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 normotensive and spontaneously hypertensive rats. 2. Intravenous (i.v.) physostigmine (50 microg 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). 3. 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 alpha1-adrenoceptor antagonist (prazosin, 1 mg kg-1) or a V1A-vasopressin receptor antagonist (AVPX, 20 microg kg-1). This physostigmine pressor effect was completely abolished in both strains when both antagonists were administered concomitantly. 4. In WKY rats, the pressor response to physostigmine (50 microg kg-1 i.v.) was inhibited in a dose-dependent manner by i. c.v. administration of atropine (ID50=3.70 nmoles), the M1 receptor antagonist pirenzepine (ID50=10.71 nmoles), the M2 receptor antagonist methoctramine (ID50=4.31 nmoles), the M3 receptor antagonist p-F-HHSiD (ID50=60.52 nmoles) and the M4 receptor antagonist tropicamide (ID50=214.20 nmoles). In the hypertensive strain, the ID50 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). 5. The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M2 and M1 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 M1 receptor subtypes in terms of expression or affinity could be responsible for the hyper-responsiveness of the hypertensive strain to cholinomimetic agents.
Lazartigues
E
E
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317 et U455, Faculté de Médecine, 37 allées Jules Guesde 31073 Toulouse Cedex, France.
Brefel-Courbon
C
C
Tran
M A
MA
Montastruc
J L
JL
Rascol
O
O
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D010277:Parasympathomimetics / Q000008:administration & dosage / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000187:drug effects / Q000503:physiopathology*; D010830:Physostigmine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D018727:Muscarinic Antagonists; D010277:Parasympathomimetics; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D001127:Arginine Vasopressin; D010830:Physostigmine