Comparison of the responses of the simian and canine coronary circulations to autonomic drugs

We studied Japanese monkeys, an anubis baboon, and dogs to determine possible differences in the responsiveness of the simian and the canine coronary vasculature to autonomic drugs. Under ketamine and pentobarbital anesthesia the left anterior descending coronary artery was perfused with autologous blood at constant pressure. All drugs were injected intraarterially. In monkeys, acetylcholine and methacholine produced vasoconstriction followed by vasodilatation, and vasoconstriction was marked after large doses. Both responses were antagonized by atropine. In dogs, the two muscarinic receptor agonists produced only vasodilatation. In the baboon, acetylcholine injected into the femoral artery produced only vasodilatation. These results indicate that vasoconstriction mediated by muscarinic receptors is characteristic of the simian coronary vasculature. In monkeys, norepinephrine produced vasoconstriction followed by vasodilatation. The former response was abolished and the latter enhanced by phentolamine. In dogs, norepinephrine produced only vasodilatation. This response was reduced and preceded by vasoconstriction after atenolol. Methoxamine produced only vasoconstriction, which was weaker in dogs than in monkeys. These results indicate that alpha-adrenoceptors in the coronary vasculature are more important in subhuman primates than in dogs.     

Antagonist properties of phentolamine at both presynaptic alpha 2-adrenoceptors and presynaptic dopamine receptors using field stimulated right cat atria

Phentolamine, which is considered a specific alpha-adrenoceptor antagonist, was tested for antagonist properties at presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors present on sympathetic nerve terminals in isolated right cat atria. Field stimulation induced a transient tachycardia which was inhibited by stimulation of presynaptic dopamine receptors using apomorphine or by stimulation of presynaptic alpha 2-adrenoceptors using clonidine. The presynaptic inhibitory effects of apomorphine were competitively antagonized by sulpiride, which is considered a specific dopamine receptor antagonist, and by phentolamine and yohimbine which are considered alpha-adrenoceptor antagonists. The presynaptic inhibitory effects of clonidine were competitively antagonized by phentolamine and yohimbine but not by sulpiride. pA2 values for phentolamine against apomorphine and phentolamine against clonidine suggest that phentolamine may be an antagonist at both presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors.     

The effects of dopexamine on the cardiovascular system of the dog.

The cardiovascular effects of dopexamine and dopamine were compared in the anaesthetized and conscious dog by the use of intravenous infusions over the dose range 3 X 10(-9) - 10(-7)mol kg-1 min-1. In the anaesthetized dog, dopexamine produced a dose-related fall in blood pressure due to peripheral vasodilatation and a small rise in heart rate and contractility. By contrast, dopamine did not significantly reduce blood pressure but produced a larger dose-related increase in contractility. At the highest infusion rate (10(-7)mol kg-1 min-1) blood pressure and heart rate were increased by dopamine. Dopexamine dilated the renal and mesenteric vascular beds with a potency similar to that of dopamine. Femoral vascular responses produced by both agents were inconsistent but the highest infusion rate of dopamine did produce vasoconstriction. With the aid of selective receptor antagonists (haloperidol, propranolol and bulbocapnine) the vasodepressor activity of dopexamine was shown to be mediated by stimulation of DA2-, beta- and DA1-receptors. The cardiac stimulation and renal vasodilatation produced by both compounds were due to stimulation of beta-adrenoceptors and DA1-receptors respectively. In the conscious dog, intravenous infusion of dopexamine caused a dose-related fall in blood pressure, renal vasodilatation and an increase in cardiac contractility and heart rate. Dopamine also increased cardiac contractility, and renal blood flow due to renal vasodilatation but without affecting heart rate. At the highest infusion rate, blood pressure was increased. Dopexamine and dopamine produced a similar incidence of panting and repetitive licking at 3 X 10(-8)mol kg-1 min-1 and emesis at 10(-7)mol kg-1 min-1, due to stimulation of dopamine receptors in the chemoreceptor trigger zone. Dopexamine produces a different cardiovascular profile from dopamine in the anaesthetized and conscious dog. Both compounds reduce renal vascular resistance, but in contrast to dopamine, dopexamine reduces afterload and produces only mild inotropic stimulation. These differences reflect contrasting activity at adrenoceptors.     

Localization of vasodilator dopamine receptors in the canine hindlimb.

1 Vascular responses to local injection of dopamine and isoprenaline have been compared in the blood-perfused gracilis muscle and hind paw pads of dogs anaesthetized with chloralose. 2 In the paw pads, dopamine (0.5 to 5.0 microgram) caused a transient vasoconstriction followed by dose-dependent vasodilatation. alpha-Adrenoceptor blockade converted this response to pure vasodilatation, which was attenuated or abolished by the dopamine-receptor antagonist, haloperidol (1 to 2 mg i.a.). In the gracilis, dopamine produced only vasoconstriction. Following alpha-adrenoceptor blockade this was abolished, but only a very small dilator response was revealed. 3 Isoprenaline (0.05 to 0.5 microgram) caused dose-dependent dilatation in both beds, which was attenuated by propranolol (0.1 mg/kg i.v.). 4 Glyceryl trinitrate (0.2 to 5.0 microgram) was used to assess vascular reactivity. When responses to isoprenaline and dopamine were compared with those to glyceryl trinitrate, both beds had approximately equal reactivity to isoprenaline. In contrast the paw pads were 10 fold more responsive to dopamine than was the gracilis. 5 We conclude that the vessels of the paw pads play an important part in the femoral dilator response to dopamine.     

Cardiovascular responses produced by the injection of dopamine into the cerebral ventricles of the unanaesthetized dog.

1 The injection of dopamine (100 to 500 microgram) into the cerebral ventricles (i.c.v.) of 10 unanaesthetized dogs produced a dose-dependent increase in arterial blood pressure and heart rate. The dogs licked, swallowed, sometimes vomited and became sedated. 2 Autonomic ganglion blockade with hexamethonium (10 mg/kg i.v.) abolished cardiovascular responses to i.c.v. dopamine, indicating that dopamine was exerting its effect within the central nervous system. 3 The dopamine receptor antagonists, haloperidol (500 microgram), chlorpromazine (200 micrograms) and ergometrine (500 micrograms), each given i.c.v., sugsequently abolished the cardiovascular responses to dopamine. 4 Pretreatment with either the beta-adrenoceptor antagonist, propranolol (600 microgram) or the alpha-adrenoceptor antagonist, phentolamine (1 mg) given i.c.v. had no significant effect on the response to dopamine. 5 It is suggested that dopamine injected into the cerebral ventricles of the unanesthetized dog causes hypertension and tachycardia by activating central dopamine receptors.     

Pharmacological basis for N-n-propylnorapomorphine induced stereotypic cage climbing and behavioral arousal in mice.

Apmorphine (APO) and its N-propyl homologue (N-n-propylnorapomorphine; NPA) are approximately equipotent in inducing stereotypic cage climbing and behavioral arousal. The time courses for the two behavioral responses of both aporphines are also quite similar. These results suggested that aporphine-induced stereotypic cage-climbing and behavioral arousal, if specific for dopamine receptor stimulation, could provide useful in vivo models for predicting dose- and time-response effects of potential antiparkinsonian agents. In the present experiments, six neurotransmitter receptor blockers (alropine, phentolamine, sotalol, cyproheptadine, naloxone, and haloperidol or spiroperidol) were compared in mice for their ability to alter cage climbing and behavioral arousal induced by NPA. Results indicated that pretreatment with the dopamine blockers haloperidol and spiroperidol, significantly antagonized both responses to NPA and shifted the cage climb dose response curve to the right 15-fold. In contrast, the muscarinic cholinergic (atropine), alpha-noradrenergic (phentolamine), beta-noradrenergic (sotalol), serotonergic (cyproheptadine), and opiate (naloxone) receptor blockers uniformly did not attenuate activity due to NPA. These results suggest that cage-climbing and arousal induced by aporphines is mediated via dopamine receptor stimulation and that these responses provide useful in vivo models for accurate evaluation of certain classes of dopamine agonists with clinical utility.     

Dopamine-induced neurogenic vasodilatation in isolated perfused muscle preparation of the dog

Summary Dopamine, injected into the lumbar aorta of the dog in doses which produce a reversible inhibition of synaptic transmission in the lumbar paravertebral ganglia (0.5–64×10^–8 moles), produces a neurogenic vasodilatation in the isolated perfused hindleg or gracilis muscle. This was abolished by acute preganglionic decentralization and by administration into the perfused preparation of -adrenoceptor blocking agents, but not of atropine or diphenhydramine. After decentralization, preganglionic electrical stimulation restored the dopamine-induced indirect vasodilatation. The neurogenic vasodilatation was also seen with intra-aortic injections of epinine (2–32×10^–8 moles) and apomorphine (1.2–19.2×10^–8 moles) and was preferentially blocked by haloperidol (0.26×10^–6 moles). (-)-Noradrenaline, injected into the lumbar aorta in baroreceptor-denervated dogs, was found to be equipotent with dopamine in eliciting the neurogenic vasodilatation; this (-)-noradrenaline-induced effect was preferentially blocked by phentolamine (8×10^–6 moles).The possibility that the neurogenic vasodilatation, which occurs upon intra-aortic injection of dopamine in the dog, is due to its ganglionic-inhibitory effect is discussed.This work was aided by grants from the Coordination Committee for Scientific Research (C.C.A.S.) and from the Fund for Interdisciplinary Research, Belgium.     

A comparison of the effects of bradykinin, 5-hydroxytryptamine and histamine on the hepatic arterial and portal venous vascular beds of the dog: Histamine H1 and H2-receptor populations

1 The hepatic arterial and hepatic portal venous vascular beds of anaesthetized dogs were separately perfused in different experiments.

2 From measurements of perfusion pressures and blood flows in the two series of experiments, hepatic arterial vascular resistance (HAVR) and hepatic portal venous vascular resistance (HPVR) respectively were calculated.

3 Bradykinin, 5-hydroxytryptamine (5-HT) and histamine were injected intra-arterially and intra-portally and dose-response curves constructed from these data.

4 Bradykinin injected intra-arterially caused dose-dependent hepatic arterial vasodilatation, and with an ED₅₀ of 2.66 × 10^-13 mol was more potent than any other vasodilator agent yet examined on this vascular bed.

5 Bradykinin injected intraportally at doses up to 10 times those which were maximal on the arterial circuit did not alter the calculated HPVR.

6 5-HT injected intra-arterially caused weak and variable rises in HAVR, indicating vasoconstriction. The maximum rise in HAVR was much less than that attained with noradrenaline in the same preparations.

7 5-HT injected intraportally caused dose-dependent rises in HPVR indicating portal constriction at doses above 15-100 μg: in some experiments small doses of 5-HT resulted in reductions in calculated HPVR.

8 Histamine has previously been shown to cause hepatic arterial vasodilatation: by intraportal injection, it caused dose-dependent rises in HPVR.

9 In order to examine the receptors responsible for the effects of histamine, dose-response curves were constructed before and after mepyramine and metiamide.

10 On the hepatic arterial vascular bed, metiamide did not antagonize the vasodilator effects of intra-arterial histamine, but these effects were antagonized by mepyramine.

11 Similarly on the hepatic portal bed, the rises in HPVR due to histamine were antagonized by mepyramine but not by metiamide.

12 The effects of histamine on both the hepatic arterial and portal venous vascular beds of the dog are therefore mediated predominantly by histamine H₁-receptors.

     

The actions of two sensory neuropeptides, substance P and calcitonin gene-related peptide, on the canine hepatic arterial and portal vascular beds.

1. The two peptides, calcitonin gene-related peptide (CGRP) and substance P (SP) were administered individually as bolus injections into the separately perfused hepatic arterial and portal vascular beds of the anaesthetized dog to assess their actions and relative molar potencies at these sites. 2. CGRP caused an immediate dose-related increase in hepatic arterial flow when injected close-arterially, reflecting a fall in resistance. This vasodilator effect was slightly increased by the prior administration of the selective beta 2-adrenoceptor antagonist, ICI 118,551. 3. On a molar basis, CGRP was more potent as an hepatic arterial vasodilator than the non-selective beta-adrenoceptor agonist, isoprenaline (Iso). 4. Intra-portal injection of CGRP also evoked hepatic arterial vasodilatation unaccompanied by other cardiovascular changes. 5. CGRP in doses up to 10 nmol had no effect on portal vascular resistance when administered intra-portally. 6. SP evoked a rapid, dose-related increase in hepatic arterial flow when injected intra-arterially. The molar ED50 for this hepatic vasodilatation was 40.2 fmol, significantly less than the ED50 for either CGRP or Iso. SP was the most potent hepatic arterial vasodilator yet examined. The vasodilator effect of SP was slightly potentiated by prior beta 2-adrenoceptor blockade. 7. SP caused hepatic arterial vasodilatation when administered by intra-portal injection; its absolute and relative potency was much reduced. 8. SP when injected intra-portally caused a graded increase in hepatic portal inflow resistance. The molar potency for this portal vasoconstriction was significantly greater than that for noradrenaline (NA); however, the maximum increase in portal resistance was significantly less to SP than to NA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological characterization of neuropeptide Y and noradrenaline mechanisms in sympathetic control of pig spleen

The mechanisms underlying the functional effects of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) and their release evoked by nerve stimulation were studied with the blood-perfused pig spleen in vivo. Infusion of selective agonists and antagonists suggested the presence of alpha 1- and beta 2-adrenoceptors mediating vasoconstriction and vasodilatation, respectively. NPY caused a slight inhibition of stimulation-evoked [3H]NA release and a clearcut non-adrenergic vasoconstriction. Local pretreatment with phentolamine and prazosin as well as with clonidine and UK 14304 reduced the perfusion pressure response to nerve stimulation. Phentolamine, yohimbine and idazoxan enhanced while clonidine and UK 14304 decreased the output of [3H]NA or NA and NPY-LI. The subsequent addition of propranolol to the alpha-adrenoceptor antagonists was followed by reappearance at a considerable portion of the perfusion pressure response while the output of [3H]NA or NA and NPY-LI was slightly reduced. It is concluded that NPY exerts pre- and post-junctional actions in pig spleen that regulate both NA release and vascular tone. alpha 1-Adrenoceptors are mainly involved in vasoconstriction, and prejunctional alpha 2 mechanisms inhibit both NA and NPY release at a low frequency of stimulation. beta 2-Adrenoceptors mediate vasodilatation when NA release is enhanced with a minor effect on mediator secretion.     

Evidence for ATP as a cotransmitter in dog mesenteric artery

Contractile responses of the dog mesenteric artery were obtained (after removal of endothelium) to transmural stimulation of the perivascular nerves and to exogenous application of ATP, noradrenaline, dopamine, 5-hydroxy-tryptamine and high potassium solution. The alpha-adrenoceptor antagonists prazosin and phentolamine preferentially reduced the response to noradrenaline and the secondary phase of the biphasic contractile response to nerve stimulation, whilst the addition of alpha, beta-methylene-ATP, which selectively desensitizes P2-purinoceptors, reduced only the contractions to ATP and the portion of the nerve-mediated response which was resistant to the alpha-adrenoceptor antagonists. The responses to nerve stimulation were reduced by the selective P1-purinoceptor agonist 2-chloroadenosine, and its effect was reversed by the P1-purinoceptor antagonist 8-phenyltheophylline. These results suggest that in dog mesenteric artery part of the response to sympathetic nerve stimulation is mediated by ATP acting on P1-purinoceptors on the arterial smooth muscle, and that P1-purinoceptors on the sympathetic nerve terminal can inhibit release of the neurotransmitters.     

The transhepatic action of ATP on the hepatic arterial and portal venous vascular beds of the rabbit: the role of nitric oxide.

1. The effect of bolus administration of adenosine 5'-triphosphate (ATP) into the portal vein on hepatic arterial pressure (the transhepatic action of ATP) and portal venous pressure, and the contribution of nitric oxide towards these responses, was studied in the in vitro dual-perfused rabbit liver. 2. At basal tone, hepatic arterial and portal venous vasoconstriction followed ATP injection, while at a tone raised with methoxamine (10(-6)-10(-5) M) ATP caused hepatic arterial vasodilatation, and a phasic vasodilatation followed by vasoconstriction in the portal venous vascular bed. 3. To determine whether the transhepatic arterial dilatation was due to the diffusion of nitric oxide (NO) from the portal venous vasculature, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), an inhibitor of NO synthesis, was infused selectively into the portal vein. L-NAME infusion potentiated portal venous vasoconstriction to ATP (-log M ED50 5.32 +/- 0.31 to 6.51 +/- 0.43, P < 0.05, Student's paired t test) indicating the possible inhibition of a NO-mediated vasodilator component of the portal venous response to ATP. There was, however, no demonstrable difference in the transhepatic arterial vasodilatation induced by ATP during this infusion. 4. Simultaneous perfusion of both the hepatic arterial and portal venous inflows with L-NAME (100 microM) resulted in a significant decrease in the amplitude of hepatic arterial responses to ATP demonstrating that these responses were ultimately mediated by an NO-dependent mechanism. 5. This study has thus demonstrated a vasodilator component of the portal venous response to ATP that is NO-mediated.(ABSTRACT TRUNCATED AT 250 WORDS)     

The action of ATP on the hepatic arterial and portal venous vascular networks of the rabbit liver: the role of adenosine

ATP is released from blood vessels during periods of hypoxia and may be responsible for hepatic arterial vasodilatation during instances of reduced hepatic portal venous flow. The role of adenosine in ATP-induced vasodilator and vasoconstrictor responses of the hepatic arterial and portal venous vascular networks respectively was studied in the isolated dual-perfused rabbit liver in vitro to ascertain whether ATP could be catabolised to adenosine during transit through the hepatic parenchyma. Intra-arterial and intra-portal injections of ATP (−10 to −4 log mol/100 g liver) resulted in dose-dependent vasodilatation in the hepatic artery and vasoconstriction in the portal vein. Addition of 8-phenyltheophylline (10 μM), a non-selective P₁-purinoceptor antagonist, to the hepatic arterial and portal venous perfusate significantly inhibited the hepatic arterial ED₅₀ for responses to intra-arterial injected ATP from −8.70±0.22 to −7.63±0.28 log mol/100 g liver (P<0.001); it also inhibited hepatic arterial responses to, mid-range, portal venous injections of ATP. The data suggest that the hepatic arterial vasodilatation to ATP is partly mediated via catabolism to adenosine and may be an important mechanism during periods of relative hepatic hypoxia associated with portal flow reduction.     

Femoral vasodilatation produced by piribedil (ET495) and its metabolite S584 in the hindleg of the dog

Summary On local injection into the innervated hindleg of the dog piribedil, like apomorphine, produced a vasodilatation blocked by haloperidol. S584, the catechol metabolite of piribedil, produced a vasodilatation which was not blocked by haloperidol. Neither propranolol nor atropine influenced the vasodilatation produced by piribedil or S584. Denervation of the hindleg abolished the responses to piribedil and S584. During the infusion of noradrenaline into the denervated hindleg, the responses to S584 reappeared but those to piribedil did not. It is concluded from these experiments that the vasodilatation produced by piribedil in the innervated hindleg of the dog, like that of apomorphine, is mediated by dopamine receptors and that the effect of piribedil cannot be explained by the formation of its catechol metabolite S584.     

Characterization of receptors on postganglionic cholinergic neurons in the guinea-pig isolated ileum.

Dopamine, apomorphine, noradrenaline and isoprenaline reduced the response of the isolated guinea-pig ileum to exogenous acetylcholine by a maximum of 40%. Propranolol reversed this inhibition whilst phentolamine and pimozide were ineffective, suggesting that the drugs were acting on a post-synaptic beta-adrenoceptor. The same agonists were more effective as inhibitors of the response to transmural electrical stimulation of the ileum, lower doses producing almost complete inhibition. This inhibition was partially antagonized by phentolamine, pimozide and propranolol. Clonidine proved to be the most potent inhibitor of the response to transmural electrical stimulation, whilst phenylephrine was ineffective. pA2 determinations showed that phentolamine was a potent antagonist of clonidine but a weak antagonist of apomorphine whilst for pimozide the opposite was true. The results suggest that there are two populations of prejunctional receptors on the cholinergic nerves innervating the smooth muscle of the guinea-pig ileum. One receptor is similar to a classical prejunctional alpha-adrenoceptor and the other resembles a central dopamine receptor.     

Catecholamines act as alpha 2-adrenoceptors to cause contraction of circular smooth muscle of guinea-pig stomach

Circular smooth muscle strips taken from the body region of the guinea-pig stomach responded to dopamine and noradrenaline with contraction at lower concentrations followed by relaxation at higher concentrations. A beta-adrenoceptor-mediated relaxation response was excluded by propranolol treatment and this allowed the remaining alpha-adrenoceptor involvement with relaxation and contraction to be incisively differentiated in terms of two distinct alpha-adrenoceptor mechanisms. Thus, the relaxation responses to the catecholamines were mimicked by phenylephrine and antagonized by prazosin, phentolamine but not by yohimbine or rauwolscine. In contrast, the catecholamine-induced contractions were mimicked by clonidine and antagonized by yohimbine and phentolamine but not by prazosin. It is therefore concluded that the alpha mechanisms via which dopamine and noradrenaline are able to relax and contract the circular smooth muscle from the body region of guinea-pig stomach are of the alpha 1- and alpha 2-type respectively.     

Blockade of the dopamine depressor response by molindone, a newly introduced neuroleptic

Pretreatment with the neuroleptics, haloperidol and molindone, significantly antagonized the dopamine-induced depressor response in the anaesthetized dogs. The depressor response to dopamine was however, not significantly affected by propranolol, atropine or antazoline pretreatment. The results suggest that molindone like haloperidol, is capable of blocking the vascular dopamine receptors responsible for mediating dopamine-induced vasodilatation in the coeliac, mesenteric and renal vascular bed and fall in blood pressure.     

A method for recording smooth muscle and vascular responses of the blood-perfused dog trachea in situ.

1 A method is described for measuring responses of dog tracheal musculature and vasculature in situ. 2 The upper two thirds of the trachea was perfused with blood through both cranial thyroid arteries at a constant pressure. The blood flow through the arteries was measured with an electromagnetic flowmeter. The response of the tracheal musculature was measured as a change in pressure in a water-filled cuff inserted into the trachea via the mouth. Drugs were injected close-arterially. 3 Acetylcholine produced dose-dependent increases in blood flow rate (vasodilatation) and in tracheal intraluminal pressure (tracheal constriction). These responses were antagonized by atropine. 4 Isoprenaline produced vasodilatation which was blocked by propranolol. Adrenaline and noradrenaline caused vasocontriction which was blocked by phentolamine. 5 All three catecholamines produced a decrease in tracheal intraluminal pressure (tracheal dilatation). The tracheal dilatation in response to adrenaline and noradrenaline was converted to constriction by propranolol. The tracheal constriction thus unmasked was abolished specifically by phentolamine. 6 From these results it is concluded that the tracheal musculature and vasculature contain muscarinic receptors, and excitatory alpha- and inhibitory beta-adrenoceptors. In the tracheal musculature beta-adrenoceptors predominate over alpha-adrenoceptors; the reverse is true in the tracheal vasculature.     

The role of H1 and H2-receptors in the coronary vascular response to histamine of isolated perfused hearts of guinea-pigs and rabbits.

1. The effects of histamine on the isolated perfused hearts of guinea-pigs and rabbits were examined. Records of contractile force, heart rate and coronary perfusion pressure were obtained. 2. Histamine exerted positive inotropic and chronotropic effects which were antagonized by burimamide and attributed to stimulation of H2-receptors. 3. The coronary vascular response to histamine differed between guinea-pigs and rabbits. In guinea-pig hearts, three phases were apparent: (a) An initial vasodilatation preceding any effects on heart force and rate was antagonized by mepyramine and therefore mediated by histamine H1-receptors in the coronary circulation. (b) A secondary vasoconstriction was attributed to the increased myocardial compression during the positive inotropic and chronotropic responses. (c) The final, more predominant, component was a prolonged vasodilatation probably associated with the increased metabolic activity of the heart. 4. The latter two components were abolished together with the myocardial responses by burimamide. The remaining coronary vascular response was biphasic, consisting of a vasodilatation immediately followed by vasoconstriction. Both were antagonized by mepyramine and therefore mediated by H1-receptors. 5. The coronary vascular response of rabbit hearts was similar but no direct vasodilatation was observed and it was concluded that histamine receptors in the coronary vasculature involve only vasoconstriction.     

Effects of dopamine on adrenergic neuromuscular transmission in the guinea-pig vas deferens.

1 In the isolated vas deferens of the guinea-pig, contractile responses to adrenergic nerve stimulation at 2 Hz were depressed by exogenous dopamine (5 microM) and this effect was abolished in the presence of phentolamine (0.3 microM), suggesting that it was due to an agonist action of dopamine on alpha-adrenotors. 2 The depression by dopamine (5 microM) of contractile responses to nerve stimulation was correlated with reduction in amplitude of single excitatory junction potentials (e.j.ps) evoked by nerve stimulation, but not with depression of spontaneous junction potentials. 3 By contrast, during repetitive nerve stimulation at 1 Hz the depressant effect of dopamine on e.j.p. amplitude became less pronounced, due to the amount of facilitation being greater than that occurring under control conditions in the same cell. 4 The alpha-adrenoceptor antagonist, phentolamine (10 microM), also increased the amount of facilitation during repetitive nerve stimulation. 5 In the presence of phentolamine (10 microM), the depressant effect of dopamine (5 microM) on single e.j.ps was abolished but its enhancing effect on facilitation was not reduced. 6 It is suggested that the enhancement of facilitation during repetitive stimulation by both dopamine and phentolamine is independent of their actions on presynaptic alpha-adrenoceptors.