significantly altered by either stimulation or section of the hypogastric nerves.

Transcription

1 J. Physiol. (1987), 384, pp With 7 text-figures Printed in Great Britain AUTONOMIC CONTROL OF PENILE ERECTION IN THE DOG BY C. J. CARATI, K. E. CREED* AND E. J. KEOGH From the Impotence Study Group, Reproductive Medicine Research Institute, Queen Elizabeth II Medical Centre, Department of Clinical Biochemistry, University of Western Australia and the *School of Veterinary Studies, Murdoch University, Western Australia (Received 29 April 1986) SUMMARY 1. In anaesthetized dogs, resting mean penile artery pressure (p.a.p.) and corpus cavernosum pressure (c.c.p.) were % and 10-15% of mean systemic blood pressure, respectively. 2. Stimulation of the pelvic nerve at 10 Hz produced an immediate drop in p.a.p. and c.c.p., followed s later by a rise in c.c.p. to the level of p.a.p. This level was % of systemic pressure, and was maintained throughout stimulation. 3. The threshold for a rise in c.c.p. was 3-5 Hz. Atropine (1 mg/kg), phentolamine (200 jctg kg-') and propranolol (200,tg kg-') had no effect on the response to pelvic nerve stimulation. 4. C.c.p., p.a.p. and their changes in response to pelvic nerve stimulation were not significantly altered by either stimulation or section of the hypogastric nerves. 5. Cutting the sympathetic chain on both sides at L5, or administration of phentolamine, had no effect on resting c.c.p. or p.a.p. However, subsequent responses to pelvic nerve stimulation were enhanced. 6. When the pelvic nerve was stimulated during excitation of the sympathetic chain, there was still an initial drop in p.a.p. and c.c.p. but the subsequent increase in c.c.p. was delayed or abolished. These effects were mimicked by close arterial injection of phenylephrine and blocked by a-adrenergic antagonists. 7. This study suggests that erections in response to pelvic nerve stimulation result from an initial increase in volume of the corpus spongiosum, followed 20 s later by a stiffening of the corpus cavernosum as its pressure increases. Only the latter process is inhibited by activity of the sympathetic fibres. INTRODUCTION The penis contains two types of erectile tissue: that of the corpora cavernosa, and the corpus spongiosum and glans. The haemodynamics of erection is different in each of these tissues. The corpus cavernosum behaves as a high-pressure system in contrast to the lower pressure measured within the interconnected corpus spongiosum and glans (Christensen, 1954; Purohit & Beckett, 1979). During erection, arterioles within * From whom reprints should be requested.

2 526 C. J. CARATI, K. E. CREED AND E. J. KEOGH the erectile tissue dilate and the penis engorges with blood. This blood becomes trapped within the corpora cavernosa, and pressures during intercourse can greatly exceed systemic blood pressure (Purohit & Beckett, 1979). In contrast, there is increased blood flow through the corpus spongiosum and the glans engorges, but the pressure remains low and blood flows freely out through the penile veins (Beckett, Reynolds & Bartels, 1978; Andersson, Bloom & Mellander, 1984). The haemodynamic changes which occur during erection are under the control of the autonomic nervous system. It is considered that the parasympathetic branches from sacral roots S1-4, which form the pelvic nerve, are the main neural pathways responsible for causing erection. Electrical stimulation of these fibres causes erection (Langley & Anderson, 1896; Dorr & Brody, 1967; Sjostrand & Klinge, 1979; Brindley, 1983; Lue, Takamura, Schmidt, Palubinskas & Tanagho, 1983; Lue, Takamura, Umraiya, Schmidt & Tanagho, 1984; Andersson et al. 1984). The penis also receives neural input from two sympathetic sources. The hypogastric nerve arises from the caudal mesenteric ganglion (derived from the sympathetic chain at T12-L5) and joins the pelvic nerve to form the pelvic plexus, beyond which the cavernous nerve runs directly to the penis. Other sympathetic fibres run caudally in the sympathetic chain to S1-S3 where they exit with the pudendal and pelvic nerves (Langley & Anderson, 1896). These sympathetic contributions have been considered to inhibit erection (Langley & Anderson, 1895), though stimulation of the hypogastric nerve in dogs had no effect on penile blood flow, as measured angiographically (Colleen, Holmquist & Olin, 1981). However, some excitatory fibres may run in the hypogastric nerves of rabbits (Sjostrand & Klinge, 1979), cats (Root & Bard, 1947; Bessou & Laporte, 1961), dogs (Frangois-Franc, 1895; Bacq, 1935) and primates (Brindley, 1983). The autonomic control of penile erection, as described above, has been deduced from cord-transection experiments with subsequent evaluation of erectile function, or by measuring penile engorgement caused by electrical stimulation of nerves and pharmacological manipulation. In most of the studies in which the latter technique was used, plethysmographic changes in the glans of the penis were recorded, with some contribution likely from protrusion of the penis due to relaxation of the retractor penis muscle. Thus, these experiments dealt with the control of the lowpressure system within the corpus spongiosum and glans. Few studies have been conducted on the high-pressure system within the corpora cavernosa (Lue et al. 1983, 1984; Purohit & Beckett, 1979) and in none have its responses to autonomic stimulation been recorded with instruments. We have investigated the autonomic control of pressure within the corpora cavernosa of the canine penis, and made preliminary observations on haemodynamic changes caused by pelvic nerve stimulation. METHODS Young adult male dogs (15-41 kg) of several breeds were anaesthetized with intravenous sodium pentobarbitone (30 mg kg-' body weight) and maintained thereafter with approximately 1 mg kg-' h-1. Systemic arterial blood pressure was monitored via a cannula in the carotid artery. The abdominal cavity was opened through a mid-line incision. The two sympathetic chains were identified at the level L5. Threads were loosely tied around these, and also the hypogastric nerves

3 CONTROL OF PENILE ERECTION of some animals, for subsequent section and electrical stimulation. The right pelvic nerve was cut lateral to the rectum, and the distal end placed on bipolar platinum electrodes. Electrical stimulation was delivered with trains of pulses of V and 1 ms duration from a Grass stimulator (SD9 or S8). A 2 min period of pelvic nerve stimulation was used to examine interactions between nerve- and drug-induced effects, with a 5-10 min rest between successive pelvic nerve stimulations. To measure the local arterial pressure, a cannula of o.d mm was inserted into the right dorsal artery of the penis and secured so that its tip was in the penile artery close to the arterial branches to the corpus cavernosum. The pressure within the right corpus cavernosum was measured through a 21G scalp vein needle inserted into the corporal body, 3-4 cm proximal to the os penis. Both cannulae were connected to Statham pressure transducers (P23) and responses measured on a Grass polygraph. Drugs were injected into the systemic circulation or into the corpus cavernosum. They were atropine sulphate (David Bull Laboratories), propranolol hydrochloride (Inderal, ICI), phentolamine mesylate (Regitine, Ciba), yohimbine (Sigma), prazosin (Pfizer), and phenylephrine (Sigma). All drugs were in aqueous solution except prazosin, which was dissolved in N,N-dimethyl formamide. Appropriate control injections of N,N-dimethyl formamide failed to produce a significant change at rest or during electrical stimulation in four of six animals, while in two there was a transient rise in corpus cavernosal pressure immediately after the injection. In order to test the effects of specific antagonists on the response to pelvic nerve stimulation, the drugs were usually injected into the systemic circulation. a-adrenergic antagonists, however, were injected directly into the corpus cavernosum via the pressure-monitoring catheter, so as to minimize effects on systemic arterial blood pressure and to ensure a high local concentration of the drug. Statistical analyses were by Student's t test, with a significance level of RESULTS The systolic and diastolic systemic arterial pressure ranged from 105 to 230 and 79 to 160 mmhg respectively in the absence of electrical stimulation. Penile artery pressure (p.a.p.) ranged from 75 to 160 mmhg, within % of mean systemic blood pressure. Fluctuations in systemic blood pressure, due to respiration for example, were reflected in p.a.p. Corpus cavernosum pressure (c.c.p.) ranged from 10 to 25 mmhg (10-15 % mean systemic arterial pressure) and did not show these fluctuations. Pelvic nerve stimulation Supramaximal stimulation of the right pelvic nerve (10-30 V, 10 Hz) produced an immediate drop in p.a.p. of mmhg, with a smaller drop in c.c.p. of 5-10 mmhg s after the onset of stimulation c.c.p. rapidly increased to reach % of mean systemic arterial pressure within 60 s (Fig. 1). Elevated c.c.p. was maintained for the duration of nerve stimulation and reflected fluctuations in p.a.p. Maximum c.c.p. was usually equal to p.a.p., which levelled off at mmhg below the pre-stimulation level, representing % of mean systemic arterial pressure. The c.c.p. was occasionally mmhg higher than p.a.p. during pelvic nerve stimulation. The bulbus glandis and pars longus glandis of the penis were swollen and the entire penis was turgid. The tip of the penis protruded from the prepuce in some animals. On stopping electrical stimulation, p.a.p. returned to pre-stimulation levels. There was often a parallel transient increase in c.c.p. which reached or slightly exceeded mean systemic arterial pressure (Fig. 1). The time taken for the c.c.p. to subside to pre-stimulation levels showed considerable variation. In some animals pressure

4 528 C. J. CARATI, K. E. CREED AND E. J. KEOGH decreased immediately upon cessation of stimulation and reached pre-stimulation levels within 40 s, whereas in others elevated c.c.p. was maintained for up to 6 min. In many animals the recovery was biphasic, with a slow initial phase followed by a rapid phase during which c.c.p. fell by % of maximum to pre-stimulation levels. Systemic 100 arterial I pressure 50 (mmhg) 1001 c.c.p. 50] (mmhg) J p.a.p (mmhg) J 50 Pelvic nerve stimulation 1 min Fig. 1. Changes in corpus cavernosum pressure (c.c.p.) and penile artery pressure (p.a.p.) during electrical stimulation of the pelvic nerve (10 Hz, 20 V, 1 ms for 2 min). The p.a.p. decreased by 30 mmhg immediately after onset of stimulation. The c.c.p. dropped by 5 mmhg, and then rose sharply 10 s later, to reach the same pressure as that in the penile artery. When pelvic nerve stimulation was stopped, p.a.p. immediately returned to pre-stimulation levels, followed by c.c.p. 1 min later. In order to compare responses from different aninials, the time course of changes in c.c.p. were analysed as follows. The onset time was measured as the interval from the beginning of stimulation to an increase in c.c.p. above pre-stimulation levels. The rise time was measured as the time elapsed from the point at which c.c.p. exceeded pre-stimulation levels to the point at which it reached 90 % of its maximum value. The recovery time was measured as the time from the end of pelvic nerve stimulation to the point at which c.c.p. had decreased to within 10 mmhg of its pre-stimulation levels. Increases in c.c.p. were obtained with frequencies of stimulation over 3 Hz. At the lower end of the frequency range (3-7 Hz) the c.c.p. took longer to rise and the rate of rise was slower than at higher frequencies (Figs. 2 and 3). At low frequencies c.c.p. sometimes failed to reach a stable plateau within a 2 min period of stimulation, and in these cases the recovery was more rapid than usual. Maximal responses for onset time and rise time were recorded at 8 Hz (Fig. 3). Increasing the frequency of stimulation resulted in a longer recovery time (Figs. 2 and 3), as did increasing the duration of stimulation. Atropine, given systemically at 1 mg kg-' body weight, had no effect on the response to pelvic nerve stimulation (n = 3). Frequency-response curves, over the range of 1-32 Hz, were not significantly different (P > 0 05) before and after atropine, except for recovery time at 32 Hz (Fig. 3). Changes in p.a.p. were also not affected

5 CONTROL OF PENILE ERECTION 529 by atropine. The effectiveness of the cholinergic blockade was confirmed by a diminished or absent vasodilator response to 100,ug acetylcholine injected into the carotid artery. The effects of x- and,-adrenergic antagonists were tested in preparations with sectioned sympathetic chains and hypogastric nerves. Phentolamine (200 jug kg-', given systemically, n = 3 or 3-5 mg given intracorporally, n = 1), prazosin ( ,tg intracorporally, n = 7), yohimbine ( ,ug intracorporally, n = 7) or propranolol ( jug kg-' systemically, n = 3) had no significant affect on the c.c.p. or p.a.p. and did not significantly modify the response to pelvic nerve stimulation. Systemic u-- pressure c.c.p. (mmhg) ] 0 p.a.p. (mmhg) j 100 Pelvic nerve Systemic pressure 100 c.c.p. (mmhg) J 0 p-a-p- (mmhg)o] pa. 100~ Pelvic nerve min Fig. 2. Changes in c.c.p. and p.a.p. evoked by graded pelvic nerve stimulation (2-32 Hz for 2 min). The threshold frequency was 2-4 Hz. Stimulation at frequencies greater than 8 Hz prolonged the recovery of c.c.p. after pelvic nerve stimulation was stopped. Hypogastric nerve stimulation Resting c.c.p. and p.a.p. were not modified by cutting the hypogastric nerves. Following section, the response to pelvic nerve stimulation was unchanged in two of eight animals, but the c.c.p. (% of systemic arterial pressure) was decreased by 4-22 % in six of the eight animals. The onset time was increased in four of eight animals, whereas rise time was increased in one animal but decreased in another. In two of the eight animals in these experiments the recovery time was less after section of the hypogastric nerves. The effects of electrical stimulation of peripheral ends of the hypogastric nerves ( Hz) were observed in eleven animals. To investigate the effect of hypogastric nerve activity on the response to pelvic nerve stimulation, both hypogastric nerves were stimulated, followed 1 min later by simultaneous stimulation of the right pelvic nerve at 10 Hz for 2 min. Hypogastric nerve stimulation was continued until the

6 530 C. J. CARATI, K. E. CREED AND E. J. KEOGH 100 Onset 6 time (o)60m Rise 60 time (%) * Recovery time (%) 60 { Frequency of pelvic nerve stimulation (Hz) Fig. 3. Effect of graded pelvic nerve stimulation on c.c.p. in the absence (@) and presence (0) of atropine (1 mg kg-' body weight). Onset time (interval from beginning of stimulation to increase in c.c.p.), rise time (time from increase in c.c.p. to 90% of its maximum value) and recovery time (time from end of stimulation to c.c.p. being within 10 mmhg of its pre-stimulation level) are expressed as the percentage of the maximum response obtained in each experiment in the absence of atropine. Data presented as mean + S.E. of mean for three dogs. Atropine had no significant effect on response to pelvic nerve stimulation, except for recovery time at 32 Hz. c.c.p. had fully recovered to pre-stimulation values. There was no effect on resting c.c.p. or p.a.p. in ten animals, either before or after section of the sympathetic chains (n = 8), or before or after administration of phentolamine ( ,g kg-', n = 2, Fig. 4A). In only one animal did stimulation of the hypogastric nerve at 3 and 10 Hz cause elevation of c.c.p. with a slight decrease in p.a.p. (Fig. 4B). Simultaneous hypogastric and pelvic nerve stimulation in this animal also caused a significantly prolonged recovery of c.c.p. These effects could not be blocked by atropine or propranolol (1 mg kg-'). The response to pelvic nerve stimulation was not modified by hypogastric nerve stimulation in nine of the remaining ten animals in these experiments. In one, hypogastric nerve stimulation significantly reduced the response of c.c.p. to pelvic nerve stimulation (Fig. 4C). In this animal, a 1 min

7 CONTROL OF PENILE ERECTION period of hypogastric nerve stimulation during pelvic nerve stimulation also caused the c.c.p. to drop to half its maximum value for the duration of the hypogastric nerve stimulation. These effects were abolished by systemic administration of phentolamine (200 jug kg-'). 531 c.c.p. 100 (mmhg) 0 p.a.p. (mmhg) 50 Hypogastric A c.c.p. 10 (mmhg) io C 0* B p.a.p. (mmhg) ] 50 Pelvic nerve Hypogastric 1 min Fig. 4. Variable effect of electrical stimulation of the hypogastric nerve. A, hypogastric nerve stimulation had no effect on c.c.p. at three frequencies (Hz). B, hypogastric nerve stimulation (10 Hz) caused an increase in c.c.p. C, hypogastric nerve stimulation (10 Hz) had no effect itself but inhibited the response to pelvic nerve stimulation (10 Hz). Sympathetic chain stimulation Cutting the sympathetic chain on both sides at level L5 produced little or no change in resting c.c.p. and p.a.p. Responses to pelvic nerve stimulation (10 Hz for 2 min) were compared before and after sympathectomy. There was no significant change (P > 0 05) in two of six animals, whereas in four the c.c.p. rose significantly earlier and in three of these the recovery was significantly prolonged. Stimulation of the peripheral end of the severed right sympathatic chain at frequencies over 1 Hz produced a simultaneous frequency-dependent increase in c.c.p. and p.a.p. of up to 20 mmhg, which was maintained for the duration of stimulation. To investigate the effect of sympathetic chain activity on the response to pelvic nerve stimulation, the right sympathetic chain was stimulated, followed 1 min later by simultaneous stimulation of the right pelvic nerve at 10 Hz for 2 min. Sympathetic chain stimulation was maintained until the c.c.p. had fully recovered to prestimulation levels. Pelvic nerve activity still produced an immediate drop in c.c.p. and p.a.p., but the subsequent increase in c.c.p. was delayed or absent (Fig. 5A). The drop in c.c.p. and p.a.p. was often more pronounced during this procedure than during pelvic nerve stimulation alone, because they dropped from the elevated basal levels caused by sympathetic chain stimulation. The p.a.p. was not otherwise affected by sympathetic chain stimulation (Fig. 5). The degree of inhibition of c.c.p. varied with the frequency of sympathetic stimulation (Figs. 5A and 6) and was greater in some dogs than in others. Sympathetic stimulation at 0'3-10 Hz significantly increased the

8 532 C. J. CARATI, K. E. CREED AND E. J. KEOGH Systemic 1504 pressure c.c.p. (mmhg) 100 p.a.p. (mmhg) 100]I Pelvic nerve Sympathetic 3 3 Systemic 1504 _ pressure c.c.p. (mmhg) 100] p.a.p. (mmhg) 100] - Pelvic nerve Sympathetic B #Prazosin c.c.p. (mmhg) 100 p.a.p. (mmhg) 100] Pelvic nerve Sympathetic rl m~in Fig. 5. Effect ofelectrical stimulation of the sympathetic chain on responses to pelvic nerve stimulation (10 Hz for 2 min). A, sympathetic stimulation at 3 Hz delayed the rise in c.c.p. and accelerated its recovery to basal levels, whereas stimulation at 10 Hz almost abolished the response. The inhibitory effect of sympathetic chain stimulation was blocked by intracavernosal injection of prazosin (200,ug). The response shown was obtained 4 min after injection of prazosin. B, sympathetic chain stimulation in another dog accelerated the return of c.c.p. to basal levels when applied during the recovery phase after pelvic nerve stimulation (10 Hz). onset time in most animals, and at 3 Hz abolished the response completely in five of eleven animals. The rise time was longer during sympathetic chain stimulation at 3-10 Hz. When the c.c.p. did rise, it still reached a plateau close to systemic blood pressure. On stopping pelvic nerve stimulation, while maintaining sympathetic stimulation at frequencies greater than 1 Hz, the recovery time was more rapid than without sympathetic stimulation (Figs. 5 and 6). The threshold for changes in onset time (0 3 Hz) was lower than for changes in recovery time (1 Hz) and rise time (3 Hz) (Fig. 5). The return of c.c.p. to pre-stimulation levels after pelvic nerve stimulation could be accelerated by sympathetic chain stimulation during the recovery phase (n = 3, Fig. 5B). The effects of sympathetic chain stimulation were mimicked by close arterial injection of phenylephrine ( jug into the dorsal artery, n = 4), but not 10

9 CONTROL OF PENILE ERECTION 533 Onset time (%) 300] Rise time (%) / Recovery time (%) Frequency of sympathetic chain stimulation (Hz) Fig. 6. Effect of graded sympathetic chain stimulation on changes in c.c.p. caused by pelvic nerve stimulation (10 Hz for 2 min). Responses are expressed as in Fig. 3. The effect of each sympathetic chain stimulation is expressed as percentage of the mean response to pelvic nerve stimulation alone (indicated by the dashed lines), for each dog. Data presented as mean + S.E. of mean for four dogs. Sympathetic chain stimulation inhibited the response to pelvic nerve stimulation. isoprenaline (10-200,g, n = 4). Injection of phenylephrine during pelvic nerve stimulation immediately reduced the c.c.p. to pre-stimulation levels in two of four dogs, and for the next min responses to pelvic nerve stimulation were diminished or absent in three of these animals (Fig. 7). On the other hand, the inhibitory action of sympathetic chain stimulation was partially reduced by intracavernosal injections of the a-adrenergic antagonist phentolamine (2-3-5 mg, n = 2). To identify which receptor subtypes were involved, prazosin (a1-adrenergic antagonist) or yohimbine (a2-adrenergic antagonist) was injected directly into the corpus cavernosum. The responses to pelvic nerve stimulation alone (10 Hz for 2 min) and during sympathetic chain stimulation (3 or 10 Hz) were compared before and after injection of the antagonist. Prazosin ( ,tg, n = 3) partially blocked the effects of sympathetic chain stimulation (Fig. 5A), but there was still a slight increase in onset time and a decrease in recovery time compared to the responses when the pelvic nerve was stimulated alone. Yohimbine (200 and 2000,ug) partially blocked sympathetic chain stimulation in two dogs but had little or no effect in three. In these

10 534 C. J. CARATI, K. E. CREED AND E. J. KEOGH Systemic pressure c.c.p. (mmhg) Wuu.umi-Su'i-UInI IUUb 1WPb 200 *oo 100^ p.a.p. (mmhg) 150 Pelvic nerve ] -l,~~~~~gilo he Systemic pressure c.c.p. (mmhg) \ min p.a.p. (mmhg) 1 / Pelvic nerve mml III III II II tilli ll III tit III its,,.iii! min joilliff III ligil Ill --I; jell IIIII loll III Fig. 7. Effect of close arterial injection of phenylephrine (PhE, 10,ug) on the response to pelvic nerve stimulation (10 Hz). PhE immediately reduced c.c.p. to pre-stimulation levels, despite continued stimulation. Responses were still reduced 25 min after injection. latter animals prazosin (200,ug) was effective. Yohhnbine enhanced the blockade produced by prazosin in one animal, but not in another. Systemic injections of the,8-adrenergic antagonist propranolol (83 and 118 jug kg-', n = 2) had no significant effect on sympathetic chain activity. DISCUSSION It has long been known that there is an increase in blood flow through the canine penis during erection (Eckhard, 1863; Dorr & Brody, 1967; Colleen et al. 1981). In the present experiments electrical stimulation of the pelvic nerve in the dog caused an immediate decrease in the pressure within the arterial tree close to the penis, indicating that there is a rapid vasodilation of at least some of the penile vessels. Lue et al. (1984) reported a similar drop in pudendal artery pressure and this was accompanied by an increase in blood flow through the vessel. The pressure in the corpus cavernosum, which is low in the flaccid state, initially became even lower on stimulation. The sinusoidal spaces in the corpus cavernosum were not freely open to the arterial supply at this time, because the pressure in the corpus cavernosum was considerably less than that in the penile artery. Andersson et al. (1984) also concluded that the blood bypassed the corpus cavernosum in the first 20 s of pelvic nerve stimulation, even though there was an increase in blood flow through the penis, presumably through the corpus spongiosum and glans.

11 CONTROL OF PENILE ERECTION 535 The initial drop in c.c.p. suggests that pelvic nerve stimulation produces relaxation of the erectile tissues. Similar observations were made by Lue et al. (1984) in dogs in which the normal arterial events had been circumvented by infusing saline directly into the corpus cavernosum, with the aorta occluded. The subsequent increase we observed in corporal pressure, however, must be due to the establishment of a low-resistance communication with the arterial system, since the pressure reached the same level as that in the penile artery and showed similar fluctuations. It is probable that in order to maintain this pressure the venous drainage from the corpora cavernosa during pelvic nerve stimulation is of high resistance. This is consistent with the conclusions of Lue et al. (1984) that there was active venous occlusion during pelvic nerve stimulation. The neurotransmitters responsible for erection remain enigmatic. The pressure changes induced by pelvic nerve stimulation were apparently not due to the activity of muscarinic receptors, since atropine failed to modify the response. Atropine did not inhibit erections induced by sacral root stimulation in baboons (Brindley & Craggs, 1976), nor erections in men exposed to erotic stimuli (Wagner & Brindley, 1980; Brindley, 1986). On the other hand, atropine partially inhibited changes in penile volume and blood flow induced by pelvic nerve stimulation in dogs (Dorr & Brody, 1967; Andersson et al. 1984) and rabbits (Sjostrand & Klinge, 1979). However, the changes measured in those studies included changes in the corpus spongiosum and glans. It may be that, whilst the low-pressure spongiosum system is partially controlled by cholinergic fibres, the corpus cavernosum is not. It also appears unlikely that increases in c.c.p. are caused by activity of adrenergic fibres, since blockade of a- and,8-adrenoceptors had no effect on responses to pelvic nerve stimulation. Furthermore, propranolol did not block increases in penile volume caused by pelvic nerve stimulation in rabbits (Sjostrand & Klinge, 1979) or erections in man (Brindley, 1986). In contrast, Domer, Wessler,<Brown & Charles (1978) used propranolol to abolish erections in cats caused by administration of fi-adrenergic agonists. However, it has been reported that the cat has erector fibres in the hypogastric nerves (Bessou & Laporte, 1960). In the present experiments in dogs, stimulation of sympathetic fibres, in either the hypogastric nerves or sympathetic chains, failed to induce erection. It is possible that,8-adrenoceptors are relevant for erection in the cat, but not in the dog or rabbit. Recently, it has been suggested that vasoactive intestinal peptide may be responsible, at least in part, for erection. It is released into venous blood during pelvic nerve stimulation in the dog (Andersson et al. 1984). However, injection of vasoactive intestinal peptide has produced equivocal results (Ottesen, Wagner, Virag & Fahrenkrug, 1984; Steers, McConnell & Benson, 1984; Adaikan, Kottegoda & Ratnam, 1986). Corpus cavernosum tissue from the dog was relaxed by muscarinic and,-adrenergic agonists with equal efficacy, whereas vasoactive intestinal peptide produced only weak contraction (Carati, Goldie, Warton, Henry & Keogh, 1985). Reports of the effect of the hypogastric nerves have been confusing. Langley & Anderson (1896) found that stimulation of the hypogastric nerves of rabbits, cats and dogs caused shrinkage of the penis, as did Semans & Langworthy (1938) in cats. However, Sjostrand & Klinge (1979) reported penile enlargement in rabbits. It has been suggested that both erectile and anti-erectile fibres are present in the hypogastric nerve of cats (Root & Bard, 1947; Bessou & Laporte, 1960) and dogs (Frangois-Franck,

12 536 C. J. CARATI, K. E. CREED AND E. J. KEOGH 1895; Bacq, 1935). Bessou & Laporte (1960) abolished the anti-erectile response with dihydroergotamine. Stimulation of the hypogastic nerve in baboons usually caused penile shrinkage, but the response becomes erectile after administration of phentolamine (Brindley, 1983). In the present experiments electrical stimulation of the hypogastric nerve failed to consistently modify c.c.p. or p.a.p. in the majority of animals. The two animals treated with phentolamine failed to show any erectile response. In the two cases where hypogastric nerve stimulation induced results, one was erectile (but not cholinergic or fl-adrenergic) and one inhibitory (a-adrenergic). Thus, it seems unlikely that the hypogastric nerve plays a significant or consistent part in erection in the dog. It is likely that there is some spontaneous sympathetic activity in the penis of the dog, since responses to pelvic nerve stimulation lasted longer in most animals after cutting the sympathetic chains. However, neither cutting the chains, nor administration of a-adrenergic blocking agents, altered the c.c.p. in the flaccid penis. In contrast, intracavernosal injections of phenoxybenzamine or phentolamine induced erections in men (Brindley, 1983) and section of the sympathetic chain in rabbits caused a transient protrusion and increase in penile volume (Sjostrand & Klinge, 1979). Stimulation of the sympathetic chain increased p.a.p., presumably due to arteriolar constriction, and a parallel increase in c.c.p., probably due to contraction of erectile tissue. It also inhibited the response of the corpus cavernosum to pelvic nerve stimulation, via a-adrenoceptors. This is consistent with the findings of Langley & Anderson (1895) and Sjostrand & Klinge (1979). These sympathetically mediated events would result from restriction of the arterial inflow (provided venous drainage could occur), an increase in venous drainage, or both. Contraction of the erectile tissue may also occur, since canine erectile tissue in vitro was contracted by cz-adrenergic agonists (Carati et al. 1985). This would not lower c.e.p., but may modify the flow of blood through the tissue, or forcibly expel blood from it. The effects of pelvic nerve stimulation during sympathetic chain stimulation suggest that a clear distinction can be made between the corpus cavernosum and other parts of the penis. Even when the rise in c.c.p. had been completely inhibited, a large drop in p.a.p. was still seen. These observations, and the changes observed during pelvic nerve stimulation, lead us to suggest that pelvic nerve stimulation produces erection in two stages in the dog. There is an immediate vasodilation, so that blood flows to the low-pressure spongiosum system and increases the volume of the penis, particularly the glans, as reported by Andersson et al. (1984), and Sjostrand & Klinge (1979). About 20 s later, blood also enters the corpus cavernosum, stiffening it as it approaches arterial pressure. Activity of the sympathetic fibres, acting through a-adrenoceptors, inhibits only the latter stage. We would like to thank Mr P. Burrows and Mrs V. Wakelam for expert assistance with the animals. This experimental work was conducted with the facilities of the Department of Surgery, University of Western Australia. It was supported by the Impotence Study Group of Western Australia and the National Health and Medical Research Council of Australia.

13 CONTROL OF PENILE ERECTION 537 REFERENCES ADAIKAN, P. G., KOTTEGODA, S. R. & RATNAM, S. S. (1986). Is vasoactive intestinal polypeptide the principal neurotransmitter involved in human penile erection? Journal of Urology 135, ANDERSSON, P-O., BLOOM, S. R. & MELLANDER, S. (1984). Haemodynamics of pelvic nerve induced penile erection in the dog: possible mediation by vasoactive intestinal polypeptide. Journal of Physiology 350, BACQ, Z. M. (1935). Recherches sur la physiologie et la pharmacologie du systeme nerveux autonome. XII. Nature cholinergique et adrenergique des diverses innervations vasomotrices du penis chez le chien. Achives internales de physiologie 40, BECKETT, S. D., REYNOLDS, T. M. & BARTELS, J. E. (1978). Angiography of the crus penis in the ram and buck during erection. American Journal of Veterinary Research 39, BESSOU, P. & LAPORTE, Y. (1960). Fibres vasodilatatrices cholinergiques innervant le penis, contenues dans les nerfs hypogastriques, chez le chat. Comptes Rendus des seances de la Societe de biologie (Paris) 155, BRINDLEY, G. S. (1983). Physiology of erection and management of paraplegic infertility. In Male Infertility, ed. HARGREAVE, T. B., pp Berlin: Springer-Verlag. BRINDLEY, G. S. (1986). Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis. British Journal of Pharmacology 87, BRINDLEY, G. S. & CRAGGS, M. D. (1976). The effect of atropine on the urinary bladder of the baboon and man. Journal of Physiology 256, 55P. CARATI, C. J., GOLDIE, R. G., WARTON, A., HENRY, P. J. & KEOGH, E. J. (1985). Pharmacology of the erectile tissue of the canine penis. Pharmacological Research Communications 17, CHRISTENSEN, G. C. (1954). Angioarchitecture of the canine penis and the process of erection. American Journal of Anatomy 95, COLLEEN, S., HoLMQuIST, B. & OLIN, T. (1981). An angiographic study of erection in the dog. Urological Research 9, DOMER, F. R., WESSLER, G., BROWN, R. L. & CHARLES, H. C. (1978). Involvement of the sympathetic nervous system in the urinary bladder internal sphincter and in penile erection in the anesthetized cat. Investigative Urology 15, DORR, L. D. & BRODY, M. J. (1967). Hemodynamic mechanisms of erection in the canine penis. American Journal of Physiology 213, ECKHARD, C. (1863). Untersuchungen fiber die Erection des Penis beim Hunde. In Beitrdge ziir Anatomie und Physiologie von C. Eckhard. III. Band. Giessen. Cited in SJOSTRAND, N. 0. & KLINGE, E. (1979). Acta physiologica scandinavica 106, FRANVOIS-FRANCK, M. (1895). Recherches sur l'innervation vao-motrice du penis. Archives de physiologie normale et pathologique 7, LANGLEY, J. N. & ANDERSON, H. K. (1895). The innervation of the pelvic and adjoining viscera. Part III. The external generative organs. Journal of Physiology 19, LANGLEY, J. N. & ANDERSON, H. K. (1896). The innervation of the pelvic and adjoining viscera. Part VII. Anatomical observations. Journal of Physiology 20, LUE, T. F., TAKAMURA, T., SCHMIDT, R. A., PALUBINSKAS, A. J. & TANAGHO, E. A. (1983). Hemodynamics of erection in the monkey. Journal of Urology 130, LUE, T. F., TAKAMURA, T., UMRAIYA, M., SCHMIDT, R. A. & TANAGHO, E. A. (1984). Hemodynamics of canine corpora cavernosa during erection. Urology 24, OTTESEN, B., WAGNER, G., VIRAG, R. & FAHRENKRUG, J. (1984). Penile erection: possible role for vasoactive intestinal polypeptide as a neurotransmitter. British Medical Journal 288, RoOT, W. S. & BARD, P. (1947). The mediation of feline erection through sympathetic pathways with some remarks on sexual behavior after deafferentation of the genitalia. American Journal of Physiology 151, PUROHIT, R. C. & BECKETT, S. D. (1979). Penile pressures and muscle activity associated with erection and ejaculation in the dog. American Journal of Physiology 231, SEMANS, J. H. & LANGWORTHY, 0. R. (1938). Observations on the neurophysiology of sexual function in the male cat. Journal of Urology 40, SJ6STRAND, N. 0. & KLINGE, E. (1979). Principal mechanisms controlling penile retraction and protrusion in rabbits. Acta physiologica scandinavica 106,

14 538 C. J. CARATI, K. E. CREED AND E. J. KEOGH STEERS, W. D., MCCONNELL, J. & BENSON, G. S. (1984). Anatomical localization and some pharmacological effects of vasoactive intestinal polypeptide in human and monkey corpus cavernosum. Journal of Urology 132, WAGNER, G. & BRINDLEY, G. S. (1980). Effect of atropine and a- and fl-blockers on human penile erection. In Vasculogenic Impotence, ed. ZORGNIOTTI, A. & Rossi, G., pp Springfield: Thomas.