Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release.
Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.
Allal
C
C
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U455 et U317, Faculté de Médecine, Toulouse, France.
Lazartigues
E
E
Tran
M A
MA
Brefel-Courbon
C
C
Gharib
C
C
Montastruc
J L
JL
Rascol
O
O
D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001919:Bradycardia / Q000097:blood / Q000139:chemically induced*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D019832:N-Methylscopolamine / Q000008:administration & dosage / Q000494:pharmacology; D009638:Norepinephrine / Q000097:blood; D010277:Parasympathomimetics / Q000008:administration & dosage / Q000633:toxicity*; D011976:Receptors, Muscarinic / Q000187:drug effects; D013619:Tacrine / Q000008:administration & dosage / Q000633:toxicity*; D014667:Vasopressins / Q000097:blood
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D014667:Vasopressins; D013619:Tacrine; D001285:Atropine; D019832:N-Methylscopolamine; D009638:Norepinephrine; D004837:Epinephrine