Serotonin receptors: Subtypes, functional responses and therapeutic relevance

Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-ht5 to 5-ht7) and ‘orphan’ receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands

The current endothelin receptor classification: Time for reconsideration?

The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of endothelin research has resulted in the molecular characterization and pharmacological recognition of ETA and ETB receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ETB receptors. In this article. Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular

Serotonin receptors as cardiovascular targets

Serotonin exerts complex effects in the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia; the eventual response depends primarily on the nature of the 5-HT receptors involved. In the light of current 5-HT receptor classification, the authors reanalyse the cardiovascular responses mediated by 5-HT receptors and discuss the established and potential therapeutic applications of 5-HT ligands in the treatment of some cardiovascular pathologie

NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig

The effects of NG-nitro-Lrarginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50μm). L-NAME (1, 3 and 10 mg·kg-1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 μm microspheres, L-NAME (1 and 3 mg·kg-1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 μm microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 μm, was reduced by L-NAME (3 mg · kg-1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis

Different pharmacological responses of atrium and ventricle: Studies with human cardiac tissue

It has been recently reported that 5-hydroxytryptamine (5-HT) increases force of contraction in atrial tissue but not in ventricular tissue. In the present study with trabeculae obtained from non-diseased human hearts, we investigated whether this difference in the contractile response is specific for 5-HT or is also observed for other substances: calcitonin gene-related peptide (CGRP), angiotensin II, adenosine, somatostatin and acetyllcholine. CGRP (10−9 to 10−7 M) and angiotensin II (10−9 to 10−5 M) caused concentration-dependent increases in force of contraction in atrial trabeculae (up to36 ± 8%and42 ± 8% of the response to 10−5 M noradrenaline, respectively). Similar to 5-HT, no effects were observed with CGRP and angiotensin II in ventricular trabeculae. Adenosine (10−8 to 10−5 M) and somatostatin (10−8 to 10−6 M) caused concentration-dependent negative inotropic effects on baseline atrial contractility (−54 ± 17%and−51 ± 25%, respectively, but no response was found on baseline ventricular contractility. Adenosine, but not somatostatin, reduced force of contraction after pre-stimulation with 10−5 M noradrenaline in atrial tissue and, to a lesser extent, in ventricular tissue. Acethlcholine exhibited a biphasic concentration-response curve in the atrial tissue, consisting of an initial negative inotropic response (10−9 to 10−7 M, from 120 ± 41mg at baseline to48 ± 16mg at 10 −7 M, fol lowed by a positive inotropic response (10−6 to 10−3 M, from 48 ± 16 mg at 10−7 M to77 ± 55mg). On the baseline ventricular for foce of contraction, acetylcholine (10−9 to 10−4 M) induced only a positive inotropic effect, starting at 10−9 M (from 252 ± 65mg at baseline to353 ± 71mg at 10−4M). After pre-stimulation with 10−5 M noradrenaline, acethylcholine reduced force of contraction in both tissue at 10−3 M(atrium: −14 ± 4%,ventricle: −61 ± 5%). The data indicate that, in atrial tissue, force of contraction can be affected by either postive or negative inotropic agents. However, in ventricular tissue only positive inotropic effects could be detected. Since atrial and ventricular tissues display different responses to the above biogenic substances, a different mechnism of regulation of contractility seems feasible

Systemic hemodynamic and regional circulatory effects of centrally administered endothelin-1 are mediated through ETA receptors

Central endothelin (ET) has been implicated in the regulation of the cardiovascular system. The effect of intracerebroventricular (i.c.v.) administration of ET-1 or IRL 1620 (5, 15 and 45 ng) on the systemic hemodynamics and regional circulation was studied in anesthetized rats using a radioactive microsphere technique. Systemic hemodynamics and regional blood circulation were determined before (baseline) and at 30 min after the injection of each dose of ET-1 or IRL 1620. Administration of saline (5 μl, i.c.v.) did not produce any significant cardiovascular effects. The lower doses of ET-1 (5 and 15 ng) did not produce any significant effect on blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral resistance (TPR) and regional blood circulation. However, the higher dose (45 ng) produced a transient rise (26%) followed by a sustained fall (48%) in BP. The decrease in BP was accompanied by significant decreases in CO (44%) and SV (39%), while HR and TPR were not affected. ET-1 (45 ng, i.c.v.) also produced a significant reduction in blood flow to the brain (75%), heart (49%), kidneys (66%), GIT (40%), portal system (52%) and musculo-skeletal system (38%), while blood flow to the skin was not affected. To determine pharmacological specificity of the central effects of ET-1, studies were performed in rats pretreated with BQ-123, a specific ETA receptor antagonist. Pretreatment with BQ-123 (10 μg, i.c.v.), 15 min prior to the administration of ET-1, completely antagonized the systemic hemodynamic as well as the regional circulatory effects of ET-1 (45 ng, i.c.v.). In order to determine whether stimulation of central ETB receptors produces any cardiovascular effects, studies were performed using IRL 1620, a specific ETB receptor agonist. Administration of IRL 1620 (5, 15 and 45 ng, i.c.v.) did not produce any effect on systemic hemodynamics and regional blood circulation in rats. It is concluded that ETA but not ETB receptors are involved in the central cardiovascular actions of ET

Characterization of the positive and negative inotropic effects of acetylcholine in the human myocardium

In the human isolated myocardium, acetylcholine (10−9 to 10−3 M) elicited a biphasic inotropic effect (a decrease in the lower and an increase in the higher concentration range) in atrial and a positive inotropic effect in ventricular trabeculae. However, under conditions of raised contractility achieved by exposure to noradrenaline (10−5 M), only negative inotropic effects were observed in both atria and ventricles. Atropine (10−6 M), but not propranolol (10−6 M), antagonized both positive and negative inotropic effects of acetylcholine, thus showing that the responses were mediated by muscarinic acetylcholine receptors. The use of subtype selective muscarinic receptor antagonists (10−7 to 10−5 M), pirenzepine (M1 > M3 > M2), AF-DX 116 (11-({2-[(diethylamino)-methyl]-1-piperidyl}acetyl)-5,11-dihydro-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one base; M2 > M1 > M and HHSiD (p-fluorohexahydro-siladifenidol hydrochloride; M3 ≥ M1 ⪢ M2) revealed that the negative inotropic effect of acetylcholine in atrial as well as the positive inotropic effect in ventricular trabeculae were best antagonized by AF-DX 116 and not by pirenzepine, suggesting the involvement of the muscarinic M2 receptor subtype, possibly linked to different second messenger systems. On the other hand, the positive inotropic effect of acetylcholine (10−6 to 10−3 M) in the atrial tissue, observed only in preparation with depressed contractility, was not effectively antagonized by either AF-DX 116 or HHSiD, but was significantly reduced by pirenzepine. Furthermore, the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethyl ammonium chloride; 10−9 to 10−3 M), which failed to significantly change the baseline contractility in either atrial or ventricular trabeculae, produced a positive inotropic effect in atrial preparations when contractility had been depressed by prior treatment with acetylcholine (10−9 to 10−7 M). This effect of McN-A-343 was effectively antagonized by pirenzepine (10−5 M). These data show that, besides the muscarinic M2 receptor mediating both negative (atria) and positive (ventricle) inotropic effects, muscarinic M1 receptors, capable of reversing depressed atrial contractility, are present in the human heart