effect on the internal sphincter.2,35 Sympathetic
efferents
The preganglionic sympathetic nerve fibers to the lower urinary tract originate in the intermediolateral cell column in the lateral horn of the spinal gray matter of cord segments, eleventh thoracic to second lumbar.20 The preganglionic fibers traverse the paravertebral trunk ganglia and pass to the inferior mesenteric and hypogastric plexuses by way of lumbar splanchnic nerves from the first to the fourth lumbar trunk ganglia. Some preganglionic neurons localize in ganglia within the two plexuses, while others terminate in ganglia within the vesical plexus around the bladder neck or in intramural ganglia in the bladder wall 5,20,36 Different opinions have been expressed in the past regarding the parts of the bladder wall which receive postganglionic sympathetic fibers. Kuntz and Saccomanno” believe that such fibers are distributed to the detrusor muscle as well as to the trigone and internal sphincter, while Langworthy and Murphp5 deny the existence of sympathetic innervation to the detrusor muscle proper. Recently, histochemical studies have demonstrated that adrenergic nerve endings can be found throughout the bladder. They are abundant at the bladder base and proximal urethra but are sparse at the dome.5*24,26-2g,37 The functional significance of the sympathetic innervation of the lower urinary tract is also controversial. Hypogastric nerve stimulation was reported to induce contraction of the trigone and internal sphincter and to inhibit micturition.2,3* It was also reported to produce an initial contraction of the detrusor muscle of short duration and small amplitude.6 Relaxation which follows is prolonged but not marked. In males some of the sympathetic nerves which supply the proximal urethra have also been seen to distribute branches to the ejaculatory ducts. 24 This observation gives an anatomic explanation to the concept that sympathetic nerves, which cause seminal emission, can also induce simultaneous contraction of the bladder neck and proximal urethra, and thereby prevent reflux of ejaculate into the bladder.2,35s3g Clinical observations indicate that sympathetic nerve lesions or sympathetic denervation of the bladder frequently results in only minor
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disturbances in detrusor function. Internal sphincter dyssynergia has been reported as uncommon in cases of spinal cord injuries less than two years in duration, with the exception of patients who have autonomic dysreflexia.40 Pelvic ganglia
The ganglia of the pelvic plexus surround the urethrovesical junction, and some are within the interstices of the detrusor muscle.41 The ganglia are organized in one of three input arrangements:13 (1) an exclusive sympathetic innervation, (2) an exclusive parasympathetic innervation, and (3) postganglionic neurons responding to stimulation of either sympathetic or parasympathetic input. Sympathetic and parasympathetic fibers may innervate the same ganglion and be connected by an interneuron. Histochemical techniques allowed the demonstration of cholinergic and adrenergic ganglionic cells in all layers throughout the bladder wa11.26 A greater degree of ganglionic complexity with third and fourth order neurons has been suggested. 18,42*43Adrenergic synaptic terminals were demonstrated in various sympathetic and parasympathetic ganglia including the peripheral parasympathetic ganglia of the intestine, bladder, and heart.5p27 El-Badawi and Schenk27,42 suggested that the activity of peripheral sympathetic and parasympathetic ganglion cells in the lower urinary tract may be coordinated through an interaction between pre- and postganglionic synapses of both the sympathetic and parasympathetic divisions. Autonomic
neuroeffector
junctions
Divergent opinions have been expressed regarding the structural organization of the peripheral autonomic innervation apparatus. Cannon and Rosenblueth44 claimed that only some smooth muscle cells, the “key cells,” were directly innervated by the postganglionic nerve endings. The non-innervated muscle cells were assumed to be indirectly activated by diffusion of released transmitter from the “key cells” into the intermuscular space. On the other hand, the “diffusion theory” claims that all smooth muscle cells receive direct innervation by means of elongated, varicose terminal nerve structures which establish contact with the muscle cells.20 Each terminal postganglionic axon ramification innervated several muscle cells forming an autonomic neuroeffector unit. Several postganglionic fibers appear to converge on each unit. The elongated varicosities of the terminal
115
axon ramifications may account for the rather high concentration of transmitter substance occurring at the postganglionic nerve endings.45 Richardson, 46 using electron microscopy, observed thin axons emerging from the Schwann sheaths to pass into the intermuscular space where they establish intimate contact with the individual smooth muscle cells. These naked axons formed elongated enlargements containing vesicles and mitochondria buried in grooves on the surface of the smooth muscle fibers. These enlargements were considered to be synaptic vesicles. At the point of synaptic contact, the axon and the muscle membranes exhibit neither specialization nor polarization of the synaptic vesicles, in contrast to what is the case in the motor end plates of skeletal muscles. An active area of research into innervation of the lower urinary tract currently involves the effects of sympathetic nerve stimulation on bladder contraction and the response of detrusor and urethral smooth muscle to the application of alpha- and beta-adrenergic agents.47-60 Alphareceptor stimulation has been correlated with depolarization of the smooth muscle cells of the bladd er and urethra and resultant contraction; whereas, beta-receptor stimulation results in cellular membrane hyperpolarization and inhibition with relaxation of smooth muscle cells. Smooth muscle physiology related to the bladder
as
The physiology of a smooth muscle in a given organ is often different from that in other organ’s smooth muscles. 61 At one extreme, the spectrum of smooth muscles includes those which are quasipostural, the so-called multiunit muscles. These muscles are activated entirely by nerves, are relatively insensitive to quick stretch, and are not spontaneously rhythmic. At the other extreme are the unitary muscles of some visceral organs, such as the uterus and the ureter. Despite marked differences among these unitary muscles, most are spontaneously active, show interfiber conduction, and are stimulated by quick stretch to contract. Although capable of independent activity, they may be regulated by intrinsic and extrinsic nerves. The bladder (and the vas deferens) combine some properties of the multiunit and unitary types. Thus, the detrusor muscle is considered to be a multiunit muscle in respect to activation and control, but resembles visceral muscles in some of the effects of mechanical stretch. Other properties of bladd er muscle include tone and accom-
116
modation,62+4 rhythmic bladder contractile activity,4 probable conduction6r which may occur through specialized regions (nexuses),65 and voiding contractions.“,66 The latter is neurogenic in origin. 66 Somatic efferents
The somatic motor nerves to the pelvic floor muscles originate from the cell complexes of the anterior horn cells of the sacral cord segments, especially second to fourth.3 Fibers leave the cord by the anterior roots, form the lateral branch of the pudendal plexus, and terminate as pudendal nerves in the musculature of the pelvic floor. Gil-VerneP and WinkleP reported that the rhabdosphincter (external urethral sphincter) in many species, including man, is not innervated by the pudendal nerves but is supplied by branches of the pelvic plexus receiving sympathetic and parasympathetic nerve fibers. However, other anatomic studies have illustrated the course of twigs of the pudendal nerve to the external urethral sphincter,23 and physiologic studies in man and animals tend to support these morphologic findings. El-Badawi and Schenk6g demonstrated histochemically that the rhabdosphincter receives triple sympathetic-parasympathetic-somatic innervation. This important study gives a morphologic basis to the observation that the action of the external sphincter is normally coordinated with that of the bladder smooth musculature.54,70 There is a continuous barrage of neural impulses in the pudendal motor nerve to the external urinary sphincter maintaining closure of the sphincter during the bladder’s storage phase. lg This tonic activity in pudendal motor neurons is a result of a constant stimulation generated in sensory muscle receptors in the striated muscle called muscle spindles. Electromyographic studies demonstrate that during voiding, the activity of the perineal muscles disappears, and a period of electrical silence begins simultaneously with or slightly before the rise of pressure in the bladder. The striated muscle component is also involved in the urethral response to vesical distention.% With progressive vesical distension during bladder storage external sphincter muscle activity increases. Role of supraspinal centers in control of bladder and sphincter function
Although reflex arcs which can produce bladder contractions are at least potentially present
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in the sacral segments of the spinal cord, activity through this level does not result in a coordinated act of micturition.‘l Coordination of micturition is known to be influenced by several supraspinal centers.20 These areas provide for normal bladder and bladder outlet function by maintaining adequate bladder capacity, sufficient temporal duration, minimal residual urine, and volitional control of micturition and urinary sphincter function, and inhibiting uninhibited reflex contractions. The regions of the central nervous system that have been implicated in innervation of the detrusor muscle and urethra include: (1) specific areas of gray and white matter of the frontal lobes anterior to the motor cortex, (2) specific thalamic nuclei, (3) several portions of the basal ganglia, (4) certain portions of the cerebellum, (5) pontine-mesencephalic reticular formation, and (6) intermediolateral cell column and ventral horn cells of the sacral spinal cord.lg Similarly the central nervous system modulates the activity of the striated external sphincter through pyramidal tracts originating from the motor cortex of the frontal lobes which synapse on the pudendal motor neurons. 4301 West Markham Little Rock, Arkansas 72201 (DR. BISSADA)
References 1. GOODMAN, L. S., and GILMAN, A.: The Pharmacological Basis of Therapeutics, New York, The MacMillan Company, 1975. 2. LEARMONTH, J. R.: A contribution to the neurophysiology of the urinary bladder in man, Brain 54: 147 (1931). Neuro3. BORS, E., and COMARR, A. E., Eds.: anatomy and neurophysiology, in Neurological Urology: Physiology of Micturition, Its Neurological Disorders and Sequelae, Baltimore, Univ. Park Press, 1971, chap. 3, p. 61. 4. 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). 5. HAMRERGER, B., and NORBERC, K. A.: Adrenergic synaptic terminals and nerve cells in bladder ganglia of the cat, Int. J. Neuropharmacol. 4: 41 (1965). Sympathetic 6. KUNTZ, A., and SACCOMANNO, G.: innervation of the detrusor muscle, J. Urol. 51: 535 (1944). 7. FLETCHER, T. F., and BRADLEY, W. F.: Afferent nerve endings in the urinary hladder of the cat, Am. J. Anat. 128: 147 (1970). Comparative morphologic features of urinary 8. IDEM: bladder innervation, Am. J. Vet. Res. 30: 1655 (1969).
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9. UEMURA, E., FLETCHER, T. F., and BRADLEY, W. E.: Distribution of lumbar afferent axons in muscle coats of cat urinary hladder, Am. J. Anat. 139: 389 (1974). Distribution of lumbar afferent axons in 10. IDEM: suhmucosa of cat urinary bladder, Anat. Rec. 183: 579 (1975). 11. UEhKJRA, E., et CL/.: Distribution of sacral aiferent axons in cat urinary bladder, Am. J. Anat. 136: 305 (1973). 12. WINTER, D. L.: Receptor characteristics and conduction velocities in bladder alferents, J. Psychiatr. Res. 8: 225 (1971). 13. BRADLEY, W. E., ROCKU’OLD, G. L., TIMM, G. W., and SCOTT, F. B.: Neurology of micturition, J. Urol. 115: 481 (1976). Sites of termination of 14. NYBERG-HANSEN, R.: interstitiospinal fibers in the cat. An experimental study with silver impregnation methods, Arch. Ital. Biol. 104: 98 (1966). 15. BRADLEY, W. E., and TEAGUE, C. T.: Spinal cord organization of micturition reflex afferents, Exp. Neurol. 22: 504 (1968). 16. BRADLEY, W. E., TIMM, G. W., and SCOTT, F. B.: Cystometry. V. Bladder sensation, Urology 6: 654 (1975). 17. NATHAN, P. W.: Awareness of bladder filling with divided sensory tract, J. Neurol. Neurosurg. Psychiatry 19: 101 (1956). 18. BRADLEY, W. E.: Ontogeny of central regulation of visceral reflex activity in the rabbit, Am. J, Physiol. 212: 335 (1967). G. W., and SCOTT, F. B.: 19. BRADLEY, W. E., Tihm, Innervation of the detrusor muscle and urethra, Urol. Clin. North Am. 1: 3 (1974). 20. NYBERG-HANSEN, R.: Innervation and nervous control of the urinary bladder. Anatomical aspects, Acta. Neurol. Stand. 42: (Suppl. 20) 7 (1966). 21. ROCKSWOLD, G. L., BRADLEY, W. E., and Caou, S. N.: Effect of sacral nerve blocks on the function of the urinary hladder in humans, J, Neurosurg. 40: 83 (1974). 22. SHISIIITO, S. : Experimental studies on the innervation of the urinary hladder. Urol. Int. 12: 254 (1961). D. L.: The im23. MCCREA, I,. E., and KIhlXfm, portance of nerve supply of the urinary hladder in surgery of the rectosigmoid, J. Int. Coll. Surg. 17: 651 (1952). 24. GOSLING, J. A., and DIXON, J. S.: The structure and innervation of smooth muscle in the wall of the hladder neck and proximal urethra, Br. J. Urol. 47: 549 (1975). 25. LANGWORTHY, 0. R., and MURPHY, E. L.: Nerve endings in the urinary bladder, J. Camp. Neinol. 71: 487 (1939). 26. EL-BADAWI, A., and SCHENK, E. A.: Dual innervation of the mammalian urinary hladder. A histochemical study of distribution of cholinergic and adrenergic nerves, Am. J. Anat. 119: 405 (1966). 27. IDEM: A new theory of the innervation of hladder musculature. Part 1. Morphology of the intrinsic vesical innervation apparatus, J. Urol. 99: 585 (1968). 28. IDEhl: Histochemical methods for separate, consecutive ant 1 simultaneous demonstration of acetylcholinesterase and norepinephrine in cryo-stat sections, J. Histochem. Cytochem. 15: 580 (1967). 29. NYO, M. \I.: Innervation of the hladder and urethra,
117
J. Anat. 105: 210 (1969). 30. CEASAR, R., EDWARDS, G. A., and RUSKA, H.: Architecture and nerve supply of mammalian smooth muscle tissue, J. Biophys. Biochem. Cytol. 3: 867 (1957). 31. FLETCHER, T. F., HAMMER, R. F., and BRADLEY, W. E.: Nerve endings in the urinary bladder of the cat, J. Comp. Neurol. 136: 1 (1969). 32. NAGASAWA, J., and MITO, S.: Electron microscopic observations on the innervation of the smooth muscle, Tohoku J. Exp. Med. 91: 277 (1967). 33. THAEMERT, J. C.: The ultrastructure and disposition of vesiculated nerve process in smooth muscle, J. Cell. Biol. 16: 361 (1963). 34. BRADLEY, W. E., TIMM, G. W., and SCOTT, F. B.: Cystometry. II. Central nervous system organization of detrusor reflex, Urology 5: 578 (1975). 35. ELLIOTT, T. R.: The innervation of the bladder and urethra, J. Physiol. 35: 367 (1907). connections of intra36. MOSELY, R. L.: Preganglionic mural ganglia of urinary bladder, Proc. Sot. Exp. Biol. Med. 34: 728 (1936). 37. OWMAN, C. H., OWMAN, T., and SJOBERG, N. 0.: Short adrenergic neurons innervating the female urethra of the cat, Experientia. 27: 313 (1971). 38. GJONE, R.: Peripheral autonomic influence on the motility of the urinary bladder in the cat. III. Micturition, Acta Physiol. Stand. 66: 81 (1966). 39. STOCKAMP, K., and SCHREITER, R.: Function of the posterior urethra in ejaculation and its importance for urine control, Urol. Int. 29: 226 (1974). 40. YALLA, S. W., ROSSIER, A. B., and FAM, B.: Dyssynergic vesicourethral responses during bladder rehabilitation in spinal cord injury patients: effects of suprapubic percussion, Crede method and bethanechol chloride, J. Urol. 115: 575 (1976). 41. BRADLEY, W. E., and TEAGUE, C. T.: Innervation of the vesical detrusor muscle by ganglia of the pelvic plexus, Invest. Urol. 6: 251 (1968). 42. EL-BADAWI, A., and SCHENK, E. A.: A new theory of the innervation of bladder musculature. Part 3. Postganglionic synapses in ureterovesicourethral autonomic pathways, J. Urol. 105: 372 (1971). 43. HAMBERGER, A., NORBERG, K. A., and SJOQVIST, F.: Evidence for adrenergic nerve terminals and synapses in sympathetic ganglia, Int. J. Neuropharmacol. 2: 279 (1963). 44. CANNON, W. B., and ROSENBLUETH, A.: Autonomic Neuro-effector Systems, New York, MacMillan, 1937. 45. VON EULER, U. S.: Noradrenaline, Springfield, Ill., Charles C Thomas, 1956. 46. RICHARDSON, K. C.: The fine structure of anatomic nerve endings in smooth muscle of the rat vas deferens, J. Anat. 96: 427 (1962). 47. GRABER, P., and TANAGHO, E. A.: Urethral responses to autonomic nerve stimulation, Urology 6: 52 (1975). 48. KLEEMAN, F. J.: The physiology of the internal urinary sphincter, J. Urol. 104: 549 (1970). 49. KRANE, R. J., and OLSSON, C. A.: Phenoxybenzamine in neurogenic bladder dysfunction. I. A theory of micturition, ibid. 110: 650 (1973). in neurogenic bladder 50. IDEM: Phenoxybenzamine dysfunction. II. Clinical considerations, ibid. 110: 653 (1973).
51. AWAD, S. A., and DOWNIE, J. W.: The effect of adrenergic drugs and hypogastric nerve stimulation on the canine urethra: a radiologic and urethral pressure study, Invest. Urol. 13: 298 (1976). 52. AWAD, S. A., et al.: Sympathetic activity in the proximal urethra in patients with urinary obstruction, J. Urol. 115: 545 (1976). 53. GHONEIM, M. A., FREITIN, 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). 54. IDEM: The influence of vesical distension on urethral resistance to flow: the expulsion phase, ibid. 47: 663 (1975). 55. TANAGHO, E. A., and MEYERS, F. H.: The “internal sphincter.” Is it under sympathetic control? Invest. Urol. 7: 79 (1969). 56. RAZ, S., and CAINE, M.: Adrenergic receptors in the female canine urethra, ibid. 9: 319 (1972). 57. KHANNA, 0. P., and GONICK, P.: Effects of phenoxybenzamine hydrochloride on canine lower urinary tract: clinical implications, Urology 6: 323 (1975). 58. KHANNA, 0. P., HEBER, D., and GONICK, P.: Cholinergic and adrenergic neuroreceptors in urinary tract of female dogs, ibid. 5: 616 (1975). 59. ALPHONSE, P.: The influence of the adrenergic system on the lower urinary tract, Urol. Dig. 13: 15 (1974). 60. RAEZER, D. M., VEIRN, A. J., JACOBOWITZ, D., and CORRIERE, J. N., JR.: Autonomic innervation of canine urinary bladder. Cholinergic and adrenergic contributions and interaction of sympathetic and parasympathetic systems in bladder function, Urology 2: 211 (1973). 61. PROSSER, C. L.: Electrical and mechanical properties of visceral smooth muscles, in Boyarsky, S., Ed.: The Neurogenic Bladder, Baltimore, Williams and Wilkins, 1967, pp. 51-55. 62. EDVARDSEN, P.: Changes in urinary bladder motility following lesions in the nervous system in cats, Acta Neurol. Stand. (Suppl.) 19: 25 (1966). 63. LAPIDES, J.: Observations on normal and abnormal bladder physiology, J. Urol. 70: 74 (1958). 64. TANG, P. C., and RUCH, T. C.: Non-neurogenic basis of bladder tonus, Am. J. Physiol. 181: 249 (1955). 65. DEWEY, M. M., and BARR, L.: Intercellular connection between smooth muscle cells: the nexus, Science 137: 670 (1962). 66. KOCK, N. G., and POMPEIUS, R.: Studies on the nature of the rhythmic activity of the human bladder, Invest. Urol. 1: 253 (1963). 67. GIL-VERNET, S.: L’innervation somatique et vegetative des organes genitourinaries, Acta Urol. Belg. 32: 265 (1964). 68. WINKLER, G.: Cartribucional estudeo de la inervacion de la visceras pelvianas, Arch. Esp. Urol. 20: 259 (1967). 69. EL-BADAWI, A., and SCHENK, E. A.: A new theory of the innervation of bladder musculature, J. Urol. 111: 613 (1974). 70. DENNY-BROWN, D., and ROBERTSON, E. G.: On the physiology of micturition, Brain 56: 149 (1933). 71. YEATES, W. K.: Neurophysiology of the bladder, Paraplegia 12: 73 (1974).
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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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Urinary
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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
signals from and efferent signals to the lower urinary tract. In early childhood the sacral cord reflex centers become the area for the transmission and modulation of descending and ascending impulses which flow between the higher centers and the lower urinary tract. The sacral segments provide the parasympathetic and somatic motor impulses while the thoracolumbar segments emit sympathetic motor impulses.* Afferent impulses reach the sacral and lumbar segments from the mucosal and muscular receptors via the pelvic, hypogastric, and pudendal nerves which also conduct the efferent signals.3 All parts of the bladder and its outlet are supplied with nerve fibers from the sympathetic and parasympathetic divisions of the autonomic nervous system although the distribution is not uniform.4-6 At present the most widely held theory of the function of the bladder nerves is that suggested by Learmonth’ who postulated a reciprocal innervation of the detrusor muscle and the internal vesical sphincter by both divisions of the autonomic nerves, that is, an over-all parasympathetic excitation of the detrusor muscle and inhibition of the sphincter, and an over-all sympathetic inhibition of the detrusor muscle and excitation of the sphincter.
The lumbar sensory pathways, unlike the sacral tierents, are most numerous in the trigone and bladder neck especially in the mucosa and submucosa, and are sparsely represented in the remainder of the detrusor muscle.16 They also innervate the contralateral as well as the ipsilatera1 detrusor. The sensory endings in the mucosa and submucosa are stimulated by exteroceptive modalities such as touch, pain, and temperature. Nathan” suggested that impulses from the bladder may reach the spinal cord rostral to the fourth thoracic segments by way of a.fYerent sympathetic fibers coursing in the sympathetic trunk. Patients with complete transverse lesions of the cord at midthoracic levels may have vague, nonspecific, and poorly localized sensation in lower abdomen indicating fullness of bladder. Furthermore, the sensory impulses from visceral structures adjacent to the bladder, such as small bowel, are conducted centrally on vagal and sympathetic pathways. Sensory muscle receptors (muscle spindles) in the striated external sphincter muscle generate impulses that travel in sensory fibers of the pudendal nerve to the sacral spinal cord.‘* Parasympathetic
efferents
Two types of sensory receptors have been identified in the bladder.‘-l2 These receptors are stimulated either by detrusor muscle contraction (tension receptors) or vesical distention (volume receptors). Complex sensory endings in the bladder muscle similar to those seen in the skin have been described; however, more recent reports suggest that what were thought to be complex sensory endings were instead artifacts of methylene blue fixation. Sacral afferents are uniformly distributed to all areas of the detrusor muscle and urethra.7J0J1,‘3 Approximately one third of the fibers cross to innervate the contralateral portion of the detrusor muscle. Proprioceptive impulses initiated by stimulation of the detrusor muscle nerve endings travel in the sensory portion of the pelvic nerve to the third and fourth sacral dorsal nerve roots and ultimately terminate in the posterior and lateral columns of the sacral spinal cord.14 Bradley et al. 13,15 believe that bladder sensory afferents do not synapse in the sacral spinal cord but, instead, long route to the detrusor nucleus in a specialized portion of the brain stem.
The preganglionic parasympathetic nerve fibers to the lower urinary tract are believed to arise from the intermediolateral nucleus of the sacral cord (second to fourth sacral in man, and first to third sacral in the cat).4,1g,20 Despite bilateral innervation to the bladder from the sacral roots, there may be functional ipsilateral dominance which awaits further elaboration.‘3,21 The motor fibers leave the cord primarily by way of the ventral root, but a few may exit through the posterior root.22 The fibers first travel within the pudendal plexus but leave it as the pelvic nerves on either side of the rectum and join the hypogastric (sympathetic) nerves to form the vesical (pelvic) plexus, best developed at the base of the bladder.20 Auxiliary pelvic nerves have been described. 23 Divergent opinions have been expressed regarding the extent of the parasympathetic innervation of the smooth muscle of the bladder.6p20*24*25Histochemical and electron microscopic studies in the cat, dog, rabbit, guinea pig, and rat bladder indicated that there is a rich and uniform distribution of acetylcholinesterase positive fibers in the smooth musculature of the bladder, bladder neck, and urethra.24~26-2g These nerve fibers have been reported to be intimately related to individual muscle cells.26,30-33
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The parasympathetic fibers mediate excitatory impulses leading to contraction of the detrusor muscle.34 Some authors also advocate a specific inhibitory effect on the internal sphincter.2,35 Sympathetic
efferents
The preganglionic sympathetic nerve fibers to the lower urinary tract originate in the intermediolateral cell column in the lateral horn of the spinal gray matter of cord segments, eleventh thoracic to second lumbar.20 The preganglionic fibers traverse the paravertebral trunk ganglia and pass to the inferior mesenteric and hypogastric plexuses by way of lumbar splanchnic nerves from the first to the fourth lumbar trunk ganglia. Some preganglionic neurons localize in ganglia within the two plexuses, while others terminate in ganglia within the vesical plexus around the bladder neck or in intramural ganglia in the bladder wall 5,20,36 Different opinions have been expressed in the past regarding the parts of the bladder wall which receive postganglionic sympathetic fibers. Kuntz and Saccomanno” believe that such fibers are distributed to the detrusor muscle as well as to the trigone and internal sphincter, while Langworthy and Murphp5 deny the existence of sympathetic innervation to the detrusor muscle proper. Recently, histochemical studies have demonstrated that adrenergic nerve endings can be found throughout the bladder. They are abundant at the bladder base and proximal urethra but are sparse at the dome.5*24,26-2g,37 The functional significance of the sympathetic innervation of the lower urinary tract is also controversial. Hypogastric nerve stimulation was reported to induce contraction of the trigone and internal sphincter and to inhibit micturition.2,3* It was also reported to produce an initial contraction of the detrusor muscle of short duration and small amplitude.6 Relaxation which follows is prolonged but not marked. In males some of the sympathetic nerves which supply the proximal urethra have also been seen to distribute branches to the ejaculatory ducts. 24 This observation gives an anatomic explanation to the concept that sympathetic nerves, which cause seminal emission, can also induce simultaneous contraction of the bladder neck and proximal urethra, and thereby prevent reflux of ejaculate into the bladder.2,35s3g Clinical observations indicate that sympathetic nerve lesions or sympathetic denervation of the bladder frequently results in only minor
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disturbances in detrusor function. Internal sphincter dyssynergia has been reported as uncommon in cases of spinal cord injuries less than two years in duration, with the exception of patients who have autonomic dysreflexia.40 Pelvic ganglia
The ganglia of the pelvic plexus surround the urethrovesical junction, and some are within the interstices of the detrusor muscle.41 The ganglia are organized in one of three input arrangements:13 (1) an exclusive sympathetic innervation, (2) an exclusive parasympathetic innervation, and (3) postganglionic neurons responding to stimulation of either sympathetic or parasympathetic input. Sympathetic and parasympathetic fibers may innervate the same ganglion and be connected by an interneuron. Histochemical techniques allowed the demonstration of cholinergic and adrenergic ganglionic cells in all layers throughout the bladder wa11.26 A greater degree of ganglionic complexity with third and fourth order neurons has been suggested. 18,42*43Adrenergic synaptic terminals were demonstrated in various sympathetic and parasympathetic ganglia including the peripheral parasympathetic ganglia of the intestine, bladder, and heart.5p27 El-Badawi and Schenk27,42 suggested that the activity of peripheral sympathetic and parasympathetic ganglion cells in the lower urinary tract may be coordinated through an interaction between pre- and postganglionic synapses of both the sympathetic and parasympathetic divisions. Autonomic
neuroeffector
junctions
Divergent opinions have been expressed regarding the structural organization of the peripheral autonomic innervation apparatus. Cannon and Rosenblueth44 claimed that only some smooth muscle cells, the “key cells,” were directly innervated by the postganglionic nerve endings. The non-innervated muscle cells were assumed to be indirectly activated by diffusion of released transmitter from the “key cells” into the intermuscular space. On the other hand, the “diffusion theory” claims that all smooth muscle cells receive direct innervation by means of elongated, varicose terminal nerve structures which establish contact with the muscle cells.20 Each terminal postganglionic axon ramification innervated several muscle cells forming an autonomic neuroeffector unit. Several postganglionic fibers appear to converge on each unit. The elongated varicosities of the terminal
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axon ramifications may account for the rather high concentration of transmitter substance occurring at the postganglionic nerve endings.45 Richardson, 46 using electron microscopy, observed thin axons emerging from the Schwann sheaths to pass into the intermuscular space where they establish intimate contact with the individual smooth muscle cells. These naked axons formed elongated enlargements containing vesicles and mitochondria buried in grooves on the surface of the smooth muscle fibers. These enlargements were considered to be synaptic vesicles. At the point of synaptic contact, the axon and the muscle membranes exhibit neither specialization nor polarization of the synaptic vesicles, in contrast to what is the case in the motor end plates of skeletal muscles. An active area of research into innervation of the lower urinary tract currently involves the effects of sympathetic nerve stimulation on bladder contraction and the response of detrusor and urethral smooth muscle to the application of alpha- and beta-adrenergic agents.47-60 Alphareceptor stimulation has been correlated with depolarization of the smooth muscle cells of the bladd er and urethra and resultant contraction; whereas, beta-receptor stimulation results in cellular membrane hyperpolarization and inhibition with relaxation of smooth muscle cells. Smooth muscle physiology related to the bladder
as
The physiology of a smooth muscle in a given organ is often different from that in other organ’s smooth muscles. 61 At one extreme, the spectrum of smooth muscles includes those which are quasipostural, the so-called multiunit muscles. These muscles are activated entirely by nerves, are relatively insensitive to quick stretch, and are not spontaneously rhythmic. At the other extreme are the unitary muscles of some visceral organs, such as the uterus and the ureter. Despite marked differences among these unitary muscles, most are spontaneously active, show interfiber conduction, and are stimulated by quick stretch to contract. Although capable of independent activity, they may be regulated by intrinsic and extrinsic nerves. The bladder (and the vas deferens) combine some properties of the multiunit and unitary types. Thus, the detrusor muscle is considered to be a multiunit muscle in respect to activation and control, but resembles visceral muscles in some of the effects of mechanical stretch. Other properties of bladd er muscle include tone and accom-
116
modation,62+4 rhythmic bladder contractile activity,4 probable conduction6r which may occur through specialized regions (nexuses),65 and voiding contractions.“,66 The latter is neurogenic in origin. 66 Somatic efferents
The somatic motor nerves to the pelvic floor muscles originate from the cell complexes of the anterior horn cells of the sacral cord segments, especially second to fourth.3 Fibers leave the cord by the anterior roots, form the lateral branch of the pudendal plexus, and terminate as pudendal nerves in the musculature of the pelvic floor. Gil-VerneP and WinkleP reported that the rhabdosphincter (external urethral sphincter) in many species, including man, is not innervated by the pudendal nerves but is supplied by branches of the pelvic plexus receiving sympathetic and parasympathetic nerve fibers. However, other anatomic studies have illustrated the course of twigs of the pudendal nerve to the external urethral sphincter,23 and physiologic studies in man and animals tend to support these morphologic findings. El-Badawi and Schenk6g demonstrated histochemically that the rhabdosphincter receives triple sympathetic-parasympathetic-somatic innervation. This important study gives a morphologic basis to the observation that the action of the external sphincter is normally coordinated with that of the bladder smooth musculature.54,70 There is a continuous barrage of neural impulses in the pudendal motor nerve to the external urinary sphincter maintaining closure of the sphincter during the bladder’s storage phase. lg This tonic activity in pudendal motor neurons is a result of a constant stimulation generated in sensory muscle receptors in the striated muscle called muscle spindles. Electromyographic studies demonstrate that during voiding, the activity of the perineal muscles disappears, and a period of electrical silence begins simultaneously with or slightly before the rise of pressure in the bladder. The striated muscle component is also involved in the urethral response to vesical distention.% With progressive vesical distension during bladder storage external sphincter muscle activity increases. Role of supraspinal centers in control of bladder and sphincter function
Although reflex arcs which can produce bladder contractions are at least potentially present
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in the sacral segments of the spinal cord, activity through this level does not result in a coordinated act of micturition.‘l Coordination of micturition is known to be influenced by several supraspinal centers.20 These areas provide for normal bladder and bladder outlet function by maintaining adequate bladder capacity, sufficient temporal duration, minimal residual urine, and volitional control of micturition and urinary sphincter function, and inhibiting uninhibited reflex contractions. The regions of the central nervous system that have been implicated in innervation of the detrusor muscle and urethra include: (1) specific areas of gray and white matter of the frontal lobes anterior to the motor cortex, (2) specific thalamic nuclei, (3) several portions of the basal ganglia, (4) certain portions of the cerebellum, (5) pontine-mesencephalic reticular formation, and (6) intermediolateral cell column and ventral horn cells of the sacral spinal cord.lg Similarly the central nervous system modulates the activity of the striated external sphincter through pyramidal tracts originating from the motor cortex of the frontal lobes which synapse on the pudendal motor neurons. 4301 West Markham Little Rock, Arkansas 72201 (DR. BISSADA)
References 1. GOODMAN, L. S., and GILMAN, A.: The Pharmacological Basis of Therapeutics, New York, The MacMillan Company, 1975. 2. LEARMONTH, J. R.: A contribution to the neurophysiology of the urinary bladder in man, Brain 54: 147 (1931). Neuro3. BORS, E., and COMARR, A. E., Eds.: anatomy and neurophysiology, in Neurological Urology: Physiology of Micturition, Its Neurological Disorders and Sequelae, Baltimore, Univ. Park Press, 1971, chap. 3, p. 61. 4. 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). 5. HAMRERGER, B., and NORBERC, K. A.: Adrenergic synaptic terminals and nerve cells in bladder ganglia of the cat, Int. J. Neuropharmacol. 4: 41 (1965). Sympathetic 6. KUNTZ, A., and SACCOMANNO, G.: innervation of the detrusor muscle, J. Urol. 51: 535 (1944). 7. FLETCHER, T. F., and BRADLEY, W. F.: Afferent nerve endings in the urinary hladder of the cat, Am. J. Anat. 128: 147 (1970). Comparative morphologic features of urinary 8. IDEM: bladder innervation, Am. J. Vet. Res. 30: 1655 (1969).
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9. UEMURA, E., FLETCHER, T. F., and BRADLEY, W. E.: Distribution of lumbar afferent axons in muscle coats of cat urinary hladder, Am. J. Anat. 139: 389 (1974). Distribution of lumbar afferent axons in 10. IDEM: suhmucosa of cat urinary bladder, Anat. Rec. 183: 579 (1975). 11. UEhKJRA, E., et CL/.: Distribution of sacral aiferent axons in cat urinary bladder, Am. J. Anat. 136: 305 (1973). 12. WINTER, D. L.: Receptor characteristics and conduction velocities in bladder alferents, J. Psychiatr. Res. 8: 225 (1971). 13. BRADLEY, W. E., ROCKU’OLD, G. L., TIMM, G. W., and SCOTT, F. B.: Neurology of micturition, J. Urol. 115: 481 (1976). Sites of termination of 14. NYBERG-HANSEN, R.: interstitiospinal fibers in the cat. An experimental study with silver impregnation methods, Arch. Ital. Biol. 104: 98 (1966). 15. BRADLEY, W. E., and TEAGUE, C. T.: Spinal cord organization of micturition reflex afferents, Exp. Neurol. 22: 504 (1968). 16. BRADLEY, W. E., TIMM, G. W., and SCOTT, F. B.: Cystometry. V. Bladder sensation, Urology 6: 654 (1975). 17. NATHAN, P. W.: Awareness of bladder filling with divided sensory tract, J. Neurol. Neurosurg. Psychiatry 19: 101 (1956). 18. BRADLEY, W. E.: Ontogeny of central regulation of visceral reflex activity in the rabbit, Am. J, Physiol. 212: 335 (1967). G. W., and SCOTT, F. B.: 19. BRADLEY, W. E., Tihm, Innervation of the detrusor muscle and urethra, Urol. Clin. North Am. 1: 3 (1974). 20. NYBERG-HANSEN, R.: Innervation and nervous control of the urinary bladder. Anatomical aspects, Acta. Neurol. Stand. 42: (Suppl. 20) 7 (1966). 21. ROCKSWOLD, G. L., BRADLEY, W. E., and Caou, S. N.: Effect of sacral nerve blocks on the function of the urinary hladder in humans, J, Neurosurg. 40: 83 (1974). 22. SHISIIITO, S. : Experimental studies on the innervation of the urinary hladder. Urol. Int. 12: 254 (1961). D. L.: The im23. MCCREA, I,. E., and KIhlXfm, portance of nerve supply of the urinary hladder in surgery of the rectosigmoid, J. Int. Coll. Surg. 17: 651 (1952). 24. GOSLING, J. A., and DIXON, J. S.: The structure and innervation of smooth muscle in the wall of the hladder neck and proximal urethra, Br. J. Urol. 47: 549 (1975). 25. LANGWORTHY, 0. R., and MURPHY, E. L.: Nerve endings in the urinary bladder, J. Camp. Neinol. 71: 487 (1939). 26. EL-BADAWI, A., and SCHENK, E. A.: Dual innervation of the mammalian urinary hladder. A histochemical study of distribution of cholinergic and adrenergic nerves, Am. J. Anat. 119: 405 (1966). 27. IDEM: A new theory of the innervation of hladder musculature. Part 1. Morphology of the intrinsic vesical innervation apparatus, J. Urol. 99: 585 (1968). 28. IDEhl: Histochemical methods for separate, consecutive ant 1 simultaneous demonstration of acetylcholinesterase and norepinephrine in cryo-stat sections, J. Histochem. Cytochem. 15: 580 (1967). 29. NYO, M. \I.: Innervation of the hladder and urethra,
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J. Anat. 105: 210 (1969). 30. CEASAR, R., EDWARDS, G. A., and RUSKA, H.: Architecture and nerve supply of mammalian smooth muscle tissue, J. Biophys. Biochem. Cytol. 3: 867 (1957). 31. FLETCHER, T. F., HAMMER, R. F., and BRADLEY, W. E.: Nerve endings in the urinary bladder of the cat, J. Comp. Neurol. 136: 1 (1969). 32. NAGASAWA, J., and MITO, S.: Electron microscopic observations on the innervation of the smooth muscle, Tohoku J. Exp. Med. 91: 277 (1967). 33. THAEMERT, J. C.: The ultrastructure and disposition of vesiculated nerve process in smooth muscle, J. Cell. Biol. 16: 361 (1963). 34. BRADLEY, W. E., TIMM, G. W., and SCOTT, F. B.: Cystometry. II. Central nervous system organization of detrusor reflex, Urology 5: 578 (1975). 35. ELLIOTT, T. R.: The innervation of the bladder and urethra, J. Physiol. 35: 367 (1907). connections of intra36. MOSELY, R. L.: Preganglionic mural ganglia of urinary bladder, Proc. Sot. Exp. Biol. Med. 34: 728 (1936). 37. OWMAN, C. H., OWMAN, T., and SJOBERG, N. 0.: Short adrenergic neurons innervating the female urethra of the cat, Experientia. 27: 313 (1971). 38. GJONE, R.: Peripheral autonomic influence on the motility of the urinary bladder in the cat. III. Micturition, Acta Physiol. Stand. 66: 81 (1966). 39. STOCKAMP, K., and SCHREITER, R.: Function of the posterior urethra in ejaculation and its importance for urine control, Urol. Int. 29: 226 (1974). 40. YALLA, S. W., ROSSIER, A. B., and FAM, B.: Dyssynergic vesicourethral responses during bladder rehabilitation in spinal cord injury patients: effects of suprapubic percussion, Crede method and bethanechol chloride, J. Urol. 115: 575 (1976). 41. BRADLEY, W. E., and TEAGUE, C. T.: Innervation of the vesical detrusor muscle by ganglia of the pelvic plexus, Invest. Urol. 6: 251 (1968). 42. EL-BADAWI, A., and SCHENK, E. A.: A new theory of the innervation of bladder musculature. Part 3. Postganglionic synapses in ureterovesicourethral autonomic pathways, J. Urol. 105: 372 (1971). 43. HAMBERGER, A., NORBERG, K. A., and SJOQVIST, F.: Evidence for adrenergic nerve terminals and synapses in sympathetic ganglia, Int. J. Neuropharmacol. 2: 279 (1963). 44. CANNON, W. B., and ROSENBLUETH, A.: Autonomic Neuro-effector Systems, New York, MacMillan, 1937. 45. VON EULER, U. S.: Noradrenaline, Springfield, Ill., Charles C Thomas, 1956. 46. RICHARDSON, K. C.: The fine structure of anatomic nerve endings in smooth muscle of the rat vas deferens, J. Anat. 96: 427 (1962). 47. GRABER, P., and TANAGHO, E. A.: Urethral responses to autonomic nerve stimulation, Urology 6: 52 (1975). 48. KLEEMAN, F. J.: The physiology of the internal urinary sphincter, J. Urol. 104: 549 (1970). 49. KRANE, R. J., and OLSSON, C. A.: Phenoxybenzamine in neurogenic bladder dysfunction. I. A theory of micturition, ibid. 110: 650 (1973). in neurogenic bladder 50. IDEM: Phenoxybenzamine dysfunction. II. Clinical considerations, ibid. 110: 653 (1973).
51. AWAD, S. A., and DOWNIE, J. W.: The effect of adrenergic drugs and hypogastric nerve stimulation on the canine urethra: a radiologic and urethral pressure study, Invest. Urol. 13: 298 (1976). 52. AWAD, S. A., et al.: Sympathetic activity in the proximal urethra in patients with urinary obstruction, J. Urol. 115: 545 (1976). 53. GHONEIM, M. A., FREITIN, 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). 54. IDEM: The influence of vesical distension on urethral resistance to flow: the expulsion phase, ibid. 47: 663 (1975). 55. TANAGHO, E. A., and MEYERS, F. H.: The “internal sphincter.” Is it under sympathetic control? Invest. Urol. 7: 79 (1969). 56. RAZ, S., and CAINE, M.: Adrenergic receptors in the female canine urethra, ibid. 9: 319 (1972). 57. KHANNA, 0. P., and GONICK, P.: Effects of phenoxybenzamine hydrochloride on canine lower urinary tract: clinical implications, Urology 6: 323 (1975). 58. KHANNA, 0. P., HEBER, D., and GONICK, P.: Cholinergic and adrenergic neuroreceptors in urinary tract of female dogs, ibid. 5: 616 (1975). 59. ALPHONSE, P.: The influence of the adrenergic system on the lower urinary tract, Urol. Dig. 13: 15 (1974). 60. RAEZER, D. M., VEIRN, A. J., JACOBOWITZ, D., and CORRIERE, J. N., JR.: Autonomic innervation of canine urinary bladder. Cholinergic and adrenergic contributions and interaction of sympathetic and parasympathetic systems in bladder function, Urology 2: 211 (1973). 61. PROSSER, C. L.: Electrical and mechanical properties of visceral smooth muscles, in Boyarsky, S., Ed.: The Neurogenic Bladder, Baltimore, Williams and Wilkins, 1967, pp. 51-55. 62. EDVARDSEN, P.: Changes in urinary bladder motility following lesions in the nervous system in cats, Acta Neurol. Stand. (Suppl.) 19: 25 (1966). 63. LAPIDES, J.: Observations on normal and abnormal bladder physiology, J. Urol. 70: 74 (1958). 64. TANG, P. C., and RUCH, T. C.: Non-neurogenic basis of bladder tonus, Am. J. Physiol. 181: 249 (1955). 65. DEWEY, M. M., and BARR, L.: Intercellular connection between smooth muscle cells: the nexus, Science 137: 670 (1962). 66. KOCK, N. G., and POMPEIUS, R.: Studies on the nature of the rhythmic activity of the human bladder, Invest. Urol. 1: 253 (1963). 67. GIL-VERNET, S.: L’innervation somatique et vegetative des organes genitourinaries, Acta Urol. Belg. 32: 265 (1964). 68. WINKLER, G.: Cartribucional estudeo de la inervacion de la visceras pelvianas, Arch. Esp. Urol. 20: 259 (1967). 69. EL-BADAWI, A., and SCHENK, E. A.: A new theory of the innervation of bladder musculature, J. Urol. 111: 613 (1974). 70. DENNY-BROWN, D., and ROBERTSON, E. G.: On the physiology of micturition, Brain 56: 149 (1933). 71. YEATES, W. K.: Neurophysiology of the bladder, Paraplegia 12: 73 (1974).
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