Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat
ABSTRACT 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 α1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [β-mercapto-β,β-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 μg), the muscarinic M1 receptor antagonist pirenzepine (ID50=4.33 μg), the muscarinic M2 receptor antagonist methoctramine (ID50=1.39 μg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50=31.19 μg). 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.
- [show abstract] [hide abstract]
ABSTRACT: Previous experimental studies have shown that intracerebroventricular (i.c.v.) injection of the GABAA receptor antagonist, bicuculline methiodide, results in marked increases in blood pressure due to an increase in sympathetic nervous system activity. It is well recognized that the central cholinergic system is also involved in the regulation of blood pressure. In the present study, we examined the role of brain acetylcholine in the pressor response induced by bicuculline methiodide in conscious Sprague-Dawley rats. I.c.v. (0.05, 0.3 and 0.5 nmol) and intrahypothalamic (40 pmol) administration of bicuculline methiodide produced blood-pressure increases in a dose-dependent manner. Hemicholinium-3 was given i.c.v. 1 h prior to bicuculline methiodide. The depletion of brain acetylcholine was demonstrated by the suppression of physostigmine-induced pressor responses, but blood pressure increases in response to carbachol remained unchanged. The pressor responses to bicuculline methiodide in animals pre-treated with hemicholinium-3 were significantly higher than those seen in saline-pre-treated groups. Likewise, bicuculline methiodide, at a dose that did not alter blood pressure alone, caused pressor responses in rats pre-treated with the nicotinic receptor antagonist, mecamylamine, whereas the muscarinic receptor antagonist, atropine, was ineffective in this respect. In conclusion, it seems likely that endogenous brain acetylcholine has a modulator role on GABAA receptor-mediated blood-pressure control via nicotinic receptors.European Journal of Pharmacology 01/1997; 317(2-3):301-7. · 2.59 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The effect of morphine was studied on physostigmine-induced hypertensive response in anesthetized rats. Physostigmine caused dose-dependent increase in blood pressure. When given at a dose (2 mg/kg i.v.) that did not alter blood pressure, morphine significantly inhibited the hypertensive effect of physostigmine administered either i.v. or i.c.v. Oxotremorine evoked a hypertensive response which was also inhibited by morphine. This inhibitory effect of morphine was prevented or reversed by naloxone. These results support the view that cholinergic and opiatergic systems interact on regulating arterial blood pressure.Archives internationales de pharmacodynamie et de thérapie. 11/1984; 271(2):275-81.
- Pharmacological Reviews 07/1996; 48(2):179-211. · 22.35 Impact Factor