Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat

The cardiovascular effects of three different acetylcholinesterase inhibito rs: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significa ntly increased both systolic and diastolic blood pressure and decreased hea rt rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pr esser effect. Tacrine was chosen as a model to study the mechanisms underly ing the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine presser effec ts. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha (1)-adrenoceptor antagonist prazosin or the vasopressin V-1 receptor antago nist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2 ), Arg(8)] vasopressin partially but significantly reduced tacrine presser effect and mostly abolished it when administered concomitantly. The tacrine presser response was inhibited in a dose-dependent manner by the i.c.v. ad ministration of the non-selective muscarinic receptor antagonist atropine ( ID50 = 1.45 mu g), the muscarinic M-1 receptor antagonist pirenzepine (ID50 = 4.33 mu g), the muscarinic M-2 receptor antagonist methoctramine (ID50 = 1.39 mu g) and the muscarinic M-3 receptor antagonist para-fluoro-hexahydr o-sila-difenidol (ID50 = 31.19 mu g). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our result s show that acetylcholinesterase inhibitors induce significant cardiovascul ar effects with a presser response mediated mainly by the stimulation of ce ntral muscarinic M-2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, aretylcholinesterase inhibito r-induced bradycardia appears to be mediated by peripheral muscarinic mecha nisms. (C) 1998 Elsevier Science B.V. All rights reserved.