URETHRAL RESPONSES TO AUTONOMIC NERVE STIMULATION* PETER GRABER, M .D .f EMIL A . TANAGHO, M .D . From the Division of Urology, University of California School of Medicine, San Francisco, California
ABSTRACT - Urethral contraction in response to cholinergic stimulation has been repeatedly proved and is a universally accepted fact . The adrenergic response is still disputed : (1) Is it a contraction or a relaxation, or a combination of both? (2) Where are the adrenergic receptors? Are they on the intrinsic urethral smooth muscles (with a biphasic response) ; in two different structures of the same organ (urethral and vascular smooth muscles) ; or on two anatomically different urethral smooth muscular units? Sympathomimetic and hypogastric nerve stimulation alone, as well as with pharmacologic blockade, showed that the contraction response to adrenergics is independent of the pelvic nerve and does persist even after urethral smooth muscle blockade by atropine, but is abolished after alpha blockade by phentolamine . The same contraction response, manifested in rise in intraurethral pressure, can be induced by pure vasoconstrictors . The relaxation response is reduced by beta blockade . Whether it is the direct response of a specific urethral group of musculature to sympathetic stimulation or an indirect urethral response to trigonal activity in answer to the same stimulus is discussed .
Stimulation of the pelvic nerve or administration of cholinergic drugs provokes a strong contraction of the smooth muscles of the bladder and urethra : the involvement of the parasympathetic system is clear . However, because of conflicting experimental results, the influence of the sympathetic system is still a matter of dispute . The discussion is polarized toward two main problems: (1) The adrenergic response - is it a contraction, a relaxation, or a combination of both? (2) The site of the specific receptors - are they on the same urethral smooth muscle (with a biphasic response), are they located in two different structures of the same anatomic organ (that is, on the urethral or on the vascular smooth muscle), or are they acting on two anatomically different structures? *Supported by University of California Grant MSC 18, Lartigau Fund . JPresent address : 38 Johannsringstrasse, Basle, Switzerland .
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The presence and anatomic organization of both cholinergic and adrenergic nerve elements in the bladder and trigone have been demonstrated by Elbadawi and Schenk .' Their findings were consolidated by the investigations of Bradley and Teague2 who succeeded in detecting and following up micropotentials on their synaptic transmission through cholinergic, adrenergic, and mixed ganglia in the pelvic and intravesical plexuses . Our experiments have been designed to study the effects of cholinergic and adrenergic nerve stimulation on the contractile element of the urethra. Material and Methods Twelve female mongrel dogs weighing 15 to 23 Kg. were anesthetized with phenobarbital at a dosage of 0 .6 Gm . per kilogram . The pelvic, hypogastric, and sympathetic nerve trunks at the fifth lumbar vertebra were exposed, and bipolar
UROLOGY / JULY 1975 / VOLUME VI, NUMBER 1
FIGURE 1 . (A) Spontaneous voiding ; detrusor contraction and rise in intravesical pressure associated with simultaneous drop in proximal (Ui) and midurethral (U2) pressures . (B) Pelvic neurostirnulation on same dog : increase of intravesical pressure, and of proximal (Ui) and midurethral (U2) pressures . (Velocity = 0 .5 nrm . per second.)
electrodes were used to stimulate one or the other of these nerves . Stimulation voltage varied between 3 and 40 volts, with a frequency of 10 Hz . Since neither the output impedance of the stimulator nor the resistance of the electrode were known, the relationship between the strength of the stimulus and the results of stimulation can only be approximately assessed . The contractile response in the bladder and the urethra was measured by a calibrated threechannel balloon catheter .' The measuring points were an open-ended tube in the bladder and two balloons, one in the proximal urethral segment and one in the midurethral segment . In all experiments the systemic arterial pressure was recorded . Direct electric stimulation of individual nerves, either separately or in combination, was done . Nerve stimulation was also done while the animal was under the effect of various pharmaceutical blocking agents . Results Direct nerve stimulation Pelvic nerve stimulation . As initially mentioned, stimulation of the intact pelvic nerve gave rise to contraction of the detrusor, proximal urethra, and midurethra of practically the same intensity . It is interesting to compare this contractile effect to the normal micturition pattern, which is also considered mainly as a parasympathetic reflex response (Fig . 1) . Micturition is
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initiated by a detrusor contraction, but a simultaneous relaxation of the urethra occurs, too . Since urethral relaxation is nonexistent in pelvic nerve stimulation, the usual result is dribbling of urine but never normal voiding and complete emptying of the bladder .' Hypo gastric nerve stimulation . Stimulation of the hypogastric nerve or the sympathetic nerve trunk usually did not produce any change in intravesical pressure but occasionally did produce a minute contraction of the detrusor . The urethral response, however, was complex and variable . Three different patterns were noted : (1) the most frequent was a rise in urethral pressure of usually less than half that obtained by pelvic nerve stimulation (Fig . 2, Br) ; (2) in some dogs the only occasional change was a drop in urethral pressure (Fig . 2, B2) ; and (3) other animals showed a combined response - the initial urethral pressure rise followed by a drop, or vice versa (Fig . 2, Ba) . Nerve stimulation combined with pharmaceutical blockade Combination of nerve stimulation and selective blocking of the cholinergic receptors by atropine and of alpha and beta adrenergic receptors by phentolamine and propranolol, allowed a further analysis of the different urethral responses . Cholinergic blockade . Pelvic nerve stimulation with the animal under the influence of atropine evoked minimal or no rise in urethral pressure . Similar blockade has been achieved by exhausting the cholinergic neurotransmitter through prolonged pelvic nerve stimulation . Adrenergic blockade : (1) Effects of blocking agents on contraction component . In an animal with combined response to stimulation, followed by drop in urethral pressure, alpha blockade abolished the pressure rise but not the pressure drop . When the animal was allowed to recover from the effect of alpha blockade and the beta receptors were then blocked, the pressure drop lessened, while the pressure rise remained the same or increased (Fig . 3) . In conclusion, the signal transmitted by the sympathetic trunk or the hypogastric nerves brings forth three possible reactions : urethral contraction, urethral relaxation, or sequence of the two, as evidenced by the urethral pressure rise or drop, or the combination of both . The contraction response manifest in urethral pressure rise is independent of the pelvic nerve
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e Vesicourethral response to direct nerve stimulation . (A) Pelvic nerve stimulation : equal pressure rise in the bladder and in the proximal urethra (U1) and midurethra (U2). (B) Sympathetic nerve stimulation in 3 different dogs : proximal and midurethral pressures show rise (131), drop (132), or rise followed by drop (133) . As a rule sympathetic stimulation studies did not lead to any change in intravesical pressure . In Baminimal rise in bladder pressure associated with rise in urethral pressure is seen . (Velocity = 0 .5 mm . per second.) FIGURE 2 .
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FIGURE 3 . Sympathetic nerve stimulation with alpha and beta blocking agents . (A) Combined urethral response to sympathetic stimulation : initial rise in urethral pressure, followed by a drop . (B) Same sympathetic stimulus after blocking alpha receptors (phentolamine) : no rise in urethral pressure, yet drop is unchanged (C and D) After blocking of beta receptors (propranolol) : pressure rise is unchanged or augmented while pressure drop is appreciably diminished or abolished . (Velocity = 0 .5 mm . per second .)
system . After blocking of the cholinergic neuromuscular junction by atropine, the pelvic nerve stimulation effect is strongly diminished ; yet the adrenergic contractile effect initiated by hypogastric nerve stimulation remains unchanged . After additional administration of phentolamine in the same animal, the hypogastric response is also abolished, which characterizes it as alpha adrenergic in nature (Fig . 4). 54
Prolonged pelvic nerve stimulation exhausted the cholinergic neurotransmitter, which resulted in minimal pressure rise . Yet, at this phase, simultaneous hypogastric stimulation produced an unimpaired rise in urethral pressure, suggesting an independent pathway for the adrenergic stimuli (Fig . 5). (2) Effects of blocking agents on relaxation component. Comparing the urethral pressure
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FIGURE 4 . Autonomic nerve stimulation after cholinergic and alpha adrenergic blockade . (A) Normal bladder and urethral responses to sympathetic and pelvic nerve stimulation . (B) Bladder and urethral (U1, Uz) response to pelvic nerve stimulation is minimized by atropine, yet sympathetic stimulation is unchanged . (C) Blocking of alpha receptors : sympathetic response is minimized by phentolamine . (Velocity = 0 .5 non . per second.)
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FIGURE 5 . Sympathetic nerve stimulation after cholinergic blockade . (A) Blocking cholinergic receptors by atropine . Markedly reduced bladder and urethral response to pelvic nerve stimulation, yet no alteration of sympathetic response . (B) Exhausting cholinergic neuromuscular transmission by prolonged pelvic nerve stimulation does not alter effect of superimposed sympathetic stimulation which still produces another independent rise in urethral pressures . (Velocity = 0 .5 mm . per second .)
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SYMPATHETIC N. STIMULATION FIGURE 6 . Effect of beta blockade on adrenergic relaxation responses . (A) Sympathetic stimulation : initial drop in midurethral (U2) pressure and continuing delayed drop in proximal and midurethral pressures (Ui and U2) . (B) After blocking beta receptors (propranolol) the initial pressure drop in U2 is replaced b y some pressure rise; delayed drop is unaffected . (Velocity = 0.5 mm . per second .)
drop after hypogastric nerve stimulation in Figures 2 and 3, an obvious difference appears . In Figure 2 the pressure drop is a net initial response whereas in Figure 3 it follows an initial pressure rise. By analogy to the "after contraction" of the detrusor the latter effect could be characterized as an "after relaxation," but "after contraction" and "after relaxation" are probably quite different in origin . The following experimental facts demonstrate the complexity of the relaxation movement : (1) beta blocking agents were more effective in abolishing the initial pressure drop but did not influence the delayed pressure drop (Fig . 6); (2) after a prolonged contraction a delayed relaxation was observed in all beta blocked animals ; (3) although the initial muscle relaxation can be considered a direct response to the stimulation, the duration of the delayed relaxation is too long to be ascribed to that fact alone . The time necessary to restore the prerelaxation level of tone is too long for a pure smooth muscle adaptation . Depending on the degree of urethral pressure drop, it may take up to fifteen minutes to return to the prestimulation baseline . On the other hand the delayed pressure drop appears to be an intregal part of the adrenergic nerve stimulation and cannot be considered a mere hysteresis 56
phenomenon . Relaxation due to hysteresis depends on the previous contractile amplitude . As a consequence, it should be more notable after pelvic nerve stimulation - when it is in fact rarely observed . Further evidence of an independent adrenergic effect is seen in the initial urethral pressure drop and in alpha blockade without previous contraction . Vascular component of adrenergic urethral responses
The complexity of the relaxation component makes us hesitate to accept the simplistic concept of a biphasic alpha and beta muscular response recognized for other organ Sys tems . 5.6 The competing interpretation localizes the antagonistic receptors in two different tissues of the same anatomic structure, that is, on the urethral and vascular smooth muscle ."' The two following observations help clarify this possibility . Stimulation of the sympathetic trunk provokes a sharp rise in systemic arterial pressure . Stimulation of the proximal end of a cut hypogastric nerve should incite no direct motor response in the urethra . However, the laboratory animals showed minimal rise in urethral pressure after stimulation of the proximal stump of the sympathetic trunk . This urethral pressure rise of
UROLOGY / JULY 1975 / VOLUME VI, NUMBER I
about 5 mm . Hg is synchronous with an appreciable arterial pressure rise . Either a direct vascular response or the indirect effect on the urethral musculature of increased circulating epinephrine could be involved (Fig . 7) . Angiotensin, which is supposed to be a pure vasoconstrictor without effects on the nonvascular smooth muscle, stimulates a sharp rise in urethral pressure . Apparently, no difference between angiotensin and epinephrine can be seen . While alpha blockade did abolish epinephrine effect on urethral pressure, it did not alter the response to angiotensin . 7 As a result of these experiments the contribution of the vascular component to the urethral pressure could be appreciated and quantitatecf . Comment At a cellular level a discussion of our results has to start with the question of possible neuromuscular transmitter localizations in the system considered . In the bladder wall, cholinergic terminal ramifications probably come into contact with every muscle cell . The sympathetic terminal fibers apparently have a different arrangement and are only associated with large groups of muscle fibers but not with individual muscle cells . Both systems have ramifications to the vascular system . A large number of intermuscular adrenergic fibers are concentrated at the base of the bladder and in the urethra, whereas such fibers are rarely observed in the rest of the detrusor .' Different contractile responses of muscle strips from these two localizations to adrenergic and cholinergic drugs and within the adrenergic drugs to alpha and beta blocking agents has been demon."," The results of strated by in vitro experiments these studies provide no direct evidence for the anatomic receptor site and do not show a biphasic response of the individual muscle cell . Both bladder and vascular smooth muscles are contained in the samples investigated and the vascular muscle contribution cannot be ignored . Our initial question was : can the rise or drop in urethral pressure, resulting from stimulation of the hypogastric nerve or from administration of adrenergic drugs, be compared to alpha and beta effects in other organ systems? At present this question remains unanswered . The interpretation of our results at a macroscopic level appears to he more significant . If we consider the over-all response of the urethra to sympathetic nerve stimulation, we can assign to
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oL-i I t STIMULATION OF PROXIMAL END OF SYMPATHETIC NERVE FIGURE 7 . Effect of systemic arterial pressure change on urethral pressure . Stimulation of proximal end of cut sympathetic trunk leads to rise in blood pressure and associated increase in urethral resistance which could he vascular response or result of circulating epinephrine . (Velocity = I mm . per second. )
the adrenergic system an important regulatory function . Our experiments demonstrated active relaxation of the urethra as one of the possible responses to adrenergic nerve stimulation ; this strongly supports the hypothesis of a synergistic effect of both cholinergic and adrenergic nerves at the initiation of micturition . The fact of an active urethral relaxation also explains the observation that a sharp increase in hypogastric nerve activity occurs at the initiation of voiding ." On the other hand the same adrenergic system is able to produce an additional closing pressure on the urethra . Anatomic considerations
The changes recorded in our study must all he considered as interpretations of pressure changes . Rise in urethral pressure is considered synonymous to muscular contraction whether this contraction is arising in the intrinsic urethral musculature or in the vascular musculature . Drop in urethral pressure is considered synonymous to muscular relaxation of the first or the second component . The fact that the vascular element plays an appreciable role in urethral pressure changes appears to be undeniable . The questionable element is the reality of a sympathetic effect on the intrinsic smooth musculature of the urethra . This smooth musculature uniformly responds to
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cholinergic stimulation, and its activity is obliterated by cholinergic blocking agents . Is the urethral intrinsic smooth musculature, in spite of its cholinergic dependence, also partly under the control of the adrenergic system? Two possibilities are to be considered : (1) The same smooth muscle fiber could receive motor supply from both cholinergic and adrenergic nerve endings and at the same time receive inhibitory adrenergic nerve endings . This hypothesis would explain all previous findings . However, it would be an overly complex myoneural setup not known to exist in any other organ . (2) There may be two different groups of smooth muscle structure in the urethral wall : one group, sphincteric in nature and under the motor control of the cholinergic nerve endings, and a second group, also sphincteric, yet totally separate and under both the motor and inhibitory control of the adrenergic system . Anatomic facts do not support this last assumption . The trigone, however, is known to be under the control of the sympathetic system and, although it does not form an integral part of the urethral sphincteric mechanism, it is closely related to the vesicourethral musculature . Trigonal response to sympathomimetics could possibly be the easiest explanation for urethral pressure changes . Trigonal contraction is known to assist in the funneling of the bladder outlet, especially through the deep trigone and its connection to the ventral circular fibers and through the extension of the superficial trigone . This fact could explain the occasional drop in urethral pressure seen with sympathetic stimulation, the result of which might mimic true initiation of voiding . Contraction of the deep trigone can have a stretching action on the detrusor muscle fibers fused with it (the ventral condensation of the middle circular layer) . This action might provoke a contraction of the detrusor, possibly extending
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into the urethral musculature - an explanation of the occasional urethral pressure rise with sympathetic stimulation . Interestingly, in our experiments, whenever urethral pressure rise was present, some rise in intravesical pressure was also detected (Fig . 7) . Urethral pressure rise followed by pressure drop could be a combination of the two previous mechanisms . A-644, University of California San Francisco, California 94143 (DR . TANAGHO)
References A., and SCHENK, E . A. : Dual innervation of the mammalian urinary bladder . A histochemical study of cholinergic and adrenergic nerves, Am . J . Anat . 119 : 405 (1966) . 2 . BRADLEY, W . E ., and TEAGUE, C . T. : Innervation of the vesical detrusor muscle by ganglia of the pelvic plexus, Invest . Urol. 6: 251 (1968) . 3 . DROUIN, G ., and McCURRY, E. H . : Catheters for studies of urinary tract pressure, ibid . 8 : 195 (1970) . 4 . GRABER, P ., RUTISHAUSER, G ., and WOLFF, C. : Experimentelle Unterschungen caber den Oellungs - and Schliessumechanismus der elektriseh stimulierten Blase, Urol . lot . 21 : 182 (1966) . 5 . LA GRANGE, R . G . : Peripheral autonomic regulation of the canine urinary bladder, Invest . Urol . 9 : 64 (1971) . 6 . RAZ, S ., and CAINE, M . : Adrenergic receptors in the female canine urethra, ibid . 9 : 319 (1972) . 7 . TANAGHO, E. A., and MEYERS, F . H . : The "internal sphincter" : is it under sympathetic control? ibid . 7 : 79 1 . ELBADAwI,
(1969) . 8 . TANAGHO, E .
9.
10 .
A., MEYERS, F . H ., and SMITH, D. R . : Urethral resistance : its components and implications. I . Smooth muscle component, ibid . 7 : 136 (1969) . MALIN, J . M ., and BOYARSKY, S . : The effects of cholinergic and adrenergic drug stimulation of detrusor muscle, ibid . 8: 286 (1970) . ROHNER, T. J,, RAEZER, D . M ., WEIN, A. J ., and SCHOENBERG, H . W . : Contractile responses of dog bladder neck muscle to adrenergic drugs, J . Urol . 105 :
657 (1971) . 11 . EDVARDSEN, P .,
and SETEKLEIV, J. : Distribution of adrenergic receptors in the urinary bladder of cats, rabbits and guinea pigs, Acta Pharmacol . 26 : 437 (1968) .
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ABSTRACT - Urethral contraction in response to cholinergic stimulation has been repeatedly proved and is a universally accepted fact . The adrenergic response is still disputed : (1) Is it a contraction or a relaxation, or a combination of both? (2) Where are the adrenergic receptors? Are they on the intrinsic urethral smooth muscles (with a biphasic response) ; in two different structures of the same organ (urethral and vascular smooth muscles) ; or on two anatomically different urethral smooth muscular units? Sympathomimetic and hypogastric nerve stimulation alone, as well as with pharmacologic blockade, showed that the contraction response to adrenergics is independent of the pelvic nerve and does persist even after urethral smooth muscle blockade by atropine, but is abolished after alpha blockade by phentolamine . The same contraction response, manifested in rise in intraurethral pressure, can be induced by pure vasoconstrictors . The relaxation response is reduced by beta blockade . Whether it is the direct response of a specific urethral group of musculature to sympathetic stimulation or an indirect urethral response to trigonal activity in answer to the same stimulus is discussed .
Stimulation of the pelvic nerve or administration of cholinergic drugs provokes a strong contraction of the smooth muscles of the bladder and urethra : the involvement of the parasympathetic system is clear . However, because of conflicting experimental results, the influence of the sympathetic system is still a matter of dispute . The discussion is polarized toward two main problems: (1) The adrenergic response - is it a contraction, a relaxation, or a combination of both? (2) The site of the specific receptors - are they on the same urethral smooth muscle (with a biphasic response), are they located in two different structures of the same anatomic organ (that is, on the urethral or on the vascular smooth muscle), or are they acting on two anatomically different structures? *Supported by University of California Grant MSC 18, Lartigau Fund . JPresent address : 38 Johannsringstrasse, Basle, Switzerland .
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The presence and anatomic organization of both cholinergic and adrenergic nerve elements in the bladder and trigone have been demonstrated by Elbadawi and Schenk .' Their findings were consolidated by the investigations of Bradley and Teague2 who succeeded in detecting and following up micropotentials on their synaptic transmission through cholinergic, adrenergic, and mixed ganglia in the pelvic and intravesical plexuses . Our experiments have been designed to study the effects of cholinergic and adrenergic nerve stimulation on the contractile element of the urethra. Material and Methods Twelve female mongrel dogs weighing 15 to 23 Kg. were anesthetized with phenobarbital at a dosage of 0 .6 Gm . per kilogram . The pelvic, hypogastric, and sympathetic nerve trunks at the fifth lumbar vertebra were exposed, and bipolar
UROLOGY / JULY 1975 / VOLUME VI, NUMBER 1
FIGURE 1 . (A) Spontaneous voiding ; detrusor contraction and rise in intravesical pressure associated with simultaneous drop in proximal (Ui) and midurethral (U2) pressures . (B) Pelvic neurostirnulation on same dog : increase of intravesical pressure, and of proximal (Ui) and midurethral (U2) pressures . (Velocity = 0 .5 nrm . per second.)
electrodes were used to stimulate one or the other of these nerves . Stimulation voltage varied between 3 and 40 volts, with a frequency of 10 Hz . Since neither the output impedance of the stimulator nor the resistance of the electrode were known, the relationship between the strength of the stimulus and the results of stimulation can only be approximately assessed . The contractile response in the bladder and the urethra was measured by a calibrated threechannel balloon catheter .' The measuring points were an open-ended tube in the bladder and two balloons, one in the proximal urethral segment and one in the midurethral segment . In all experiments the systemic arterial pressure was recorded . Direct electric stimulation of individual nerves, either separately or in combination, was done . Nerve stimulation was also done while the animal was under the effect of various pharmaceutical blocking agents . Results Direct nerve stimulation Pelvic nerve stimulation . As initially mentioned, stimulation of the intact pelvic nerve gave rise to contraction of the detrusor, proximal urethra, and midurethra of practically the same intensity . It is interesting to compare this contractile effect to the normal micturition pattern, which is also considered mainly as a parasympathetic reflex response (Fig . 1) . Micturition is
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initiated by a detrusor contraction, but a simultaneous relaxation of the urethra occurs, too . Since urethral relaxation is nonexistent in pelvic nerve stimulation, the usual result is dribbling of urine but never normal voiding and complete emptying of the bladder .' Hypo gastric nerve stimulation . Stimulation of the hypogastric nerve or the sympathetic nerve trunk usually did not produce any change in intravesical pressure but occasionally did produce a minute contraction of the detrusor . The urethral response, however, was complex and variable . Three different patterns were noted : (1) the most frequent was a rise in urethral pressure of usually less than half that obtained by pelvic nerve stimulation (Fig . 2, Br) ; (2) in some dogs the only occasional change was a drop in urethral pressure (Fig . 2, B2) ; and (3) other animals showed a combined response - the initial urethral pressure rise followed by a drop, or vice versa (Fig . 2, Ba) . Nerve stimulation combined with pharmaceutical blockade Combination of nerve stimulation and selective blocking of the cholinergic receptors by atropine and of alpha and beta adrenergic receptors by phentolamine and propranolol, allowed a further analysis of the different urethral responses . Cholinergic blockade . Pelvic nerve stimulation with the animal under the influence of atropine evoked minimal or no rise in urethral pressure . Similar blockade has been achieved by exhausting the cholinergic neurotransmitter through prolonged pelvic nerve stimulation . Adrenergic blockade : (1) Effects of blocking agents on contraction component . In an animal with combined response to stimulation, followed by drop in urethral pressure, alpha blockade abolished the pressure rise but not the pressure drop . When the animal was allowed to recover from the effect of alpha blockade and the beta receptors were then blocked, the pressure drop lessened, while the pressure rise remained the same or increased (Fig . 3) . In conclusion, the signal transmitted by the sympathetic trunk or the hypogastric nerves brings forth three possible reactions : urethral contraction, urethral relaxation, or sequence of the two, as evidenced by the urethral pressure rise or drop, or the combination of both . The contraction response manifest in urethral pressure rise is independent of the pelvic nerve
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e Vesicourethral response to direct nerve stimulation . (A) Pelvic nerve stimulation : equal pressure rise in the bladder and in the proximal urethra (U1) and midurethra (U2). (B) Sympathetic nerve stimulation in 3 different dogs : proximal and midurethral pressures show rise (131), drop (132), or rise followed by drop (133) . As a rule sympathetic stimulation studies did not lead to any change in intravesical pressure . In Baminimal rise in bladder pressure associated with rise in urethral pressure is seen . (Velocity = 0 .5 mm . per second.) FIGURE 2 .
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FIGURE 3 . Sympathetic nerve stimulation with alpha and beta blocking agents . (A) Combined urethral response to sympathetic stimulation : initial rise in urethral pressure, followed by a drop . (B) Same sympathetic stimulus after blocking alpha receptors (phentolamine) : no rise in urethral pressure, yet drop is unchanged (C and D) After blocking of beta receptors (propranolol) : pressure rise is unchanged or augmented while pressure drop is appreciably diminished or abolished . (Velocity = 0 .5 mm . per second .)
system . After blocking of the cholinergic neuromuscular junction by atropine, the pelvic nerve stimulation effect is strongly diminished ; yet the adrenergic contractile effect initiated by hypogastric nerve stimulation remains unchanged . After additional administration of phentolamine in the same animal, the hypogastric response is also abolished, which characterizes it as alpha adrenergic in nature (Fig . 4). 54
Prolonged pelvic nerve stimulation exhausted the cholinergic neurotransmitter, which resulted in minimal pressure rise . Yet, at this phase, simultaneous hypogastric stimulation produced an unimpaired rise in urethral pressure, suggesting an independent pathway for the adrenergic stimuli (Fig . 5). (2) Effects of blocking agents on relaxation component. Comparing the urethral pressure
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FIGURE 4 . Autonomic nerve stimulation after cholinergic and alpha adrenergic blockade . (A) Normal bladder and urethral responses to sympathetic and pelvic nerve stimulation . (B) Bladder and urethral (U1, Uz) response to pelvic nerve stimulation is minimized by atropine, yet sympathetic stimulation is unchanged . (C) Blocking of alpha receptors : sympathetic response is minimized by phentolamine . (Velocity = 0 .5 non . per second.)
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FIGURE 5 . Sympathetic nerve stimulation after cholinergic blockade . (A) Blocking cholinergic receptors by atropine . Markedly reduced bladder and urethral response to pelvic nerve stimulation, yet no alteration of sympathetic response . (B) Exhausting cholinergic neuromuscular transmission by prolonged pelvic nerve stimulation does not alter effect of superimposed sympathetic stimulation which still produces another independent rise in urethral pressures . (Velocity = 0 .5 mm . per second .)
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SYMPATHETIC N. STIMULATION FIGURE 6 . Effect of beta blockade on adrenergic relaxation responses . (A) Sympathetic stimulation : initial drop in midurethral (U2) pressure and continuing delayed drop in proximal and midurethral pressures (Ui and U2) . (B) After blocking beta receptors (propranolol) the initial pressure drop in U2 is replaced b y some pressure rise; delayed drop is unaffected . (Velocity = 0.5 mm . per second .)
drop after hypogastric nerve stimulation in Figures 2 and 3, an obvious difference appears . In Figure 2 the pressure drop is a net initial response whereas in Figure 3 it follows an initial pressure rise. By analogy to the "after contraction" of the detrusor the latter effect could be characterized as an "after relaxation," but "after contraction" and "after relaxation" are probably quite different in origin . The following experimental facts demonstrate the complexity of the relaxation movement : (1) beta blocking agents were more effective in abolishing the initial pressure drop but did not influence the delayed pressure drop (Fig . 6); (2) after a prolonged contraction a delayed relaxation was observed in all beta blocked animals ; (3) although the initial muscle relaxation can be considered a direct response to the stimulation, the duration of the delayed relaxation is too long to be ascribed to that fact alone . The time necessary to restore the prerelaxation level of tone is too long for a pure smooth muscle adaptation . Depending on the degree of urethral pressure drop, it may take up to fifteen minutes to return to the prestimulation baseline . On the other hand the delayed pressure drop appears to be an intregal part of the adrenergic nerve stimulation and cannot be considered a mere hysteresis 56
phenomenon . Relaxation due to hysteresis depends on the previous contractile amplitude . As a consequence, it should be more notable after pelvic nerve stimulation - when it is in fact rarely observed . Further evidence of an independent adrenergic effect is seen in the initial urethral pressure drop and in alpha blockade without previous contraction . Vascular component of adrenergic urethral responses
The complexity of the relaxation component makes us hesitate to accept the simplistic concept of a biphasic alpha and beta muscular response recognized for other organ Sys tems . 5.6 The competing interpretation localizes the antagonistic receptors in two different tissues of the same anatomic structure, that is, on the urethral and vascular smooth muscle ."' The two following observations help clarify this possibility . Stimulation of the sympathetic trunk provokes a sharp rise in systemic arterial pressure . Stimulation of the proximal end of a cut hypogastric nerve should incite no direct motor response in the urethra . However, the laboratory animals showed minimal rise in urethral pressure after stimulation of the proximal stump of the sympathetic trunk . This urethral pressure rise of
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about 5 mm . Hg is synchronous with an appreciable arterial pressure rise . Either a direct vascular response or the indirect effect on the urethral musculature of increased circulating epinephrine could be involved (Fig . 7) . Angiotensin, which is supposed to be a pure vasoconstrictor without effects on the nonvascular smooth muscle, stimulates a sharp rise in urethral pressure . Apparently, no difference between angiotensin and epinephrine can be seen . While alpha blockade did abolish epinephrine effect on urethral pressure, it did not alter the response to angiotensin . 7 As a result of these experiments the contribution of the vascular component to the urethral pressure could be appreciated and quantitatecf . Comment At a cellular level a discussion of our results has to start with the question of possible neuromuscular transmitter localizations in the system considered . In the bladder wall, cholinergic terminal ramifications probably come into contact with every muscle cell . The sympathetic terminal fibers apparently have a different arrangement and are only associated with large groups of muscle fibers but not with individual muscle cells . Both systems have ramifications to the vascular system . A large number of intermuscular adrenergic fibers are concentrated at the base of the bladder and in the urethra, whereas such fibers are rarely observed in the rest of the detrusor .' Different contractile responses of muscle strips from these two localizations to adrenergic and cholinergic drugs and within the adrenergic drugs to alpha and beta blocking agents has been demon."," The results of strated by in vitro experiments these studies provide no direct evidence for the anatomic receptor site and do not show a biphasic response of the individual muscle cell . Both bladder and vascular smooth muscles are contained in the samples investigated and the vascular muscle contribution cannot be ignored . Our initial question was : can the rise or drop in urethral pressure, resulting from stimulation of the hypogastric nerve or from administration of adrenergic drugs, be compared to alpha and beta effects in other organ systems? At present this question remains unanswered . The interpretation of our results at a macroscopic level appears to he more significant . If we consider the over-all response of the urethra to sympathetic nerve stimulation, we can assign to
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VOLUME VI, NUMBER 1
oL-i I t STIMULATION OF PROXIMAL END OF SYMPATHETIC NERVE FIGURE 7 . Effect of systemic arterial pressure change on urethral pressure . Stimulation of proximal end of cut sympathetic trunk leads to rise in blood pressure and associated increase in urethral resistance which could he vascular response or result of circulating epinephrine . (Velocity = I mm . per second. )
the adrenergic system an important regulatory function . Our experiments demonstrated active relaxation of the urethra as one of the possible responses to adrenergic nerve stimulation ; this strongly supports the hypothesis of a synergistic effect of both cholinergic and adrenergic nerves at the initiation of micturition . The fact of an active urethral relaxation also explains the observation that a sharp increase in hypogastric nerve activity occurs at the initiation of voiding ." On the other hand the same adrenergic system is able to produce an additional closing pressure on the urethra . Anatomic considerations
The changes recorded in our study must all he considered as interpretations of pressure changes . Rise in urethral pressure is considered synonymous to muscular contraction whether this contraction is arising in the intrinsic urethral musculature or in the vascular musculature . Drop in urethral pressure is considered synonymous to muscular relaxation of the first or the second component . The fact that the vascular element plays an appreciable role in urethral pressure changes appears to be undeniable . The questionable element is the reality of a sympathetic effect on the intrinsic smooth musculature of the urethra . This smooth musculature uniformly responds to
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cholinergic stimulation, and its activity is obliterated by cholinergic blocking agents . Is the urethral intrinsic smooth musculature, in spite of its cholinergic dependence, also partly under the control of the adrenergic system? Two possibilities are to be considered : (1) The same smooth muscle fiber could receive motor supply from both cholinergic and adrenergic nerve endings and at the same time receive inhibitory adrenergic nerve endings . This hypothesis would explain all previous findings . However, it would be an overly complex myoneural setup not known to exist in any other organ . (2) There may be two different groups of smooth muscle structure in the urethral wall : one group, sphincteric in nature and under the motor control of the cholinergic nerve endings, and a second group, also sphincteric, yet totally separate and under both the motor and inhibitory control of the adrenergic system . Anatomic facts do not support this last assumption . The trigone, however, is known to be under the control of the sympathetic system and, although it does not form an integral part of the urethral sphincteric mechanism, it is closely related to the vesicourethral musculature . Trigonal response to sympathomimetics could possibly be the easiest explanation for urethral pressure changes . Trigonal contraction is known to assist in the funneling of the bladder outlet, especially through the deep trigone and its connection to the ventral circular fibers and through the extension of the superficial trigone . This fact could explain the occasional drop in urethral pressure seen with sympathetic stimulation, the result of which might mimic true initiation of voiding . Contraction of the deep trigone can have a stretching action on the detrusor muscle fibers fused with it (the ventral condensation of the middle circular layer) . This action might provoke a contraction of the detrusor, possibly extending
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into the urethral musculature - an explanation of the occasional urethral pressure rise with sympathetic stimulation . Interestingly, in our experiments, whenever urethral pressure rise was present, some rise in intravesical pressure was also detected (Fig . 7) . Urethral pressure rise followed by pressure drop could be a combination of the two previous mechanisms . A-644, University of California San Francisco, California 94143 (DR . TANAGHO)
References A., and SCHENK, E . A. : Dual innervation of the mammalian urinary bladder . A histochemical study of cholinergic and adrenergic nerves, Am . J . Anat . 119 : 405 (1966) . 2 . BRADLEY, W . E ., and TEAGUE, C . T. : Innervation of the vesical detrusor muscle by ganglia of the pelvic plexus, Invest . Urol. 6: 251 (1968) . 3 . DROUIN, G ., and McCURRY, E. H . : Catheters for studies of urinary tract pressure, ibid . 8 : 195 (1970) . 4 . GRABER, P ., RUTISHAUSER, G ., and WOLFF, C. : Experimentelle Unterschungen caber den Oellungs - and Schliessumechanismus der elektriseh stimulierten Blase, Urol . lot . 21 : 182 (1966) . 5 . LA GRANGE, R . G . : Peripheral autonomic regulation of the canine urinary bladder, Invest . Urol . 9 : 64 (1971) . 6 . RAZ, S ., and CAINE, M . : Adrenergic receptors in the female canine urethra, ibid . 9 : 319 (1972) . 7 . TANAGHO, E. A., and MEYERS, F . H . : The "internal sphincter" : is it under sympathetic control? ibid . 7 : 79 1 . ELBADAwI,
(1969) . 8 . TANAGHO, E .
9.
10 .
A., MEYERS, F . H ., and SMITH, D. R . : Urethral resistance : its components and implications. I . Smooth muscle component, ibid . 7 : 136 (1969) . MALIN, J . M ., and BOYARSKY, S . : The effects of cholinergic and adrenergic drug stimulation of detrusor muscle, ibid . 8: 286 (1970) . ROHNER, T. J,, RAEZER, D . M ., WEIN, A. J ., and SCHOENBERG, H . W . : Contractile responses of dog bladder neck muscle to adrenergic drugs, J . Urol . 105 :
657 (1971) . 11 . EDVARDSEN, P .,
and SETEKLEIV, J. : Distribution of adrenergic receptors in the urinary bladder of cats, rabbits and guinea pigs, Acta Pharmacol . 26 : 437 (1968) .
UROLOGY / JULY 1975 / VOLUME V1, NUMBER 1
