Spontaneously hypertensive rats cholinergic hyper‐responsiveness: central and peripheral pharmacological mechanisms

Abstract

1 The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular eects of physostigmine were investigated in conscious normotensive and spontaneously hypertensive rats. 2 Intravenous (i.v.) physostigmine (50 mg kg 71) induced in both strains a long pressor response, accompanied by a bradycardia. This pressor response was larger in spontaneously hypertensive (+41+6 mmHg) than in Wistar-Kyoto (+25+2 mmHg) rats (P50.05). 3 Pretreatment with atropine sulphate (0.4 mg kg 71 i.v.), completely abolished the physostigmineinduced pressor response in both normotensive and hypertensive rats. In both strains, the physostigmine pressor response was signi®cantly reduced by the systemic administration of either an a 1 -adrenoceptor antagonist (prazosin, 1 mg kg 71 ) or a V 1A -vasopressin receptor antagonist (AVPX, 20 mg kg 71 ). This physostigmine pressor eect was completely abolished in both strains when both antagonists were administered concomitantly. 4 In WKY rats, the pressor response to physostigmine (50 mg kg 71 i.v.) was inhibited in a dosedependent manner by i.c.v. administration of atropine (ID 50 =3.70 nmoles), the M 1 receptor antagonist pirenzepine (ID 50 =10.71 nmoles), the M 2 receptor antagonist methoctramine (ID 50 =4.31 nmoles), the M 3 receptor antagonist p-F-HHSiD (ID 50 =60.52 nmoles) and the M 4 receptor antagonist tropicamide (ID 50 =214.20 nmoles). In the hypertensive strain, the ID 50 were found to be signi®cantly higher for atropine (7.34 nmoles), pirenzepine (21.60 nmoles) and p-FHHSiD (139.50 nmoles) (P50.05). 5 The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M 2 and M 1 cholinoceptors to induce a rise in blood pressure mediated by an increase in plasma vasopressin and sympathetic out¯ow. Moreover, our results suggest that some modi®cations of the M 1 receptor subtypes in terms of expression or anity could be responsible for the hyper-responsiveness of the hypertensive strain to cholinomimetic agents.

Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats

“…In the study conducted by Lazartigues et al (1999), increases in HR were observed in the WKY, but not in the SHR.…”

“…In literature, muscarine (a parasympathomimetic agent) has been reported be have activity similar to that of acetyl choline, although being more potent. Previous reports in literature alludes to the fact that muscarine reduces BP, while atropine (a parasympatholytic agent) has been reported in literature to have various effects on BP; from increases (Bartholow, 1908;Fraser, 1957;Wess et al, 1987), to no effect in WKY rats and SHR (Lazartigues et al, 1999;Mestivier et al, 2001), and to immediate and dose-dependent reductions, at the doses of 5-50 mg/kg given intravenously in conscious unanaesthetized WKY rats and hypertensive rats (SHR, and Sprague-Dawley rats made hypertensive by subcutaneous implantation of deoxycorticosterone acetate) (Abraham et al, 1981a(Abraham et al, , 1981bCantor et al, 1983).…”

Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

“…Potential cardiac effects are also important and have been examined in a limited number of animal studies, which demonstrate bradycardia and atrioventricular block due to the potentiation of parasympathetic nervous control (mediated through the vagus nerve). (James et al, 1979;Lazartigues et al, 1999) Despite this risk, electrocardiogram monitoring has not been routinely performed in pre-clinical studies investigating nerve agent pre-treatment. Coadministration with competitive muscarinic receptor antagonists (e.g.…”

The snake venom peptide Bj‐PRO‐7a is a M1 muscarinic acetylcholine receptor agonist

“…Although additional experiments are still necessary to identify whether Bj-PRO-7a acts or not on any further metabotropic receptors or ion channels, this work provides a novel tool for investigation of mAChRs in addition to potential therapeutic applications of this natural peptide. Finally, the characterization of Bj-PRO-7a as M1 receptor agonist brings new insights to explain the antihypertensive actions of this peptide family (23), which was shown to be not fully explained by ACE inhibition.…”

“…Five subtypes of mAChRs (M1-M5) belonging to the superfamily of G-protein-coupled receptors mediate the effects of acetylcholine by central and peripheral cholinergic neurotransmission, including on blood pressure control (22). In this context, Lazartigues et al (23) suggested that modifications in M1 muscarinic receptors could be at the origin of hyper-responsiveness of a hypertensive rat strain to cholinergic drugs. Moreover, altered cardiovascular responses were observed in M1 mAChR knock-out mice (24).…”