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

1 The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular effects of physostigmine were investigated in conscious nor motensive and spontaneously hypertensive rats. 2 Intravenous (i.v.) physostigmine (50 mu g kg(-1)) induced in both strains a long pressor response, accompanied by a bradycardia. This presser respon se was larger in spontaneously hypertensive ( + 41 +/- 6 mmHg) than in Wist ar-Kyoto (+ 25 +/- 2 mmHg) rats (P < 0.05). 3 Pretreatment with atropine sulphate (0.4 mg kg(-1) i.v.), completely abol ished the physostigmine-induced presser response in both normotensive and h ypertensive rats. In both strains, the physostigmine pressor response was s ignificantly reduced by the systemic administration of either an alpha(1)-a drenoceptor antagonist (prazosin, 1 mg kg(-1)) or a V-1A-vasopressin recept or antagonist (AVPX, 20 mu g kg(-1)). This physostigmine pressor effect was completely abolished in both strains when both antagonists were administer ed concomitantly. 4 In WKY rats, the presser response to physostigmine (50 mu g kg(-1) i.v.) was inhibited in a dose-dependent manner by i.c.v. administration of atropi ne (ID50 = 3.70 nmoles), the M-1 receptor antagonist pirenzepine (ID50 = 10 .71 nmoles), the M-2 receptor antagonist methoctramine (ID50 = 4.31 nmoles) , the M-3 receptor antagonist p-F-HHSiD (ID50 = 60.52 nmoles) and the M-4 r eceptor antagonist tropicamide (ID50 = 214.20 nmoles). In the hypertensive strain, the ID50 were found to be significantly higher for atropine (7.34 n moles), pirenzepine (21.60 nmoles) and p-F-HHSiD (139.50 nmoles) (P<0.05). 5 The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M-2 an d M-1 cholinoceptors to induce a rise in blood pressure mediated by an incr ease in plasma vasopressin and sympathetic outflow. Moreover, our results s uggest that some modifications of the M-1 receptor subtypes in terms of exp ression or affinity could be responsible for the hyper-responsiveness of th e hypertensive strain to cholinomimetic agents.