Biomedical subjects

R Massingham

Publications and source records attributed to R Massingham.

At least 37 records · Page 2Linked to original sources

PubMed1991

Caffeine-induced contractions in rabbit isolated renal artery are differentially inhibited by calcium antagonists.

Caffeine (1-60 mM) induced concentration-dependent, endothelium-independent phasic contractile responses in isolated rabbit renal artery ring preparations. For concentrations of caffeine over 2 mM, responses were mainly the result of intracellular calcium ion mobilization since they were relatively resistant to removal of calcium ions from the bathing medium. The L-type slow calcium channel blocker, nifedipine (10 microM), had no effect and high concentrations of verapamil and diltiazem (10-30 microM) only slight and inconsistent effects (not concentration-dependent) upon these caffeine responses. Likewise, the highly lipophilic calcium antagonists flunarizine and lidoflazine (3-30 microM) only slightly displaced caffeine concentration-response curves to the right and reduced the maximum response. These small inhibitory effects of flunarizine and lidoflazine were not augmented in a calcium-free medium. In contrast, the other lipophilic calcium antagonists, bepridil and fendiline (3-30 microM), produced marked, non-competitive type inhibition of caffeine responses, completely inhibiting responses to the alkaloid at the highest concentration. Furthermore, the inhibitory effects of bepridil and fendiline were markedly augmented in calcium-free medium. These results clearly differentiate bepridil and fendiline from the other calcium antagonists studied. In addition they provide further evidence for effects other than at the cell membrane which could theoretically contribute to the efficacy of bepridil and fendiline as anti-anginal agents.

Animals↗

PubMed1990

Studies on the activity of bepridil as a scavenger of free radicals.

Bepridil, a calcium antagonist with anti-anginal, anti-ischemic, and anti-arrhythmic properties was assessed for its ability to scavenge free radicals. Bepridil reduced the stable free radical 1,1-diphenyl-2-picrylhydrazil (DPPH) in the molar ratio 2:1 and, in this respect, was as active as the reference anti-oxidants hydroquinone and alpha-tocopherol. Allopurinol and SOD inhibited cytochrome c reduction in a hypoxanthine-xanthine oxidase superoxide generating system, whereas bepridil was ineffective. Deoxyribose degradation induced by the .OH radical was prevented by bepridil (IC50 = 0.050 mM). This ability to scavenge .OH was similar to that of dimethyl sulfoxide (DMSO) (IC50 = 0.056 mM) and more potent than that observed with mannitol and allopurinol (IC50 values of 0.74 mM and 0.92 mM, respectively). The powerful .OH scavenging activity of bepridil was confirmed in vivo on alloxan induced diabetes in mice. Bepridil exerted a marked protective effect at 0.150 mmol/kg whilst, ethanol and DMSO were active at the doses of 90 and 94 mmol/kg, respectively. These results demonstrate that bepridil is a potent .OH radical scavenger. This property may contribute to the therapeutic activity of this drug in myocardial ischaemia.

Allopurinol↗

PubMed1989

Bepridil: a pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia.

In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.

Angina Pectoris↗

PubMed1989

Functional, behavioral, and histological changes induced by transient global cerebral ischemia in rats: effects of cinnarizine and flunarizine.

Temporary cerebral ischemia (15 min) produced by "four-vessel occlusion" in the rat causes neurological disorders, changes in behavior (locomotor hyperactivity), and neuronal damage in the neocortex, striatum, and especially the CA1 zone of the hippocampus. We have studied the effects of two calcium overload blockers, flunarizine (50 mg/kg p.o. twice a day) and cinnarizine (100 mg/kg p.o. twice a day), on these alterations. Cinnarizine markedly improved the functional abnormalities of ischemia but had little or no effect upon the neuronal damage. In contrast, flunarizine provided far greater neuronal protection but with less obvious effects upon behavioral parameters. However, there was evidence of sedation 2 h after treating animals with this dose of flunarizine that might have masked any positive effect of the drug on behavior. We conclude that under the present experimental conditions, there is no correlation between the early and late behavioral changes observed following a temporary cerebral ischemic episode and the histological damage observed in certain vulnerable neurons, particularly in the hippocampus, 72 h after the insult.

Animals↗

PubMed1989

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem.

1. The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5 mg kg-1 i.v.) and those of verapamil and diltiazem (0.2 mg kg-1 i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2. The four drugs caused a bradycardia with the following order of potency: bepridil greater than CERM 11888 greater than diltiazem greater than verapamil. 3. All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order: verapamil much greater than diltiazem greater than bepridil greater than CERM 11888. 4. Verapamil and diltiazem did not affect conduction or the RP in atria while bepridil weakly slowed the former and markedly increased the latter. CERM 11888 caused a lengthening of RP but this was a delayed effect. 5. In the ventricle, bepridil and CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV. Verapamil and diltiazem had no significant effects at the ventricular level. 6. Our results confirm that the main sites of action of calcium antagonists are the SA and AV nodes. Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of bepridil.

Anesthesia↗

PubMed1989

Comparative effects of bepridil, its quaternary derivative CERM 11888 and verapamil on caffeine-induced contracture in ferret hearts.

1. The effects of bepridil, its quaternary derivative: CERM 11888 (methyl-pyrrolidinium bromide) (10(-7)-10(-5) M), and verapamil (10(-7)-10(-6) M) were compared on caffeine-induced contracture of isolated ventricular trabeculae of the ferret. 2. Bepridil diminished the amplitude of contracture in a concentration-dependent fashion, and this effect was significantly different from that of CERM 11888 which, like verapamil, only reduced the amplitude at the highest concentration used. 3. Bepridil (10(-6) M) significantly shortened the time to peak tension and accelerated the relaxation phase of contracture. This latter effect was different from that of CERM 11888. Verapamil (10(-6) M) also tended to accelerate the relaxation phase. At 10(-5) M these actions of bepridil on the time to peak and relaxation tended to reverse. 4. At all concentrations bepridil and verapamil reduced the rate of repriming of contracture and this effect of bedpridil was significantly different from that of its quaternary derivative which only showed a significant effect at 10(-5) M. 5. These results demonstrate a clear intracellular effect of bepridil in the ferret heart. Verapamil and CERM 11888 had only weak intracellular effects even at high concentrations. 6. Analysis of the results suggests that the main sites of action of bepridil in this model are the sarcoplasmic reticulum and one or two calcium compartments in the sarcolemma.

Animals↗

PubMed1988

Potentiation of the gastric antisecretory activity of histamine H2-receptor antagonists by clebopride.

The substituted benzamide, clebopride, at doses (0.03-3 mg kg-1 i.p.) that were without effect per se on the secretion of gastric acid in pylorus ligated (Shay) rats, potentiated the antisecretory effects of the histamine H2 receptor antagonists cimetidine and ranitidine in this model but not those of the muscarine receptor antagonist pirenzepine nor those of the proton pump inhibitor omeprazole. By contrast, clebopride was without influence on the inhibitory effects of cimetidine on pentagastrin-induced secretion in perfused stomach (Ghosh and Schild) preparations in anaesthetized rats. The significance of these findings is discussed in relation to the previously described potentiating effects of clebopride on the anti-ulcer activity of cimetidine in various experimental models, and the potential beneficial effects of such combined therapy in the clinic.

Animals↗

PubMed1986

Effect of diltiazem upon contractile responses to phenylephrine, cirazoline, Sgd 101/75, St 587 and B-HT 920 in rabbit aorta and dog saphenous vein preparations.

Diltiazem (10 microM) did not significantly affect concentration-response curves to the full, relatively selective alpha 1-adrenoceptor agonists phenylephrine and cirazoline in rabbit aorta and dog saphenous vein preparations. The effects of these 2 agonists remained resistant to diltiazem even in tissues pretreated with phenoxybenzamine (0.03 or 0.1 microM, 20 min) to reduce the alpha-adrenoceptor reserve. Sgd 101/75 and St 587 were partial agonists in both vascular preparations. The concentration-response curves to these relatively selective alpha 1-adrenoceptor agonists were also unaffected, or only slightly attenuated, by diltiazem. B-HT 920 at low concentrations preferentially stimulated the dog saphenous vein preparation and only at high concentrations elicited small contractions of the rabbit aorta. The responses to B-HT 920 were mediated by alpha 2-adrenoceptors in the vein and by alpha 1-adrenoceptors in the aorta yet concentration-response curves to this agonist were significantly attenuated by diltiazem in both tissues. The results indicate that the resistance of certain alpha-adrenoceptor-mediated responses in vascular preparations to calcium entry blockers need not be associated with the presence of a significant receptor reserve and that calcium dependency of a response may be determined by the agonist.

Adrenergic alpha-Agonists↗

PubMed1986

Involvement of enteric neurones in the response of guinea-pig ileum preparations to metoclopramide.

The role of myenteric neurones in mediating the stimulant effects of metoclopramide in vitro in the guinea-pig ileum has been investigated using the non-ionic surfactant Triton X-100. Histological examination of the ileum 30 days after application of Triton X-100 to the serosal surface demonstrated a marked reduction in the number of ganglion cells and nerve elements in the myenteric plexus. Longitudinal muscle-myenteric plexus (LM-MP) preparations from Triton X-100-treated animals were unresponsive to dimethylphenylpiperazinium and responded poorly or not at all to electrical field stimulation. Metoclopramide (30 microM) elicited small contractions in LM-MP preparations from control and sham-operated animals but failed to contract Triton X-100-treated tissues. However, tissues responded in a similar manner to exogenous acetylcholine (ACh). These results demonstrate the importance of a prejunctional site of action for metoclopramide in this tissue and suggest that contractile responses to the drug are mediated indirectly, probably by increased release of ACh from myenteric neurones.

Acetylcholine↗

PubMed1986

Synergistic interactions between piracetam and dihydroergocristine in some animal models of cerebral hypoxia and ischaemia.

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.

Anesthesia↗

PubMed1985

Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs.

This minireview is concerned with a re-examination of the locus of action and the possible peripheral mechanisms involved in the gastrointestinal (GI) stimulant effects of metoclopramide. Such a re-evaluation is opportune given the increasing use of this drug in the therapy of certain GI tract disorders. To provide an orientation on this subject the location in the GI tract and function of several relevant receptor types have been reviewed. In the past metoclopramide has been reported to enhance contractions of a variety of GI preparations to electrical stimulation, acetylcholine, carbachol and ganglion stimulants, to inhibit responses to alpha 2-adrenoreceptor agonists and 5-hydroxytryptamine, as well as blocking those to dopamine. Also in such preparations metoclopramide facilitates the release of acetylcholine to transmural stimulation. One important question is whether this effect is mediated via a specific prejunctional receptor. In this respect 2 suggestions have been made. Firstly that the drug may act as a preferential, prejunctional muscarinic antagonist thus inhibiting the negative feedback inhibition of acetylcholine release and secondly that metoclopramide may be a prejunctional agonist (partial) at 5-hydroxy-tryptamine receptors. Although the latter possibility appears most tenable at present, the involvement of a specific receptor remains to be confirmed. The important finding that dopamine receptors are probably not involved in the local stimulant effects of metoclopramide has important implications for future research orientated towards the discovery of a new generation of GI drugs lacking the side effects associated with central dopamine receptor blockade. Several compounds (cinitapride, BRL 20627A and cisapride) are now in the early stages of clinical evaluation.

Animals↗

PubMed1985

A comparison of the stimulatory effects of metoclopramide and cinitapride in the guinea-pig isolated ileum.

The pharmacological effects of a new benzamide derivative cinitapride, have been compared to those of metoclopramide in guinea-pig isolated ileum and longitudinal smooth muscle-myenteric plexus preparations treated with propranolol (3 microM). Cinitapride (EC50 = 0.74 microM) was 6 times more potent than metoclopramide (EC50 = 4.69 microM) in enhancing the twitch response of co-axially stimulated preparations and 11 times more potent in eliciting contractions in non-stimulated tissues, their respective EC50 values being 0.58 microM and 6.52 microM. These contractile effects of cinitapride and metoclopramide amounted to approximately 25% of the maximum response of the tissues to acetylcholine (1 microM). Neither cinitapride nor metoclopramide, in concentrations up to 10 microM, significantly affected concentration-response curves to exogenous acetylcholine or 5-hydroxytryptamine but both drugs elicited a concentration-dependent potentiation of the ileum responses to a fixed concentration (10 microM) of the ganglion stimulant dimethylphenylpiperazinium (DMPP). Analysis of the twitch-enhancing and contractile effects of cinitapride using a variety of drugs suggested that a common, prejunctional locus of action upon the cell bodies or axons of postganglionic, parasympathetic neurones of the myenteric plexus is involved in both of these responses. In hexamethonium (100 microM) and methysergide (0.1 microM)-treated longitudinal smooth muscle preparations desensitization or blockade of 5-hydroxytryptamine receptors using high concentrations of the same agonist (30 microM) or quipazine (10 microM) or the putative antagonists cocaine (30 microM) or tubocurarine (10 microM) produced small inhibitions (congruent to 20%) of the contractile responses to metoclopramide and cinitapride but did not affect twitch responses to these drugs. It is concluded that cinitapride is a more potent stimulant of guinea-pig intestinal smooth muscle than metoclopramide in vitro although the mechanism of action of both drugs appears to be similar and involves a prejunctional enhancement of acetylcholine release from intramural cholinergic neurones. Attempts to implicate a prejunctional facilitatory 5-hydroxytryptamine receptor in the mediation of the stimulant effects of these drugs were not conclusive and additional studies are required to fully explore this possibility.

Acetylcholine↗

PubMed1985

Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes.

The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.

Adrenergic alpha-Agonists↗

PubMed1984

Phenoxybenzamine-induced inhibition of cirazoline pressor responses in pithed rats pretreated with organic or inorganic calcium entry blocking drugs.

In groups of propranolol-treated pithed rats pretreatment with either verapamil (1 mg/kg i.a., 20 min) or the inorganic calcium entry blocker (CEB), cobalt (23.8 mg/kg i.a., 20 min) reduced maximum obtainable pressor responses to the relatively selective alpha 2-adrenoceptor agonist B-HT 920 (0.1-1000 micrograms/kg i.v.) equally, by approximately 50%. Verapamil and cobalt at these doses had little or no effect upon pressor responses induced by the relatively selective alpha 1-adrenoceptor agonist cirazoline (0.1-1000 micrograms/kg i.v.). Phenoxybenzamine (0.1 mg/kg i.v., 15 min) displaced to the right and reduced by 44% the maximum obtainable pressor responses to cirazoline. Treatment of animals with the combination of either verapamil or cobalt followed by phenoxybenzamine, at the dose levels and pretreatment times given above, produced significantly greater inhibitions of cirazoline pressor responses (83% and 88% reduction in the maximum obtainable pressor responses to cirazoline respectively) than were observed following administration of phenoxybenzamine alone. Since yohimbine (1 mg/kg i.v.) did not significantly affect the residual responses to cirazoline following treatment with phenoxybenzamine the mechanism responsible for this interaction between CEBs and phenoxybenzamine is not mediated via postjunctional alpha 2-adrenoceptors. Additional studies are required to assess the involvement of a possible subtype of alpha 1-adrenoceptors which appear to mediate vascular responses sensitive to CEBs.

Adrenergic beta-Agonists↗

PubMed1983

A comparison of the effects of verapamil and cinnarizine upon responses elicited by selective alpha 1- and alpha 2-adrenoceptor agonists in the autoperfused canine hindlimb.

In an attempt to extend the hypothesis that activation of vascular postsynaptic alpha 2-adrenoceptors requires an influx of Ca2+ ions, the effects of 2 calcium entry blocking drugs verapamil and cinnarizine have been examined as inhibitors of the pressor responses to methoxamine and B-HT 920 in autoperfused dog hindlimb preparations. Verapamil (0.1-1 mg i.a.) selectively antagonized responses to B-HT 920 and had little or no effect upon responses to methoxamine, thus supporting this hypothesis. However cinnarizine, over the dose range studied (0.1-1 mg/kg i.a.) produced quantitatively similar inhibitions of the hindlimb responses to B-HT 920 and methoxamine. These results suggest that cinnarizine may have a different site of action to verapamil in resistance vessels of the dog hindlimb.

Adrenergic alpha-Agonists↗

PubMed1983

Calcium entry blocking drugs, 'calcium antagonists' and vascular smooth muscle function.

The group of drugs known as "calcium antagonists' is under extensive investigation in experimental animals and man and a re-evaluation of their pharmacological properties is overdue. Recent proposals to adopt the more specific nomenclature of calcium entry blockers for some of these compounds (Vanhoutte & Bohr, 1981) should be supported since there is much confusion in the literature with this class of compound. In this review, which concentrates on vascular smooth muscle, only nifedipine, verapamil, their close chemical analogues and diltiazem are recognised as being relatively selective calcium entry blocking drugs. Whilst definitive evidence for calcium entry blockade must include the demonstration of a selective inhibition of Ca2+-influx into a tissue over a range of concentrations also inhibiting contraction, it is nevertheless possible to define several simple pharmacological criteria which may aid in the identification of such activity. These criteria include the selective antagonism of K+ and Ca2+-induced contractions, relative to those of noradrenaline in suitable vascular smooth muscle preparations and a selective inhibition of alpha 2- as opposed to alpha 1-adrenoreceptor mediated pressor responses in, for example, pithed rat preparations. Recent pharmacological and biochemical studies have identified 3 major subgroups of "calcium antagonist' drugs but the compounds within each subgroup varies with the technique adopted. It is therefore suggested that a combination of both pharmacological and ligand-binding studies be used for purposes of classification. Which mechanism, if any, of inhibiting calcium entry is therapeutically most desirable remains an important question for future research.

Animals↗

PubMed1982

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part II: Sites and mechanisms of action of dopamine receptor agonists.

Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.

Animals↗

PubMed1982

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part I: Subclassification and functional description.

The dopamine receptors of the peripheral cardiovascular system are not a pharmacologically uniform population. A number of studies indicate that they belong to at least two distinct subtypes for which it is proposed to adopt the name DA1- and DA2-dopamine receptors in an attempt to follow the nomenclature presently in fashion for several vascular receptors. Typical DA1-dopamine receptors are those occurring postjunctionally in the renal and mesenteric arterial beds where their stimulation mediates direct smooth muscle relaxation. Typical DA2-dopamine receptors are those present on postganglionic sympathetic neurons (axonal varicosities and perhaps ganglionic cell bodies) where their excitation leads, under appropriate physiological conditions, to a reduction of the neural release of norepinephrine. The latter effect can manifest itself by a passive fall in vascular resistance and heart rate. Other populations of dopamine receptors not yet well characterized pharmacologically but of theoretical interest as additional potential target sites for cardiovascular drugs might be present on nephrons and in the adrenal cortex. Their stimulation can mediate a natriuretic effect and a reduction of aldosterone release, respectively. The pharmacological evidence favoring the subclassification of cardiovascular dopamine receptors into two distinct subtypes is reviewed. Furthermore, the main agonists and antagonists of these receptors and the complexity of their pharmacological profile are mentioned. Part II of this minireview will be dedicated to the description of the sites and mechanisms of the antihypertensive action of dopamine receptor agonists.

Animals↗