neural input to the bladder. This vesico-sympathetic reflex represents a

J. Physiol. (1976), 259, pp. 223-237 223With 9 text-ftguremPrinted in Great Britain

REFLEX ACTIVATION OF SYMPATHETICPATHWAYS TO VESICAL SMOOTH MUSCLE ANDPARASYMPATHETIC GANGLIA BY ELECTRICAL

STIMULATION OF VESICAL AFFERENTS

By W. C. DE GROAT AND R. J. THEOBALDFrom the Department of Pharmacology, Medical School,

University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

(Received 29 December 1975)

SUMMARY

1. Activation of the sympathetic input to the urinary bladder byelectrical stimulation of afferent fibres in the pelvic nerve evoked threeresponses: (1) an initial transient rise in intravesical pressure, (2) aninhibition of neurally evoked bladder contractions and (3) an inhibition oftransmission in vesical parasympathetic ganglia. Similar responses wereelicited by stimulation of the hypogastric nerve.

2. The reflex responses were observed in acute spinal preparations(T10-T12) and in cats with intact spinal cords, but were abolished bybilateral transaction of the hypogastric nerves.

3. The inhibition of bladder contractions was antagonized by theadministration of propranolol (200-400 jug, I.A.), a f8-adrenergic blockingagent. The inhibition of ganglionic transmission was antagonized bydihydroergotamine (30-75 ,sg, I.A.), an cz-adrenergic blocking agent. Theinitial rise in intravesical pressure was not antagonized by either agent.

4. Electrical stimulation of other afferents (carotid sinus nerve andsciatic nerve) did not consistently elicit responses in the urinary bladder.However, stimulation of these afferents as well as pelvic nerve afferentsevoked reflex firing in nerve filaments on the surface of the urinary bladder.The firing was abolished by transaction of the ipsilateral hypogastricnerve.

5. It is concluded that stimulation of vesical afferents activates a spinalsympathetic reflex which results in closing of the internal urethralsphincter and a depression of bladder activity. The latter occurs by adirect depression of detrusor smooth muscle as well as a block of theneural input to the bladder. This vesico-sympathetic reflex represents anegative feed-back mechanism which may have an important role in themaintenance of urinary continence.

8 PHY 259

IV. C. DE GROAT AND R. J. THEOBALD

INTRODUCTION

Electrical stimulation of the sympathetic innervation (hypogastricnerves) to the urinary bladder of the cat produces an initial transient risein intravesical pressure, which is due primarily to a contraction of thetrigone, followed by an inhibition of spontaneous or evoked bladdercontractions (see reviews by Langworthy, Kolb & Lewis, 1940; Kuru,1965). The inhibitory response seems to be mediated by two distinctmechanisms: (1) a depression of the vesical smooth muscle and (2) adepression of transmission in vesical parasympathetic ganglia. The formeris mediated by activation of f8-receptors and the latter by a-adrenergicreceptors (de Groat & Saum, 1972; Saum & de Groat 1972a, b).

Gjone (1965) suggested that vesico-sympathetic pathways provided atonic inhibitory input to the bladder that depended upon supraspinalmechanisms. On the other hand, Edvardsen (1968) showed that thesympathetic inhibitory pathway was reflexly activated by raised intra-vesical pressure during bladder filling. He proposed that the reflex path-way had its afferent limb in the pelvic nerves and was organized at thespinal level. De Groat & Lalley (1972) provided electrophysiological datato support this proposal. They showed that electrical stimulation ofbladder afferents in the pelvic nerve or distension of the bladder evokedreflex firing in the hypogastric nerve. The firing persisted after transactionof the spinal cord at the thoracic level. Reflex discharges evoked byelectrical stimulation were enhanced by raising intravesical pressure tolevels below the micturition threshold but were markedly reduced athigher intravesical pressures which induced micturition. The depressionof the reflex was abolished by transaction of the spinal cord. De Groat &Lalley (1972) proposed that the vesico-sympathetic reflex provides anegative feed-back control which is important during the accumulationand storage of urine but which is turned off by a supraspinal mechanismduring micturition.The present experiments were undertaken to examine the effects on the

bladder of the vesico-sympathetic reflex. It was shown that reflex activa-tion of the sympathetic input to the bladder by electrical stimulation ofvesical afferents mimicked the effects produced by electrical stimulationof the sympathetic efferent pathway. These include: (1) transient bladdercontraction and (2) inhibition of vesical ganglia and vesical smoothmuscle. The effects were not obtained consistently by stimulation of otherafferents which evoked reflexes in the hypogastric nerves; thus demon-strating a very selective activation of the inhibitory pathway.

224

SYMPATHETIC INHIBITION OF URINARY BLADDER 225

METHODS

Experiments were performed on cats of either sex anaesthetized with chloralose(50-70 mg/kg, i.v.) after induction with halothane. Following intubation of thetrachea the urinary bladder and its innervation were exposed through a mid lineabdominal incision. The pelvic nerves were isolated bilaterally at two sites (2-3 cmand 7-8 cm from the neck of the bladder) and were then crushed or transactedbetween these two points (approximately 6 cm from the bladder). Ganglia wereidentified on the surface of the bladder and post-ganglionic fibres were isolated andprepared for monophasic recording. Hypogastric nerves bilaterally and preganglio-nic fibres to the left inferior mesenteric ganglion were prepared for stimulation orrecording. The urinary bladder was cannulated by passing a polyethylene tube (i.d.2 mm) through the external urethral orifice or through an incision in the urethra intothe bladder. The cannula was secured in place by a ligature around the urethra. Thecannula was filled with physiological saline solution and connected to a pressuretransducer to record pressure within the bladder. In some experiments the spinalcord was transacted at the lower thoracic level. Either the inferior mesenteric arteryor the left renal artery were cannulated for intra-arterial administration of drugs tothe bladder. Skin flaps were tied to a metal frame supporting the animal and thearea was covered with warmed paraffin oil. In some experiments the carotid sinusnerves and the sciatic nerves were also exposed for stimulation.

Isolated nerves were placed on bipolar silver electrodes for stimulation or record-ing. Stimulation was produced by rectangular pulses of 0-05 msec duration at vary-ing frequencies and intensities. Action potentials were displayed on an oscilloscope,photographed with 35 mm film and averaged with PDP-8 digital computer, theoutput of which was plotted on a Cal Comp plotter. The magnitude of averagedpotentials was measured with a computer programmne which determined the ampli-tude or area of the evoked responses.

After completion of the surgical procedure most animals were paralysed withgallamine triethiodide and artificially respired. End tidal CO2 Was maintained at3-5-4 O by varying the rate and depth of respiration. Experience with unparalysedpreparations indicated that the dose of chloralose administered was sufficient toproduce surgical anaesthesia for the duration of the experiments. In addition, duringthe experiments depth of anaesthesia was often checked by discontinuing theadministration of gallamine and allowing the animal to recover from paralysis.Arterial blood pressure was measured in the femoral artery via a polyethylenecannula attached to a strain gauge pressure transducer. The animals temperaturewas maintained between 36 and 380 C with a heating pad. End-tidal C02, systemicblood pressure and bladder contractions were displayed on a rectilinear, multi-channel paper recorder.The following drugs were used: dihydroergotamine methanesulphonate, pro-

pranolol hydrochloride, gallamine triethiodide, phenoxybenzamine hydrochloride,(-)-noradrenaline bitartrate. Doses are expressed as the salt and refer to intra-arterial (I.A.) administration unless otherwise indicated.

RESULTS

It was shown in previous experiments that electrical stimulation of thesympathetic nerves (hypogastric) to the bladder evoked three distinctresponses: (1) an initial bladder contraction followed by (2) an inhibitionof bladder smooth muscle and (3) an inhibition of transmission in vesical

8-2

W. C. DE GROAT AND R. J. THEOBALD

ganglia. In the present experiments it was demonstrated that reflexactivation of the vesico-sympathetic pathways by stimulation of bladderafferents in the pelvic nerves elicited similar responses.

Bladder contractionsThe rise in intravesical pressure evoked by stimulation of the hypo-

gastric nerves is very transient (15-30 s) (Fig. 1, HG stim.) and is thoughtto reflect primarily a contraction of the trigonal region of the bladder(Langworthy et al. 1940; Kuru, 1965). The bladder contractions elicited by

AFF stim. EFF stim. HG stim. AFF stim.

-~ ~ ~ ~~~.... .._ p.

Time (min)

Fig. 1. Bladder contractions elicited by repetitive stimulation (I10 c/s) of pel-

vic nerve afferents (AFF stim.), pelvic nerve efferents, (EFF stim.) and sym-pathetic efferents in the hypogastric nerve (HG stim.). Pelvic nerves weretransacted bilaterally. Stimuli were applied during the periods indicatedby the brackets to the central end ofthe transacted pelvic nerves (AFF stim.)and to the peripheral end of the pelvic nerve on the left side (EFF stim.).The record on the extreme right (AFF stim.) was obtained after the hypo-gastric nerves were transacted bilaterally. Ordinate, intravesical pressure.

stimulation of the central ends of the transacted pelvic nerves (AFFstimulation) had a similar configuration (mean duration 14 s, range12-36 s) but differed markedly from the responses produced by stimula-tion of pelvic efferent fibres (Fig. 1). The afferent-evoked contractions,which in different preparations achieved peak amplitudes ranging from15 to 82 cmH20 (mean 60 cmH2O), were observed in twenty of twenty-four experiments in both intact and acute spinal preparations. They wereelicited over a wide range of stimulus frequencies (0-5-20 c/s) and atintensities ranging from 0-5-1 V (threshold) to 5-7 V which producedmaximal responses. The contractions were abolished by transaction of thehypogastric nerves bilaterally in seven experiments but were not affectedby the administration of a- or 8-adrenergic blocking agents (dihydro-ergotamine, 15-75 (tg,phenoxybenzamine, 5 mg/kg i.V., propranolol,200-500phg) in doses which blocked adrenergic inhibitory mechanisms inthe bladder (Fig. 2).

226


Inhibition of bladder contractionsIn twenty of twenty-four experiments, AFF-stimulation depressed the

bladder contractions evoked by intermittent stimulation of pelvic efferentfibres (Figs. 2 and 3). The maximum inhibition in different experimentsranged from 16 to 63% (mean 44%) and was similar in magnitude andduration to the depression evoked by stimulation of a hypogastric nerve(HG stimulation) range 25-89% depression (mean 62%). The inhibition

AFF stim. HG stim.0 20] I,E 0_~

Propranolol AFF stim.

E jB

I l l l I £ I l l l l l l I I l l l l 1

Time (min)

Fig. 2. Inhibition of neurally evoked bladder contractions by stimulationof the hypogastric nerve or pelvic nerve afferents. Bladder contractionswere elicited by stimulation (3 c/s, for 5 s every 30 s) of preganglionicefferents in the left pelvic nerve. In the upper trace the contractions wereinhibited by stimulation of the left hypogastric nerve (HG stim., 10 c/s)and by bilateral stimulation of the central ends of the transacted pelvicnerves (AFF stim., 10 c/s). The inhibitory responses were blocked followingthe administration of propranolol (300 /zg I.A.) (bottom record). Stimuliwere applied during the period indicated by the brackets. Ordinate, intra-vesical pressure.

which immediately followed the initial contraction, was maintained duringcontinuous stimulation at frequencies between 1 and 15 c/s and persistedfor 1-4 min after the termination of the stimulus. The response was seenin intact and acute spinal preparations. The intensity of stimulationnecessary to produce a detectable depression ranged from 1-5 to 2 V indifferent experiments (Fig. 4). Unilateral stimulation of pelvic afferentsproduced bladder contractions and inhibition in some experiments, butthe responses were consistently weaker than those elicited by bilateralstimulation and were not regularly studied. The depression of bladdercontractions by HG-stimulation and by AFF-stimulation was antagonizedby the administration of the beta adrenergic blocking agent, propranolol

2W. C. DE GROAT AND R. J. THEOBALD(10 experiments, 200-400 jg) (Fig. 2) but not by an a-blocking agent,dihydroergotamine (seven experiments, 30-75 jug). Bilateral transactionof the hypogastric nerves also abolished the inhibition to AFF-stimulation(six experiments), but did not block the inhibition to HG-stimulation at asite peripheral to the transaction (Fig. 3). In three of ten experimentsafter the administration of propranolol the amplitude of the evokedbladder contractions increased as shown in Fig. 2. A similar enhancementwas observed in two of six experiments when the hypogastric nerves weretransacted.

HG stim. AFF stim.

0 40 3B

Time (min)Fig. 3. Block of the sympathetic inhibitory reflex to the urinary bladderby bilateral transection of the hypogastric nerves. Bladder contractionswere evoked by stimulation of preganglionic efferents in the left pelvicnerve (3 c/s). A, contractions were inhibited by stimulation of the hypo-gastric nerve (HG stim., 15 c/s) and pelvic nerve afferents (AFF stim., 15C/s). B, after transection of the hypogastric nerves bilaterally the inhibitionto AFF stim. was abolished; however, HG stim. peripheral to the site ofsectioning was still effective. Stimulation applied during the period markedby brackets. Ordinate, intravesical pressure.

Inhibition of ganglionic transmissionInhibition of transmission in the vesical parasympathetic ganglia by

AFF-stimulation was demonstrated in ten of twenty-two experiments(Figs. 5, 6). This inhibition by AFF stimulation ranged from 27 to 64%(mean 37 %/). Inhibitory responses were obtained at frequencies ofstimulation between 3 and 30 c/s and at intensities above 4 V. Ganglionicinhibition elicited by AFF stimulation was detectable within 2-3 s afterthe onset of stimulation. In some experiments (seven) the inhibition was

228


maintained during the period of stimulation, but in others (3) it persistedfor only 4-6 s and then was replaced by facilitation which persisted for1-2 min after the termination of the stimulus. In one experiment AFFstimulation produced only facilitation. Ganglionic facilitation was alsoobserved with HG-stimulation (de Groat & Saum, 1972).

I100-~~ ~~~U 100

775 75C ~~~~~~~~~~~~0a

OU, ,U,t

L.

E 5o so-E / ~~~~~~~~~~~E

X E~U'4 I

..o,25 j 25NO

0 I00 4 8 12 16

Intensity

Fig. 4. Relationship between the intensity of pelvic nerve afferentstimulation (abscissa, V) and the magnitude of the evoked reflex dischargerecorded in the hypogastric nerve and the evoked inhibition of bladdercontractions. The left ordinate depicts the size of the reflex as a percentageof the maximum reflex discharge (a*-) and the right ordinate, in-hibition ofbladder contractions as a % of the maximum inhibition ( -U).Reflexes were measured as the area of a computer average of ten indi-vidual responses. Data points obtained from four to six experiments.

The ganglionic inhibition elicited by AFF stimulation was blocked bydihydroergotamine (30-75 ,sg) in eight experiments (Fig. 5), but was notaffected by propranolol. Bilateral transaction of the hypogastric nervesalso abolished the inhibition of ganglionic transmission by AFF stimula-tion (Fig. 6).

Reflex firing on sympathetic post-ganglionic fibres to thebladder in response to veical afferent stimulation

Since AFF stimulation elicited sympathetic-induced changes in bladderactivity, it would be expected that AFF stimulation would also evokereflex firing in sympathetic post-ganglionic fibres to the bladder. This wasconfirmed in the present experiments by recording from nerve filamentson the surface of the bladder. Since the pelvic efferent fibres were

230 W. C. DE GROAT AND R. J. THEOBALD

Control AFF stim.

Untreated

A ||B

Aftera-ABA

C D~~~~~~~~~~[40 ms

Fig. 5. Antagonism by an z-adrenergic blocking agent (dihydroergotamine)of the depression of transmission in vesical parasympathetic gangliaelicited by stimulation of pelvic nerve afferents. A, control discharge re-corded from a vesical post-ganglionic nerve fibre in response to stimulation(0 5 cls) at a submaximal intensity (3 V) of preganglionic axons in thepelvic nerve. B, depression of the responses by bilateral pelvic nerve afferentstimulation (AFF stim., 10 c/s, 6 V). C and D are, respectively, a controlresponse and a response during afferent stimulation after the administra-tion of an a-adrenergic blocking agent (30 ptg). Vertical calibration is20 ,uV, negativity upwards. Records are computer averages of fiveindividual responses.

Control AFF stim.

Intact

A B

HGN-x

C>-D[

r100MsFig. 6. Effect of hypogastric nerve transaction (HGN-x) on the ganglionicinhibition elicited by stimulation of bilateral pelvic nerve afferents (AFFstim., 20 c/s). A and C, the control discharges recorded from a vesicalpost-ganglionic nerve filament in response to stimulation of efferent fibresin the left pelvic nerve (0 5 c/s) at a submaximal intensity (3 V). A is beforeand C is after HGN-x. B, inhibition of transmission during bilateralafferent stimulation. D, block of the inhibition after transaction of thehypogastric nerve. Vertical calibration is 250 #uV negativity upward.


transacted bilaterally in these preparations it is reasonable to assume thatall reflexes recorded in these nerves must have been sympathetic in origin.As shown in Fig. 7, AFF stimulation evoked firing at the level of the

inferior mesenteric ganglion at a latency of 25-30 ms (Fig. 7 B) and firingin vesical nerve filaments at a considerably longer latency of 120-130 ms(Fig. 7C). The latter discharge was abolished by transacting the ipsilateral

A AFF stim. HG stim Sciatic C.S.N.20 r .

E0

Time (min)

B E AfA

C F

D TM G

ms

Fig. 7. A, the changes in intravesical bladder pressure during stimulationof pelvic nerve afferents (AFF stim., 10 c/s, 8 V), the left hypogastric nerve(HG stim., 10 c/s, 8 V), the sciatic nerve (15 c/s, 8 V) and carotid sinus nerve(C.S.N., 15 c/s, 8 V). B, discharge recorded from the left hypogastric nervein response to AFF stim (0-5 c/s, 10 V). C, E, F and G, discharges recordedfrom a vesical post-ganglionic nerve filament in response to AFF stim. (4V),and stimulation of the hypogastric nerve (10 V), the carotid sinus nerve(15 V) and the sciatic nerve (10 V), respectively. D, response in a vesicalpost-ganglionic filament to AFF stim. after bilateral transaction of thehypogastric nerves. Vertical calibration is 20 1sV for B and E, 4 #V for Cand D and 10 #V for F and G, negativity upwards. Horizontal calibrationis 100 msec for records B-E, 200 msec for records F and G. Records arecomputer averages of ten individual responses.

2V. C. DE GROAT AND R. J. THEOBALD

hypogastric nerve, or by transacting the preganglionic nerves (inferiorsplanchnic) to the inferior mesenteric ganglion, but was not affected bytransacting the contralateral hypogastric nerve. Stimulation of theipsilateral hypogastric nerve at intensities (8-15 V, 0 05 ms) sufficient toactivate non-myelinated post-ganglionic axons also evoked firing in nervefibres on the surface of the bladder at latencies of 65-100 ms (Fig. 7E).With a conduction distance of approximately 100 mm, the estimatedconduction velocity for the vesical sympathetic pathway from theinferior mesenteric ganglion to the bladder was 1-5-0-75 m/s.The intensity of AFF stimulation required to evoke reflex firing in the

vesical sympathetic pathways was the same (1-5-2 V) as that whichelicited contractions and inhibition in the bladder. An intensity responsecurve for afferent-evoked reflexes in the hypogastric nerve and inhibitionof bladder contractions is shown in Fig. 4.

AFF stim. C.S.N. Sciatic

I

E

I I I I I I I I

Time (min)

Fig. 8. The effect of electrical stimulation of various afferent fibres onbladder contractions evoked by stimulation of efferent fibres in the pelvicnerve (2-5 c/s at an intensity of 4 V). AFF stim., stimulation of pelvicnerve afferents (15 c/s, 10 V), C.S.N., stimulation of the carotid sinus nerve(15 c/s, 10 V), sciatic, stimulation of the sciatic nerve (15 c/s, 10 V).Stimulation applied during period indicated by the brackets. Ordinate,intravesical pressure.

Reflex firing and bladder responses to stimulation of other afferentsStimulation of other afferent fibres also evokes reflex firing in the

hypogastric nerves (de Groat & Lalley, 1972, 1973, 1974). It was ofinterest therefore to determine whether these afferents might also evokedischarges in vesical nerve filaments and influence bladder activity.

In all experiments, stimulation of the carotid sinus nerve (C.S.N.) andsciatic nerve evoked reflexes in the hypogastric nerve at latencies of130-170 and 90-130 ms respectively. On the other hand, reflex firing invesical nerves was not obtained consistently. C.S.N. stimulation, in three often experiments, evoked reflex firing in the latter at a latency of 260-340 ms, whereas sciatic nerve stimulation evoked reflexes in five of twelve

232


experiments at latencies ranging from 160 to 215 msec (Fig. 7 F, G). Thestimulus thresholds ranged from 2 to 5 V.

In the same experiments stimulation of the C.S.N. failed to elicit bladdercontractions (Fig. 7) although AFF stimulation and HG stimulation pro-duced the normal responses. Stimulation of the sciatic nerve elicited smallcontractions (5-15 cm H20) in two of seventeen experiments. In one ofthese preparations the contraction was abolished by transaction of thehypogastric nerves.

Control h em_ AFF stim.

C.S.N. 4JTb HG stim.

Sciatic NEPI

100Ms1

Fig. 9. Transmission in vesical parasympathetic ganglia: failure of sciaticor carotid sinus afferent stimulation to mimic adrenergic inhibition. Con-trol, the discharge recorded from a vesical post-ganglionic nerve fibre inresponse to stimulation of the left pelvic nerve (0-5 c/s) at a submaximalintensity. Remaining records are post-ganglionic responses recordedduring simultaneous stimulation of the carotid sinus nerve (C.S.N., 10 c/s,10 V), the sciatic nerve (10 c/s, 10 V), stimulation of pelvic nerve afferents(AFF stim. 10 c/s, 6 V), the left hypogastric nerve (HG stim., 10 c/s, 10 V)and 5 s after the administration of noradrenaline (NEPI (NA), 10 11g).Vertical calibration is 350 1uV, negativity upwards.

Attempts to depress evoked bladder contractions with sciatic nerve orC.S.N.-stimulation yielded inconsistent results. In most experiments, noeffects were observed (Fig. 8). In four of seventeen experiments, stimula-tion of the sciatic nerve (5-100/s) produced weak inhibition (less than20 %). The effects were often elicited only with intense stimuli, 50-80 V(i.e. 30-50 times the threshold for evoking a sympathetic reflex) and wereoften associated with a rise in blood pressure. Propranolol (200-400 jug)blocked the inhibition in two preparations. C.S.N. stimulation (2-10 V,15-30 c/s) also produced weak depressant actions in three of seventeen


experiments. Since the inhibition persisted after transaction of the hypo-gastric nerves (one experiment) and was commonly accompanied by a risein blood pressure, it is likely that it was mediated by adrenal medullaryrelease of catecholamines which in turn affected the bladder.In the majority of experiments (fifteen), sciatic and C.S.N. stimulation

did not affect transmission in vesical ganglia (Fig. 9) although AFFstimulation, HG stimulation and injected noradrenaline produced asignificant depression of transmission. In two experiments sciatic andc.s.n. stimulation did depress transmission. The depression was abolishedby the administration of dihydroergotamine (50-75 ,ug).

DISCUSSION

The present results showed that electrical stimulation of vesical afferentsevoked sympathetic reflex responses in the urinary bladder. The responsesconsisted of: inhibition of evoked bladder contractions, inhibition oftransmission in vesical ganglia and a transient rise in intravesical pressure,which most likely reflects a contraction of the trigone and closing of theinternal sphincter (see Langworthy et at. 1940). All of these responseswere abolished by transaction of the hypogastric nerves, the major sym-pathetic innervation to the bladder. In addition, the inhibitory reflexeswere blocked by the administration of appropriate adrenergic blockingagents.These reflex effects were elicited by activation of low threshold afferents

in the pelvic nerves; the same afferent population (Ay8) which evokesparasympathetic reflexes in the sacral outflow and sympathetic reflexeson the hypogastric nerves (de Groat & Ryall, 1969; de Groat & Lalley,1972). These afferents supply tension receptors in the bladder wall.The central pathway mediating the sympathetic reflexes to the bladder

must be organized in the lumbo-sacral cord, since the reflexes wereobserved in acute spinal preparations as well as in cats with an intactspinal cord. Recordings from nerve filaments on the surface of the bladderrevealed that vesical afferent stimulation evoked reflex firing-at relativelylong latencies (100-160 ms); however, an examination of the peripheralpathway indicated that a major part of that latency (70-100 ms) mustrepresent conduction time in the post-ganglionic axons from the inferiormesenteric ganglion to the bladder. The central delay for the reflexprobably ranges between 10 and 25 ms (de Groat & Lalley, 1972).

Stimulation of other afferents (e.g. sciatic and carotid sinus) alsoevoked reflex firing in the sympathetic outflow to the bladder, but did notconsistently produce bladder contractions or inhibition. The pathwaysactivated by these afferents must have some other function in bladder;

234


possibly the regulation of vascular tone. The occasional inhibitory effectselicited by stimulation of carotid sinus afferents may be related in part tothe adrenal medullary release of catecholamines since they were associatedwith a rise in blood pressure and in one experiment were not abolished bytransaction of the hypogastric nerves. The differential effects of vesical,sciatic, and carotid sinus afferents on the lumbar sympathetic outflow andbladder activity is an excellent example of the high degree of specificity thatcan exist in the reflex control of the sympathetic nervous system.The present data provide further evidence for the existence in the

bladder of two distinct sympathetic inhibitory mechanisms: (1) ganglionicinhibition, mediated by a-adrenergic receptors, and (2) inhibition ofvesical smooth muscle mediated by fl-adrenergic receptors (de Groat &Saum, 1972). However, these mechanisms as well as the sympathetic-induced contraction of the trigone seemed to be activated by the sameafferent pathway since they could not be differentiated on the basis ofthreshold or frequency of stimulation. Thus they seem to be closely linkedto form a basic vesico-sympathetic reflex unit having as its major functionthe regulation of urine storage. This should not imply, however, that thesethree mechanisms are mediated by the same group of preganglionic orpost-ganglionic neurones. Indeed, there is some evidence to suggest thatganglionic inhibition and inhibition of smooth muscle are mediated bydifferent peripheral pathways (de Groat & Saum, 1972).As noted in previous studies (de Groat & Saum, 1972), the fl-adrenergic

inhibition of smooth muscle appeared to have the greatest influence onbladder activity. Blockade of ganglionic inhibition with dihydroergot-amine did not alter the depression by AFF stimulation of evoked bladdercontractions, whereas the administration of propranolol completelyabolished the depression. It is difficult to predict, however, the relativeimportance of the two inhibitory mechanisms under more physiologicalconditions.

Pharmacological (fl-blockade) or surgical interruption of the sympa-thetic innervation to the urinary bladder of cats increases bladder activity,decreases bladder capacity and produces a shift to the left in bladderpressure-volume curves (Langworthy et al. 1940; Gjone, 1965; Edvardsen,1968; de Groat & Saum, 1972). This suggests that the sympathetic outflowto the bladder is tonically active and makes a significant contribution tothe neural control of the organ. The vesico-sympathetic reflexes outlinedabove probably represent an important component of this control. How-ever, other sympathetic mechanisms may also be involved, since in some ofthe present experiments when the afferent limb of the vesico-sympatheticreflex pathway had been interrupted by bilateral transaction of thepelvic nerves, a subsequent transaction of the hypogastric nerves or the


administration of propranolol produced sustained increase in evokedbladder contractions.The sympathetic system may also have a role in the control of micturi-

tion in man. Transection of the vesical sympathetic pathways elicits atransient decrease in bladder capacity and an increase in the frequency ofurination. More prominent effects occur in the trigonal region of the blad-der, where sympathectomy produces an immediate relaxation of muscletone, and dilatation of ureteric orifices and internal urethral sphincter(Learmonth, 1931; Retief, 1950). Reduction of the sympathetic input tothe bladder by pharmacological (alpha blockade) or surgical blockadereduces the resistance of the internal sphincter and therefore has beenuseful in the treatment of certain types of urinary retention (Learmonth,1931; Krane & Olsson 1973a, b; Caine & Raz, 1975; Stockamp &Schreiter, 1975).In summary, it is clear that vesico-sympathetic reflexes have the

potential for exerting an important regulatory influence on bladderactivity (Kuru, 1965; Gjone, 1965; Edvardsen, 1968; de Groat & Saum,1972; de Groat & Lalley, 1972; de Groat, 1975). The pathway represents inpart a negative feed-back system whereby an increase in bladder pressuretends to increase inhibitory input to vesical ganglia and smooth muscle,thus allowing the bladder to accommodate to larger volumes. Increasedsympathetic firing to the trigone would complement these mechanismsby increasing the tone of the bladder neck (internal urethral sphincter).There is also electrophysiological data suggesting that with the onset ofmicturition, the vesico-sympathetic reflexes are depressed by supra-spinal controls (de Groat & Lalley, 1972; de Groat, 1975). This would allowmicturition to proceed uninhibited and the bladder to empty completely.

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neural input to the bladder. This vesico-sympathetic reflex represents a