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

The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular effects of physostigmine were investigated in conscious normotensive and spontaneously hypertensive rats. Intravenous (i.v.) physostigmine (50 μg kg −1 ) 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 ( P <0.05). Pretreatment with atropine sulphate (0.4 mg kg −1  i.v.), completely abolished the physostigmine‐induced pressor response in both normotensive and hypertensive rats. In both strains, the physostigmine pressor response was significantly reduced by the systemic administration of either an α 1 ‐adrenoceptor antagonist (prazosin, 1 mg kg −1 ) or a V 1A ‐vasopressin receptor antagonist (AVPX, 20 μg kg −1 ). This physostigmine pressor effect was completely abolished in both strains when both antagonists were administered concomitantly. In WKY rats, the pressor response to physostigmine (50 μg kg −1  i.v.) was inhibited in a dose‐dependent 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 significantly higher for atropine (7.34 nmoles), pirenzepine (21.60 nmoles) and p‐F‐HHSiD (139.50 nmoles) ( P <0.05). 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 outflow. Moreover, our results suggest that some modifications of the M 1 receptor subtypes in terms of expression or affinity could be responsible for the hyper‐responsiveness of the hypertensive strain to cholinomimetic agents.British Journal of Pharmacology (1999) 127 , 1657–1665; doi: 10.1038/sj.bjp.0702678