Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs.
1. In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5'-monophosphate (AMP), N6-cyclohexyladenosine (CHA, 400 fold A1-selective), 5'-N-ethyl-carboxamidoadenosine (NECA, A1 approximately A2) and 2-phenylaminoadenosine (PAA, 5 fold A2-selective) were compared in open-chest, fentanyl-pentobarbitone anaesthetized dogs. 2. Graded doses of CHA (10 to 1000 micrograms kg-1), NECA (0.5 to 100 micrograms kg-1) or PAA (0.1 to 20 micrograms kg-1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 micrograms kg-1 min-1) were also evaluated. 3. AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose-dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC). 4. After cardiac autonomic blockade with atropine (0.2 mg kg-1) and propranolol (1 mg kg-1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi. 5.Myocardial contractility, as assessed by E,,,,, measurements, was stimulated by AMP in control animals. Following cardiac autonomic blockade, PAA increased contractility while AMP and CHA had no significant effects.6. Despite marked.differences in receptor selectivity in vitro, no marked differences between the actions of these Al- and A2-selective Ado receptor agonists on the cardiovascular system in vivo were apparent.Difficulties therefore exist in the application of in vitro Ado receptor selectivity data to the prediction of the cardiovascular effects of Ado agonists in vivo.
Gerencer
R Z
RZ
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Finegan
B A
BA
Clanachan
A S
AS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000145:classification / Q000187:drug effects*
D011983:Receptors, Purinergic; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; D000249:Adenosine Monophosphate; D001285:Atropine; D011433:Propranolol; C026708:2-phenylaminoadenosine; D000241:Adenosine