Failure of CGS15943A to block the hypotensive action of agonists acting at the adenosine A3 receptor

Abstract

1. Adenosine receptor agonists were evaluated for their activity at the putative adenosine A3 receptor which mediates a 'xanthine-resistant' hypotensive response in the anaesthetized rat. The compounds tested were: the A1/A3 receptor agonist, N-[2-(4-aminophenyl)ethyl]adenosine (APNEA), the non-selective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236) and N6-cyclopentyl adenosine (CPA), the A2a receptor-selective agonists, 2-[[2-[4-(2-carboxyethyl) phenyl] ethyl] amino]-N- ethylcarboxamidoadenosine (CGS21680) and 2-phenylaminoadenosine (CV1808), and the moderately A2b selective agonist, N-[(2-methylphenyl)methyl]adenosine (metrifudil). 2. In confirmation of literature findings, APNEA (1-1000 nmol kg-1) induced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P-sulphophenyltheophylline (8-sPT; 40 mg kg-1, i.v.), whereas the bradycardia was attenuated. The non-xanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]triazolo[1,5-c]- quinazin-5-imine (CGS15943A; 3 mg kg-1 i.v.), also attenuated the bradycardia without affecting the hypotension. 3. The adenosine A1 receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antagonized by 8-sPT (40 mg kg-1) and CGS15943A (3 mg kg-1). 4. The adenosine A2a receptor-selective agonists, CGS21680 and CV1808, produced only a hypotensive response which was antagonized by 8-sPT (40 mg kg-1) and to a much greater extent by CGS15943A (3 mg kg-1), consistent with the response being mediated solely by A2a receptors. 5. The modestly A2b receptor-selective agonist, metrifudil, produced a dose-dependent fall in blood pressure and at higher doses a fall in heart rate. The hypotension induced by metrifudil was not antagonized by either 8-sPT (40 mg kg-1) or CGS15943A (3 mg kg-1) even though the bradycardia was abolished, suggesting that this agonist activates the putative A3 receptor.6. The non-selective adenosine receptor agonist, NECA, produced a hypotension and bradycardia that was attenuated by 8-sPT (40 mg kg-1), confirming previous work. The non-xanthine antagonist,CGS15943A (3 mg kg-'), also attenuated the hypotension and bradycardia. The bradycardia was blocked to a much greater extent, suggesting that NECA may therefore induce hypotension partly by activating the putative A3 receptor.7. In conclusion, we have confirmed that the putative A3 receptor mediating hypotension in the anaesthetized rat is not blocked by 8-sPT, and further shown that it is not blocked by CGS15943A. The A2a agonists CGS21680 and CV1808 showed no discernible activity at the A3 receptor, whereas APNEA,NECA, CPA and metrifudil appear to activate this receptor. The adenosine A1 receptor agonist,GR79236, shows considerable selectivity for the A1 receptor but may activate the A3 receptor at high doses.