Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat.
The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart 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 pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.
Lazartigues
E
E
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317 et U455, Faculté de Médecine, Toulouse, France.
Freslon
J L
JL
Tellioglu
T
T
Brefel-Courbon
C
C
Pelat
M
M
Tran
M A
MA
Montastruc
J L
JL
Rascol
O
O
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001285:Atropine / Q000494:pharmacology; D001286:Atropine Derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002714:Chlorisondamine / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003959:Diamines / Q000494:pharmacology; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D048448:Phenylcarbamates; D010830:Physostigmine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068836:Rivastigmine; D013599:Systole; D013619:Tacrine / Q000494:pharmacology
D018674:Adrenergic Antagonists; D065092:Antidiuretic Hormone Receptor Antagonists; D001286:Atropine Derivatives; D002219:Carbamates; D002317:Cardiovascular Agents; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D003959:Diamines; D048448:Phenylcarbamates; D010880:Piperidines; C058297:4-fluorohexahydrosiladifenidol; D010890:Pirenzepine; D013619:Tacrine; D001285:Atropine; C006649:methylatropine; D010830:Physostigmine; D002714:Chlorisondamine; C054938:methoctramine; D000068836:Rivastigmine