The benzazepine SCH 23390 increases plasma levels of cortisol in the conscious dog

Summary The effect of neuroleptics on the hypothalamopituitary-adrenal system has been early recognized, but never adequately related to antipsychotic or side effects produced by dopamine antagonists. We are now presenting results showing that the newly characterized dopamine D-1 receptor antagonist, SCH 23390 (0.1 mg/kg i.v.) as well as the mainly dopamine D-2 receptor antagonists, haloperidol (0.1 mg/kg i.v.) and chlorpromazine (1 mg/kg i.v.), produced an increase of cortisol levels (108, 144 and 226% respectively, 20 min after the injection) determined by radioimmunoassay in blood samples collected from superficial veins of the legs of conscious dogs. The 5-HT₂ receptor antagonist, cyproheptadine (0.2 mg/kg i.v.), did not modify the cortisol levels. These results suggest that cortisol increase is an effect common to neuroleptic compounds, independently of their relative antagonistic action at dopamine D-1 or D-2 receptors.     

Ergometrine and apomorphine as selective antagonists of dopamine in the canine renal vasculature

1 Increases in renal blood flow were produced by intra-arterial injections of dopamine (5-50 mug) in anaesthetized dogs pretreated with alpha- and beta-adrenoceptor antagonists.2 Intra-arterial administration of ergometrine (0.5 mg) or apomorphine (1 mg) produced a depression of the renal dilator responses to dopamine, without affecting renal dilatations in response to intra-arterial acetylcholine (0.1-1 mug) or histamine (2-50 mug).3 The depression of dopamine responses lasted 10-15 min, and was greater with ergometrine than with apomorphine.4 It is concluded that both ergometrine and apomorphine can be used as specific blocking agents at vascular dopamine receptors. Ergometrine is the preferred drug for this purpose.     

Comparison of the vasodilator action of dopamine and dopamine agonists in the renal and coronary beds of the dog.

1 The effects of dopamine and the dopamine receptor agonists, SK&F 38393 and bromocriptine, on renal and coronary blood flow in the anaesthetized dog were examined. Dopamine was found to dilate both vascular beds, whereas SK&F 38393 increased renal blood flow but did not have any dilator activity in the coronary vasculature. Bromocriptine did not cause vasodilatation in either vascular bed. 2 The vasodilator responses to dopamine and SK&F 38393 were significantly reduced by the dopamine receptor antagonists, ergometrine or metoclopramide. 3 It is proposed that the selective action of SK&F 38393 on the renal vasculature suggests that the dopamine receptors of the renal and coronary vascular beds may be of different types.     

Effect of dopamine and blockade of dopaminergic and adrenergic receptors on coronary blood flow in ischemic rabbit myocardium

The effect of a broad dose range of dopamine on coronary blood flow was studied in rabbits with coronary artery occlusion. Dopaminergic and adrenergic receptor blockade was established to distinguish the mechanism of the dopamine-induced increase in coronary blood flow. Dopamine, 10, 100, or 1,000 micrograms/kg/min, was infused in the presence of dopaminergic, beta-, or alpha-adrenergic receptor blockade. Coronary blood flow, as measured by radiolabeled microspheres, and hemodynamic parameters were monitored in 60 anesthetized open-chest rabbits. Dopamine, 1,000 micrograms/kg/min, significantly increased coronary blood flow 157% in normal and 118% in occluded rabbit myocardium. Propranolol (2 mg/kg) prevented the dopamine-induced increases in coronary blood flow within occluded and nonoccluded myocardium. Practolol (2 mg/kg) blunted the coronary blood flow increases within occluded myocardium, but flow within normal myocardium remained significantly elevated. In animals given phenoxybenzamine (2 mg/kg), dopamine infusion produced significant blood pressure reductions along with no change in either occluded or nonoccluded coronary blood flow. Bulbocapnine (8 mg/kg), a dopamine receptor antagonist, did not block blood flow increases in normal myocardium, but prevented significant increases in blood flow within occluded myocardium. It can be concluded that direct or indirect vasodilator receptors (dopaminergic, beta 1-, and beta 2-adrenoceptors) must be stimulated and perfusion pressure must not fall in order for dopamine to produce increases of coronary blood flow within occluded myocardium.     

Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor

The objective of this study was to examine the interaction of dopamine D2 receptor antagonists and dopamine uptake inhibitors on the regulation of extracellular dopamine release in the nucleus accumbens of Wistar rats employing in vivo microdialysis and in vitro dopamine uptake studies. Application of the D2 receptor antagonists raclopride (100 microm) or sulpiride (100 microm) alone through the microdialysis probe in the nucleus accumbens for 60 min increased the extracellular levels of dopamine in the nucleus accumbens to 150% and 200% of basal, respectively. Perfusion of the nucleus accumbens for 60 min with the dopamine uptake inhibitors, 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909; 100 microm) or 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride (GBR 12935; 100 microm) alone, increased the extracellular levels of dopamine in the nucleus accumbens to 400% and 350% of basal, respectively. Co-perfusion of 100 microM GBR 12909 or GBR 12935 with either 100 microM sulpiride or raclopride produced a significant reduction in the GBR 12909 or GBR 12935 induced increase in the extracellular levels of dopamine to basal levels. In vitro, GBR 12909 (1-9 nM) dose-dependently inhibited active uptake of [3H]dopamine in homogenates of the nucleus accumbens. Addition of 100 microm sulpiride had little effect on GBR 12909 inhibition of [3H] dopamine uptake, suggesting that dopamine D2 receptor antagonists are not blocking the actions of the GBR-type dopamine uptake inhibitors at the dopamine transporter. Overall, the data suggest that complex interactions occur in vivo between D2 antagonists and GBR-type dopamine uptake inhibitors, which negate their effects on elevating the extracellular levels of dopamine in the nucleus accumbens.     

Effects on Central Dopaminergic Systems of d-Coclaurine and d-Reticuline, extracted from Magnolia salicifolia.

The present investigation was undertaken to study effects of benzyltetrahydro-isoquinoline alkaloids, d-coclaurine and d-reticuline, extracted from dried flower buds of MAGNOLIA SALICIFOLIA M AX. on gross behavioural parameters following intracerebroventricular administration in mice and on dopamine uptake in the mouse iris. d-Coclaurine 25 microg produced an inhibition of locomotor activity, ptosis and catalepsy. One hour after injection it produced stereotyped behaviour, such as sniffing and gnawing. Pretreatment with d-coclaurine 25 microg suppressed locomotor activation and rotational behaviour induced by apomorphine and methamphetamine. d-Reticuline 100 microg produced catalepsy and a decrease in locomotor activity. d-Reticuline blocked locomotor activation and rotational behaviour induced by apomorphine, but not those induced by methamphetamine. 1-N-Methylcoclaurine 25 microg produced muscular twitch and tremor. It produced clonic convulsions at the dose of 100 microg. d-Coclaurine 20 mg/kg, i.v. suppressed dopamine uptake in the mouse iris pre-treated with alpha-methyl-p-tyrosine. It is indicated that d-coclaurine has a neuroleptic-like property in blocking effects of dopaminergic stimulating agents, but this does not necessarily explain inhibition of dopamine uptake in the mouse iris. Mode of action of d-reticuline may be different from that of d-coclaurine.     

The effect of dopamine on blood flow in skeletal muscles

To explain some mechanisms of the peripheral action of dopamine experiments were carried out on anesthetized rabbits in which the blood flow in calf muscles was measured during rest and during evoked twitches, using the method of 133Xe clearance of Lassen et al.; the arterial blood pressure and ECG were simultaneously recorded. Dopamine reduced the blood flow, particularly after a muscular effort. That effect of dopamine was not blocked by the alpha- and beta-adrenoceptor antagonists phentolamine and propranolol, the dopamine receptor antagonist haloperidol, or by the agent blocking sympathetic nerve endings compound BW392C60. Only low doses of dopamine given after propranolol pretreatment caused an increase in the blood flow. Dopamine depressed the arterial blood pressure, particularly the diastolic one. Pretreatment with phentolamine and haloperidol did not antagonize that effect, while pretreatment with propranolol or BW392C60 abolished or reversed the action of dopamine. The depression by dopamine of the blood flow in an important area of skeletal muscles indicates that part of the circulating blood may be shifted to other vascular beds, e.g. to the viscero - renal one.     

Decrease in rat striatal acetylcholine levels by some direct- and indirect-acting dopaminergic antagonists.

Several direct- or indirect-acting dopamine receptor antagonists were found to decrease rat striatal acetylcholine levels. The maximum decrease of about 50% was produced by pimozide (0.5 mg/kg), by haloperidol (0.5 mg/kg) and by reserpine (2.5 mg/kg). The decreases in acetylcholine produced by pimozide and by haloperidol were found to be specific for the striatum and did not alter diencephalonic, mesencephalonic, cerebellar or hemispheric acetylcholine levels. Furthermore, these two drugs completely blocked the increase in striatal acetylcholine produced by the dopamine receptor agonist, apomorphine, and had no effect on striatal choline acetyltransferase and cholinesterase. These data suggest that haloperidol and pimozide act on the striatal cholinergic neurons through strong blockade of dopamine receptors. Reserpine presumably decreased striatal acetylcholine levels indirectly by depleting biogenic amines. Clozapine and 1-fenfluramine were unable to block the action of apomorphine, as was shown previously for chlorpromazine. It is thus suggested that these drugs are reversible dopamine receptor antagonists. Their weaker action in decreasing striatal acetylcholine may depend upon this property.     

Effects of dopamine antagonists on fluid intake and salt preference in male and female rats

The effects of three dopamine antagonists (pimozide, clozapine, sulpiride) on fluid consumption by water-deprived rats trained to choose between a saline solution and water in a 15 min drinking test were examined. Rats of each sex were allocated to three groups and given access to 0.125% NaCl, 0.6% NaCl, and 1.7% NaCl, respectively, as the alternative to water. Dose-dependent reductions in fluid consumption were produced by pimozide (0.1- 3.0 mg kg(-1)) and clozapine (0.3-10.0 mg kg(-1)), but not by sulpiride (1.0-30 mg kg(-1)). There were instances of a hyperdipsic effect of sulpiride. The dopamine antagonists produced significant changes in saline preference, but in no case was a decrease in preference detected. Instead, there was evidence for induction of preference, or enhancement of preference, in both sexes. So far as determinants of preference for the salt are concerned, it appears that in the rat, dopamine may have a predominantly inhibitory action.     

Studies on renal dopamine receptors with a new agonist.

SK & F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) is a new dopamine receptor agonist which selectively increased renal blood flow when administered i.v. to dogs at cumulative doses of 3.3-1333 microgram/kg. Consistent changes in arterial blood pressure heart rate and cardiac output were not observed. The renal response, which was mediated locally in the kidney, was not antagonized by adequate blocking doses of atropine, propranolol, metiamide and/or mepyramine nor by reserpinization or treatment with indomethacin. It was inhibited, however, by the selective peripheral dopamine receptor antagonist, bulbocapnine. Perhaps as a result of its action on renal blood flow, SK & F 38393 produced a diuresis in normally hydrated rats which was characterized by an increased excretion of sodium, potassium and chloride and a increased urinary pH. Compounds of this type may be useful in better defining dopaminergic receptors and in the treatment of disease states where renal ischemia is present.     

Alpha-adrenergic effects of dopamine and dobutamine on the coronary circulation

After beta-adrenergic blockade, dopamine causes coronary vasoconstriction that is blocked by non-selective alpha-adrenergic antagonists. This study was carried out to determine the relative importance of alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in response to dopamine. Because dobutamine has been reported to cause alpha-adrenergic stimulation, the response to dobutamine was also examined. The circumflex coronary artery was cannulated and perfused at a constant blood flow rate in 14 dogs; coronary vasomotor responses were assessed from changes in perfusion pressure. Central effects were eliminated by vagotomy and stellate ganglionectomy; propranolol (1 mg/kg i.v.) was administered to block beta-adrenergic effects. The coronary responses to intracoronary bolus doses of dopamine and dobutamine were determined; the effects of selective alpha 1-blockade with prazosin (600 micrograms/kg i.v.) and selective alpha 2-blockade with idazoxan or rauwolscine (1-5 micrograms/kg per min intracoronary for 10 min) were examined. Dopamine produced dose-related coronary vasoconstriction; this response was not significantly altered by alpha 1-blockade with prazosin, but was abolished by the addition of alpha 2-adrenergic blockade with idazoxan or rauwolscine. Dobutamine did not produce coronary vasoconstriction at any dose tested. These data demonstrate that coronary vasoconstriction produced by dopamine is mediated through postjunctional alpha 2-adrenergic receptors.     

DA-1 RECEPTORS MEDIATE RENAL EFFECTS OF THE DOPAMINE PRODRUG, GLUDOPA, IN CONSCIOUS RABBITS

1. Eight male rabbits were implanted with Doppler flow probes around the lower abdominal aorta and left renal artery. A 2 week recovery period was allowed prior to the experiment. 2. Normal saline, gludopa at 25 micrograms/kg per min and at 100 micrograms/kg per min were each infused i.v. for 60 min. One week later the same protocol was administered to four of these animals in addition to DA-1 antagonist SCH 23390 (0.3 mg/kg i.v.) before gludopa infusion. 3. Gludopa elicited significant increases in urine flow, urinary sodium excretion and renal blood flow, and decreased renal vascular resistance. These changes were abolished by the DA-1 antagonist. Blood pressure, heart rate and hindlimb blood flow remained unchanged. 4. Urine dopamine excretion was increased 1200-fold and 7800-fold after gludopa administration at 25 micrograms/kg per min and 100 micrograms/kg per min, respectively, while plasma dopamine concentration and plasma renin activity (PRA) were not significantly altered. However, PRA was elevated by gludopa with DA-1 antagonism. 5. The renal vasodilation, natriuresis and diuresis produced by gludopa in conscious rabbits appears to be mediated by locally generated dopamine via DA-1 receptors.     

The action of aminophylline on the acutely transplanted dog heart: effect of alpha- and beta-adrenoceptor blockade.

1 Aminophylline inhibits the coronary vasodilator actions of adenosine. Our previous studies suggested that low dose infusions of aminophylline reduce coronary blood flow in the isolated heart. In the present study we investigated the actions of aminophylline on coronary blood flow and myocardial contractility in a transplanted heart model. Drugs were given by close coronary arterial infusion. 2 Aminophylline in low doses (200 mug/min) reduced coronary blood flow by 21 plus or minus 2% (mean plus or minus s.e. mean) but did not alter myocardial contractility or heart rate. Higher doses (500 and 1000 mug/min) increased coronary blood flow and myocardial contractility without changing heart rate. 3 Alpha-adrenoceptor blockade with phenoxybenzamine did not affect the response to a low dose of aminophylline (200 mug/min). 4 Propranolol in doses of 10 and 30mug/min blocked beta-adrenoceptors but did not change coronary blood flow. The higher dose reduced myocardial contractility. 5 The effects of a high dose of aminophylline (1000 mug/min) on coronary blood flow were not changed by either alpha- or beta-adrenoceptor blockade, although propranolol (30 mug/min) reduced the augmentation in myocardial contractility. 6 The results show that when given in doses which do not alter myocardial contractility, aminophylline reduces coronary blood flow in the isolated heart and that this is not mediated through an alpha-adrenoceptor mechanism. They also show that the increases in coronary blood flow and positive inotropic effects obtained with higher doses of aminophylline are not mediated through catecholamines and suggest that higher doses of aminophylline have a small direct coronary vasodilator action. The low dose vasoconstrictor response may be produced by inhibition of the coronary vasodilator action of locally produced adenosine.     

Pupillary supersensitivity to substance P following prolonged treatment with tetrodotoxin or substance P antagonists

Pilocarpine contracts the sphincter pupillae muscle via an effect on muscarinic receptors and phenylephrine contracts the dilator pupillae muscle via an effect on alpha-adrenergic receptors. These effects are thought to mimic the action of the parasympathetic and sympathetic nervous systems, respectively. Intracellular injection of substance P (SP) produces an atropine-resistant constriction of the pupil. This response is thought to mimic the effect of local sensory reflexes on the sphincter pupillae muscle, involving SP-containing trigeminal nerve endings. Repeated intraocular injections of tetrodotoxin, a general blocker of nervous conduction, over a period of 3 weeks produced supersensitivity to pilocarpine, phenylephrine and SP in the rabbit iris. These findings support the view that, like acetylcholine and noradrenaline, SP or an SP-like compound acts as a neurotransmitter in the iris. Also, long-term topical application of an SP antagonist, (D-Pro2,D-Trp7,9)-SP or (Arg5,D-Trp7,9)-SP5-11, to the rabbit eye produced supersensitivity to SP but not to pilocarpine, thus supporting the view that the SP antagonists interact specifically with the SP receptors. The isolated rabbit iris sphincter muscle responds to electrical stimulation with a cholinergic twitch followed by a slow non-cholinergic contraction that can be blocked by antagonists to SP. Analysis of the motor activity of the iris sphincter muscle after long-term topical treatment of the eye with an SP antagonist followed by an interval of 2 days after termination of treatment revealed a greatly enhanced non-cholinergic contraction compared with the cholinergic twitch, a finding that seems to be consistent with the idea that supersensitivity to SP had developed.     

Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.

Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H and muscarinic M 1 and M3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA2 = 6.67+/-0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (pA2 = 9.44+/-0.02) and NPC-14695 (pA2 = 9.18+/-0.03) also behaved as competitive antagonists, whereas tiotropium bromide (pD'2 = 9.06+/-0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (pA2 = 5.64+/-0.04) and fexofenadine (pA2 < 4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long lasting mydriasis (> 120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED50 = 30 microg/ml) and tiotropium bromide (ED50 = 10 microg/ml) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.     

Absence of postsynaptic DA2 dopamine receptors in the dog renal vasculature.

In experiments designed to look for functional postsynaptic DA2 dopamine receptors in the dog renal vasculature, the vascular effects of two selective DA2 receptor agonists, bromocriptine and quinpirole, were studied in pentobarbital-anesthetized dogs. Intra-arterial (i.a.) injections of bromocriptine reduced renal blood flow before and after blockade of alpha-adrenoceptors. I.a. quinpirole produced dose-related increases in renal blood flow which were not altered by blockade of alpha- or beta-adrenoceptors or DA1 dopamine receptors. Neither of the selective DA2 dopamine receptor antagonists, domperidone or YM 09151-2, altered the renal vascular effects of quinpirole, but these were reduced by combined H1 and H2 histamine receptor blockade. The results of these experiments do not support the existence of postsynaptic DA2 dopamine receptors mediating vasodilation in the canine renal vasculature.     

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.     

A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists

1 The effect of the putative 5-hydroxytryptamine (5-HT) receptor antagonists, methysergide, methergoline, mianserin, cyproheptadine, cinanserin (all at 10 mg/kg), methiothepin (5 mg/kg) and (-)-propranolol (20 mg/kg) on the behavioural responses to tranylcypromine (10 mg/kg) followed 30 min later by L-tryptophan (100 mg/kg) was examined.2 Methysergide, methergoline, methiothepin and (-)-propranolol inhibited head weaving, forepaw treading and hind-limb abduction. Methysergide and methergoline increased reactivity. In contrast, cypropheptadine, cinanserin and mianserin had no effects on the behaviour.3 Similar findings were obtained when the behaviours were elicited by administration of tranylcypromine (10 mg/kg) followed by the putative 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg).4 When the behaviours were elicited by the putative 5-HT receptor agonist, quipazine (50 mg/kg), all the drugs effectively inhibited head weaving and forepaw treading.5 When the dose of cypropheptadine was doubled to 20 mg/kg an inhibition of the tranylcypromine/L-tryptophan induced behaviours was seen.6 Methiothepin produced a marked inhibition of apomorphine-induced locomotor activity whilst all the others enhanced this response, suggesting that only methiothepin inhibits the 5-HT behaviours by dopamine antagonism and that the increased reactivity seen following tranylcypromine/L-tryptophan after pretreatment with methysergide or methergoline might be due to enhanced dopamine function.7 Pretreatment with p-chlorophenylalanine resulted in enhanced behavioural responses to both 5-MeODMT and quipazine.8 Both methergoline and methiothepin decreased the rate of 5-HT synthesis in whole brain but not spinal cord and methergoline decreased spinal cord 5-HIAA concentration. None of the other drugs had any significant effects on the concentration of 5-HT, 5-HIAA or 5-HT synthesis rate in brain or spinal cord.9 Experiments with compounds structurally related to quipazine and with molecular models suggested that quipazine produces behavioural changes probably by stimulating the 5-HT receptor in a similar way to 5-HT but that it would bind weakly, in agreement with ligand-receptor binding studies.10 It is suggested, therefore, that cyproheptadine, cinanserin and mianserin fail to inhibit 5-HT and 5-MeODMT-induced behaviours because they are weak antagonists whilst they are able to inhibit the same behaviours induced by quipazine because it is a weak agonist.11 These data indicate that extreme care should be taken in accepting or rejecting 5-HT as a mediator of behaviours or of other responses unless several antagonists or agonists have been examined.     

Effect of bromocriptine on cardiac function and coronary blood flow

The present study was designed to investigate the effects of bromocriptine, a dopamine receptor agonist, on systemic and coronary hemodynamics and to determine the mechanisms involved in the action of this compound. Intravenous infusion of bromocriptine (1 microgram/kg/min for 20 min) to pentobarbital-anesthetized dogs produced significant decreases in blood pressure, heart rate, total peripheral resistance, peak dP/dt, left ventricular pressure, and coronary blood flow. There were significant increases in stroke volume and coronary vascular resistance, whereas the index of contractility was unaffected. Cardiac output was decreased 30 min after the termination of bromocriptine infusion. The cardiovascular actions of bromocriptine were significantly antagonized by the dopamine receptor antagonist, sulpiride. Bromocriptine also failed to exert these effects when administered to animals that were treated with ganglionic blocking agents. These results suggest that the hypotensive action of bromocriptine is mainly due to a decrease in total peripheral resistance. In addition, the actions of bromocriptine on cardiac function are the result of activation of presynaptic dopamine receptors and the drug does not have any direct action on the myocardium.     

Vascular dopamine receptors in the canine hindlimb.

1 Increases in femoral blood flow were produced by intra-arterial injections of dopamine (5-50 mug) in some but not all anaesthetized dogs studied, following treatment with the alpha-adrenoceptor antagonist, phentolamine. 2 The dilator effect of dopamine was not due to inhibition of adrenergic vasomotor tone as it was not affected by pharmacological procedures which completely abolished the activity of vastomotor nerves. 3 Blockade of vascular beta-adrenoceptors using propanolol reduced the flow increases produced by dopamine much less than it did those produced by isoprenaline. 4 Responses to dopamine were significantly depressed by intra-arterial administration of ergometrine (0.5 mg). This dose of ergometrine did not reduce femoral dilator responses to acetylcholine, histamine, isopienaline, bradykinin, or 5-hydroxytryptamine. 5 It is concluded that the femoral vascular bed in the dog contains specific vasodilator receptors for dopamine. Ergometrine appears to be a selective antagonist of dopamine at these receptors.