Novel vascular effects of Isoprenaline following pacing-induced heart failure in the dog

Isoprenaline produced concentration-dependent contractions of the in vitro canine saphenous vein which were attenuated by phentolamine (10(-6) M) and pacing-induced heart failure. Both at control and peak heart failure, a biphasic response was seen in the dorsal pedal artery, consisting of an initial relaxation followed by a contraction; phentolamine and heart failure enhanced the relaxation component. In the presence of propranolol, the isoprenaline-induced contraction was sensitive to yohimbine, but resistant to prazosin. Therefore it is concluded that isoprenaline interacts not only with vascular beta-adrenoceptors, but also with alpha 2-adrenoceptors. Endothelial denudation resulted in a diminished response to isoprenaline in control saphenous vein and dorsal pedal artery but not in vessels from dogs with heart failure. The observation that the contractile response to isoprenaline diminishes in heart failure implies a specific down-regulation of peripheral vascular alpha 2-adrenoceptors.     

The effects of prazosin, phentolamine and phenoxybenzamine on inhibitory alpha-adrenoceptors in the guniea-pig isolated ileum.

1 The relaxant effect of noradrenaline on strips of guinea-pig isolated terminal ileum was blocked by pretreatment with prazosin, phentolamine, yohimbine and phenoxybenzamine. 2 The presence of a very high concentration of noradrenaline (50 micrometers) during exposure to the blocking agent protected against the blocking effect of the drugs. 3 Yohimbine, prazosin and phentolamine partially protected against irreversible blockade by phenoxybenzamine. 4 Spontaneous release of acetylcholine in the unstimulated ileum was blocked by noradrenaline (0.05-5.9 micrometers) this effect of noradrenaline was antagonized by phentolamine (0.13-26 micrometers) and yohimbine (0.051-0.51 micrometers) but not prazosin (0.53-5.3 micrometers) or phenoxybenzamine (4.2-42 nm). All four antagonists reversed the noradrenaline-induced relaxation of the ileum. 5 Acetylcholine output in the transmurally stimulated ileum was inhibited by noradrenaline. This effect of noradrenaline was antagonized by phentolamine and yohimbine but not by prazosin or phenoxybenzamine. The first two antagonists blocked the noradrenaline-induced inhibition of evoked twitches of the ileum while the last two had no effect. 6 The results show (a) that prazosin has no effect on presynaptic alpha-adrenoceptor located on cholinergic nerve endings in the guinea-pig ileum and (b) that prazosin, phentolamine and phenoxybenzamine act on the same subgroup of postsynaptic alpha-adrenoceptors on the smooth muscle of the guniea-pig ileum.     

The effects of uptake1 on alpha-adrenoceptor antagonist potency in dog saphenous vein.

1 The effects of alpha-adrenoceptor antagonists on contractile responses to noradrenaline and methoxamine were examined in isolated saphenous vein strips of the dog. 2 Phentolamine, labetalol and thymoxamine antagonized responses to methoxamine to a greater extent than responses to noradrenaline. 3 Cocaine (3.0 x 10(-5) mol/l) increased the potency of noradrenaline by about eight fold, but had little or no effect on the potency of methoxamine. 4 In the presence of cocaine (3.0 x 10(-5) mol/l) the potency of the antagonists against noradrenaline was increased such that the pA2 values were then similar to those obtained against methoxamine. 5 It is concluded that the lower potency of phentolamine, labetalol and thymoxamine as antagonists of noradrenaline than of methoxamine is due to the presence of an avid saturable uptake1 process in the saphenous vein.     

Vasoactive responses of a human cystic artery: adrenoceptor characterization.

1. The pharmacology of various agonists and antagonists was studied in the human isolated cystic artery. 2. The estimated pA2s for the alpha 1-adrenoceptor antagonist prazosin against the alpha-adrenoceptor agonists phenylephrine, alpha-methylnoradrenaline and noradrenaline were not significantly different. Similar results were seen for estimated pA2s of the alpha 2-adrenoceptor antagonist yohimbine against these same agonists. Equivalent responses to exogenous noradrenaline and to transmural electrical stimulation were blocked to the same degree by an antagonist with alpha 1-adrenoceptor blocking properties (prazosin). Responses to transmural electrical stimulation, however, tended to be more resistant than equivalent responses to exogenous noradrenaline to blockade by antagonists with alpha 2-adrenoceptor blocking properties (phentolamine, yohimbine). 3. Relaxation to isoprenaline was observed in partially contracted arterial strips using isoprenaline concentrations of up to 10(-6) M, but cumulative addition of higher concentrations of isoprenaline sometimes then evoked a contraction from the relaxation nadir. The relaxation effect of isoprenaline was antagonized by propranolol (10(-5) M). 4. These findings suggest the human cystic artery has almost exclusively alpha 1-adrenoceptors postjunctionally, although prejunctional alpha 2-adrenoceptors may be present; and, it also has some postjunctional beta-adrenoceptors which mediate relaxation.     

In vitro evidence for dopaminergic receptors in human renal artery

Effects of dopamine on human renal arteries were pharmacologically investigated in vitro. Norepinephrine (5 X 10(-10)-5 X 10(-5) M) produced concentration-dependent contractions of isolated renal arterial strips, which were significantly depressed by prior administration of phentolamine or phenoxybenzamine. Isoproterenol (4 X 10(-10)-4 X 10(-6) M) concentration dependently relaxed the strips under potassium contracture, but a high dose (4 X 10(-5) M) constricted them. Biphasic responses to isoproterenol were changed to concentration-dependent contractions by prior administration of propranolol, and abolished by propranolol together with phentolamine. Dopamine (5 X 10(-8)-5 X 10(-4) M) produced concentration-dependent contractions of human renal arteries, which were not significantly influenced by propranolol but which were reversed to relaxations by phentolamine. Dopamine-induced relaxations, which were obtained after administration of phentolamine, were not significantly affected by propranolol, but were significantly depressed by combined application of propranolol and haloperidol, or of propranolol and droperidol. Results suggest that isolated human renal arteries have dopaminergic receptors in their smooth muscles which show relaxations of renal arteries after alpha-adrenoceptor blockade.     

Effects of oxyfedrine on isolated portal vein and other smooth muscles

1. Oxyfedrine (0.01-1.0 mug/ml), inhibited spontaneous myogenic activity in rat isolated portal vein and carbachol-induced contractions of rat isolated uterus, and relaxed the rabbit duodenum and the guinea-pig tracheal chain preparation. These actions were prevented by the beta-adrenoceptor blocking drug alprenolol. Oxyfedrine was a relatively weak beta-adrenoceptor stimulant (10-100 times less active than isoprenaline) but its actions were more prolonged.2. In the same concentrations, oxyfedrine reduced or prevented the inhibition of myogenic activity of the rat portal vein induced by isoprenaline and by repeated doses of oxyfedrine itself, acting as a partial agonist at beta-adrenoceptor sites.3. Oxyfedrine, 1-12 mug/ml increased myogenic activity in the rat portal vein. This effect was not due to direct or indirect stimulation of alpha-adrenoceptors (because it was unaffected by phentolamine) or to potentiation of acetylcholine or 5-hydroxytryptamine.4. Oxyfedrine (>20 mug/ml) inhibited spontaneous myogenic activity in the portal vein and relaxed the saphenous vein contracted with noradrenaline. This spasmolytic effect of the drug was not due to beta-adrenoceptor stimulation or to inhibition of phosphodiesterase since it was unaffected by alprenolol and by concentrations of imidazole which antagonized the effects of the active phosphodiesterase inhibitor, papaverine. In the portal vein this effect of oxyfedrine was similar to that of the calcium inhibitor iproveratril; some of the effects of oxyfedrine on venous smooth muscle may be mediated through effects on calcium transport.     

Effects of alpha blockers on blood pressure and on the Ca-contracture of cat aortic strips

To further clarify the hypotensive mechanism of adrenergic alpha blockers, effects of several alpha blockers on systemic blood pressure and on Ca-contracture of isolated, cat aortic strips were studied. For this purpose, the effects of known adrenergic alpha blockers, phentolamine, phenoxybenzamine, and a newly synthesized adrenergic alpha blocker (2-(N-(n-Butyloyl)homopiperazine-N'-yl)-4-amino-6,7-dimethoxy quinazoline; E-643) were compared with those of nitroglycerin and verapamil. Systemic blood pressure was decreased by administration (2 x 10(-8) moles/kg i.v.) of all drugs except phenoxybenzamine. The order of maximal fall of diastolic blood pressure after the injection was; nitroglycerin greater than E-643 greater than phentolamine greater than verapamil greater than phenoxybenzamine. Although "adrenaline reversal" was observed after 2 x 10(-7) moles/kg of phenoxybenzamine, i.e. a 10-fold increase in the dose of phenoxybenzamine, there was no decrease in systemic blood pressure with this dose. All these drugs in a concentration of 2 x 10(-6) M inhibited the Ca-contracture (phasic and tonic) of the depolarized aortic strips. The order of inhibition of phasic and tonic contracture was: nitroglycerin greater than E-643, verapamil greater than phentolamine greater than phenoxybenzamine. The pA2 values for phentolamine and E-643 in antagonizing contractions produced by noradrenaline of cat aortic strips were 7.8 and 8.2, respectively. Hypotensive effects of these drugs (except phenoxybenzamine), parallel the inhibitory effects on the Ca-contracture of the aortic strips. These results suggest that alpha blockers such as phentolamine and E-643 exert a systemic hypotensive effect not through their alpha blocking action but by an inhibitory action on the contractile Ca-mechanism.     

alpha-Adrenoceptor blocking properties of a new antihypertensive agent, 2-[4-(n-butyryl)-homopiperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (E-643)

Postsynaptic alpha-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxybenzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo alpha-adrenoreceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The alpha-blocking effect of E-643 was reversible. E-643 protected alpha-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the alpha-adrenoceptors.     

Alpha 2-adrenoceptor blockade prevents cardiac glycoside-evoked neurotransmitter release from sympathetic nerves in dog saphenous vein.

1 The effect of alpha-adrenoceptor antagonists upon neurotransmitter release evoked by cardiac glycosides from sympathetic nerve terminals has been investigated in dog saphenous vein. 2 In rings of saphenous vein preloaded with [3H]-noradrenaline, acetylstrophanthidin (ACS) caused a concentration-dependent efflux of 3H (EC50 ca. 4.4 microM) that was attenuated by phentolamine and yohimbine but not by prazosin. 3 In helical strips of saphenous vein superfused with ACS at EC50 the efflux of 3H-compounds in general, and of [3H]-noradrenaline in particular, occurred after a short delay and increased with time to a maximum reached at 75 min. Phentolamine and phenoxybenzamine, but not prazosin reduced the efflux of [3H]-noradrenaline and of total 3H-compounds throughout the time-course of the ACS-evoked effect. 4 In helical strips of saphenous vein the glycoside ouabain also caused an increase in [3H]-noradrenaline and in total 3H-efflux that was attenuated by phentolamine. 5 By contrast with the above, in bovine adrenal medullary chromaffin cells, which appear to have no functional alpha-adrenoceptors, ACS caused a small, but significant increase in 3H-efflux which was not prevented by phentolamine. 6 Phentolamine, at concentrations that attenuate markedly the ouabain- or ACS-evoked increase in 3H-efflux from dog saphenous vein, did not cause significant inhibition of cocaine-sensitive [3H]-noradrenaline uptake nor did it reduce the extent of the 3H-efflux evoked either by tyramine or by reduced extracellular Na+.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of rabbit portal vein to histamine.

1 Histamine produced a dose-dependent contraction of the isolated portal vein of the rabbit. This contraction was not antagonized by atropine, methysergide, indomethacin, cocaine or 6-hydroxy-dopamine, nor by pretreatment of the rabbit with reserpine. 2 The response to histamine was blocked by H1-receptor antagonists only when the blocking agent was used in very high concentrations, and was not antagonized by the H2-receptor blocking agent, metiamide, H1-receptor antagonists did not block the effects of 5-hydroxytryptamine. 3 The contractions elicited by histamine, 5-hydroxytryptamine and noradrenaline were blocked by phentolamine. 4 Desensitization to high doses of 5-hydroxytryptamine caused a concomitant depression in the response to histamine but not to noradrenaline or acetylcholine. 5 The results suggest that the contractions of rabbit portal vein elicited by histamine are not mediated by receptors of the H1- or the H2-type, but may involve an action of histamine at a receptor which is also involved in the action of 5-hydroxytryptamine.     

The effects of alpha- and beta-adrenoceptor activation on tension and membrane properties of the longitudinal smooth muscle of the chicken rectum.

1. Isolated longitudinal muscle strips from the chicken rectum responded to isoprenaline, adrenaline and noradrenaline with a prolonged relaxation. The concentrations required to produce 50% of the maximum relaxation were 1.3 x 10(-8) M for isoprenaline, 1.7 x 10(-8) M for adrenaline and 10(-6) M for noradrenaline. The relaxing potency of isoprenaline is about equal to that of adrenaline, but more than 50 times that of noradrenaline. 2. Propranolol, 3.4 x 10(-6) M, blocked the isoprenaline-induced relaxation, and in the presence of this drug the responses to adrenaline and noradrenaline were converted into small, transient relaxations. The residual relaxation was blocked by phentolamine, 2.6 x 10(-6) M. 3. These catecholamines suppressed spontaneous spike discharge and produced membrane hyperpolarization. Propranolol, 3.4 x 10(-6) M, prevented the inhibitory effects of isoprenaline, and reduced but did not completely abolish those of adrenaline and noradrenaline. 4. Adrenaline and noradrenaline, but not isoprenaline, reduced membrane resistance in some preparations. 5. In the rectal muscle of the chicken, the beta-adrenoceptor mediates a prolonged relaxation and the alpha-adrenoceptor a fast and short-lasting relaxation which is usually obscured by the beta-response and unmasked only after blockade of the beta-adrenoceptors. The alpha- and beta-mediated relaxations are each associated with the suppression of spontaneous spike activity.     

Action of beta-adrenoceptor antagonists on the response to isoprenaline in the oestrogen dominated rabbit uterus.

1. Log dose-response curves to isoprenaline from spontaneously contracting muscle strips from rabbit uterus have been obtained. The effects of the alpha-adrenoceptor antagonists phentolamine and phenoxybenzamine, the beta- adrenoceptor antagonists propranolol and practolol, and (+)-propranolol on the log dose-response curves were studied. 2. Phentolamine 5.3 times 10- minus 7 M had a stimulating effect on the muscle strips, moving the log dose-response curve of isoprenaline to the right. Phenoxybenzamine 2.9 times 10- minus 5 M had no effect on the curves. 3. Propranolol 3.4 times 10- minus 6 M had no effect on the curves from circular muscle strips, with either phentolamine 5.4 times 10- minus 7 M or with phenoxybenzamine 2.9 times 10- minus 5 M as alpha-blocker. The curves from the longitudinal muscle strips were shifted somewhat to the right, the same shift, however, being obtained with (+)-propranolol 3.4 times 10- minus 6 M. 4. Practolol 3.8 times 10- minus 6, 3.8 times 10- minus 5 and 3.8 times 10- minus 4 M was without effect on the curves, either in the circular or in the longitudinal strips. 5. It is concluded that neither propranolol at 3.4 times 10- minus 6 M nor practolol act as beta-adrenoceptor antagonists in oestrogen dominated rabbit uterus. In all other tissues investigated, propranolol or practolol block the effect of isoprenaline. Whether the effect of isoprenaline in this tissue may be termed a beta-effect, is then a question of definition. In addition there is no evidence for any extraneuronal uptake mechanisms for isoprenaline. 6. Variations in sensitivity to beta-stimulation with the time of the year were observed, the sensitivity being greatest in the winter and lowest in the summer.     

An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.     

Effects of some adrenergic and cholinergic drugs on isolated spleen strips from the COD, Gadus morhua

The effects of drugs on isolated spleen strips from the cod, Gadus morhua, have been investigated. Affinities and intrinsic activities for various agonists were determined from cumulative dose-respinse curves. Contractions were produced by acetylcholine, methacholine or carbachol. The response to acetylcholine was considerably potentiated by the acetylcholinesterase inhibitor BW 284 C51. Methacholine-induced responses were competitively blocked by atropine (pA₂ = 8.2), indicating the presence of muscarinic receptors. Nicotine did not contract the spleen strips. Adrenaline, noradrenaline or phenylephrine contracted the preparations and so did isoprenaline in high concentrations. Competitive blockade of the noradrenaline-induced contraction was obtained with yohimbine (pA₂ = 6.1), phentolamine (pA₂ = 6.0) and propranolol (pA₂ = 3.4), and non-competitive blockade with phenoxybenzamine (pM₅₀ = 7.0), indicating that α-adrenoceptprs mediate the contractions produced by the adrenergic agonists. Isoprenaline caused a slight relaxation of preparations precontracted with methacholine. This effect was abolished by propranolol suggesting the presence of β-adrenoceptors. Judged from the pA-values for the competitive antagonists, arterial and capsular/trabecular smooth muscles have slightly different α-adrenoceptor properties.     

ADRENORECEPTORS IN THE HUMAN PENIS

• 1 Adrenaline, noradrenaline and phenylephrine caused contraction of the corpus cavernosum muscle of the human penis. These sympathomimetic amines did not produce inhibitory effects even in the presence of the α-adrenoreceptor blocker, phentolamine. The effect of dopamine was similar to that produced by these three sympathomimetic amines. Higher doses of isoprenaline and salbutamol also contracted this preparation.
• 2 Cocaine and guanethidine enhanced the motor response to adrenaline, noradrenaline and phenylephrine while the action of dopamine was blocked by these two drugs.
• 3 The motor response to adrenaline, noradrenaline and phenylephrine was antagonized by phentolamine and often potentiated by the β-adrenoreceptor blocking drug, propranolol. The contractions produced by high doses of salbutamol and isoprenaline were also abolished by phentolamine. These findings indicate that the motor response to sympathomimetic amines is the result of activation of α-adrenoreceptors in the corpus cavernosum muscle.
• 4 At low doses, isoprenaline and salbutamol relaxed the corpus cavernosum muscle strip. The inhibitory action was blocked by low concentrations of the β-adrenoreceptor antagonist, propranolol but not by practolol (β₁-adrenoreceptor antagonist) and butoxamine (β₂-adrenoreceptor antagonist). β-adrenorecepcors are present in the corpus cavernosum muscle but these are unlikely to be either of the β₁ or β₂ type. The possible existence of a third type of β-adrenoreceptor is suggested.

     

The nature of the adrenergic receptors of the trachea of the guinea-pig

The adrenergic receptors of the guinea-pig isolated trachea have been characterised as β-receptors by established criteria. No evidence was obtained that any α-receptors are present. (-)-Isoprenaline was 17 times more potent than (-)-adrenaline which was 10 times more potent than (-)-noradrenaline. High concentrations of piperoxan, thymoxamine and dihydrogenated ergot alkaloids did not antagonise the catecholamines, while phentolamine and phenoxybenzamine potentiated them, isoprenaline almost as much as noradrenaline. Propranolol, pronethalol and the 3, 4-dichloro-analogues of (+)-noradrenaline, adrenaline and isoprenaline each specifically antagonised the catecholamines, isoprenaline moreso than noradrenaline. The characteristics of this blockade by pronethalol and propranolol fulfilled established criteria for competitive antagonism; propranolol (pA₂ against noradrenaline 6·56 + 0·21) was 18·6 (11·4 to 30·5) times more potent than pronethalol, (pA₂ against noradrenaline 5·29 + 0·07).     

The activities of alpha- and beta-adrenoceptive blocking agents in reducing intestinal relaxation due to sympathetic stimulation in the pithed rat

A pithed rat preparation, stimulated electrically via the pithing rod left in position, was employed to examine the effects of drugs, administered intravenously, on relaxation of a loop of ileum. Relaxation due to injected isoprenaline could be largely blocked by propranolol but that due to nervous stimulation or injected noradrenaline was blocked to only a lesser extent by either propranolol or phenoxybenzamine alone. The combination of phenoxy-benzamine and propranolol was more effective against relaxation from nervous stimulation than either drug alone but was still not as effective against this as against noradrenaline, or as propranolol alone against isoprenaline. It is concluded that intestinal relaxation after nervous stimulation involves both α- and β-adrenergic activity, in variable proportions. Adrenoceptive antagonists are not as effective in blocking these receptors as they are for those concerned in relaxation after injected catecholamines.     

Inactivation of released norepinephrine in rat tail artery by neuronal uptake

The relationship between adrenergic nerve activity and neuronal uptake was investigated. Helically cut strips of rat tail artery were mounted in organ chambers and isometric contractions were recorded. Spontaneous contractions were occasionally observed and these contractions were blocked by phentolamine. Cumulative addition of cocaine produced contractions of the strips. These contractions were blocked by phentolamine and reduced after denervation with 6-hydroxydopamine. Cocaine potentiated the contractile responses to exogenous norepinephrine and caused a shift to the left in the concentration--response curve. Contractions in response to low-frequency field stimulation were potentiated by cocaine; contractions produced by high frequencies were not altered by the drug. Cocaine had no effect on contractions produced by depolarization of the prejunctional membrane with high potassium. The relative rates of relaxation following high- and low-frequency stimulation were increased similarly by cocaine. The results indicate (1) the spontaneous activity of rat tail artery is related to the leakage of norepinephrine from nerve endings; (2) contraction in response to cocaine alone probably results from inhibition of neuronal uptake and the release of endogenous norepinephrine; and (3) the amine uptake mechanism is not operative during depolarization of prejunctional membrane.     

Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis.

Seven drugs that are known to relax smooth muscle (phenoxybenzamine, phentolamine, thymoxamine, imipramine, verapamil, papaverine, naftidrofuryl) caused erection when injected intracavernosally. Salbutamol, hydralazine, lignocaine and bupivacaine caused tumidity but not erection. Metaraminol and guanethidine caused shrinkage followed by tumidity. Neostigmine, atropine, propranolol and idazoxan had no effect in the doses tried. It is argued that the seven drugs that cause erection do so by relaxing vascular and trabecular smooth muscle within the cavernosal space, and that the two that cause shrinkage of the penis do so by constricting vascular and trabecular smooth muscle within the cavernosal space. It is argued that muscarinic and beta-adrenergic transmission play no important part in erectile mechanisms within the corpora cavernosa. Papaverine, phenoxybenzamine and metaraminol, given intracavernosally, are already used therapeutically. Uses are suggested for thymoxamine, phentolamine, verapamil and guanethidine.     

Receptor-responses in fresh human ciliary muscle.

The physiological and pharmacological properties of ciliary muscle isolated from fresh human eyes were investigated. The muscle exhibited no spontaneous activity. Concentration-dependent contractions in response to carbachol were competitively antagonized by atropine (pA2 = 8.95). The muscle, precontracted by carbachol (2.7 X 10(-4)M), responded to the application of isoprenaline by concentration-dependent relaxation blocked by propranolol (3.5 X 10(-9)M to 3.5 X 10(-8)M; pA2 = 9.15). Angiotensin-evoked contractions were antagonized by 8-Ala-angiotensin II (4.5 X 10(-8)M) in a competitive manner, but were not inhibited by phentolamine or propranolol. Contractions generated by electrical stimulation of the muscle (30 ms, 20 Hz, 60 pulses) were antagonized by atropine (10(-7) M) and tetrodotoxin (6.3 X 10(-7) M). Phentolamine and propranolol did not influence these responses. An increase of the external potassium concentration ([K+]o) from 5.4 to 158.8 mM produced a mechanical response, antagonized by atropine, but not influenced by tetrodotoxin, phentolamine or propranolol. The human ciliary muscle appears to carry muscarinic and angiotensin receptors and beta 2-adrenoceptors. The estimate of Katropine for muscarinic receptors mediating carbachol-induced contractions agrees with estimates of Katropine reported for human and rabbit iris.