FAILURE OF CGS15943A TO BLOCK THE HYPOTENSIVE ACTION OF AGONISTS ACTING AT THE ADENOSINE A(3) RECEPTOR

1 Adenosine receptor agonists were evaluated for their activity at the putative adenosine A(3) receptor which mediates a 'xanthine-resistant ' hypotensive response in the anaesthetized rat. The compounds tested were: the A(1)/A(3) receptor agonist, N-[2-(4-aminophenyl)ethyl]adenos ine (APNEA), the nonselective adenosine receptor agonist, 5'-N-ethylca rboxamidoadenosine (NECA), the adenosine A(1) receptor-selective agoni sts, N-[(1S,trans)-2-hydroxycyclopentyl]adeno (GR79236) and N-6-cyclop entyl adenosine (CPA), the Al, receptor-selective agonists, 2-[[2-14-( 2-carboxyethyl) phenyl] ethyl] amino]-N-ethylcarboxamidoadenosine (CGS 21680) and 2-phenylaminoadenosine (CV1808), and the moderately A(2b) s elective agonist, N-[(2-methylphenyl)methyl] adenosine (metrifudil). 2 In confirmation of literature findings, APNEA (1-1000 nmol kg(-1)) in duced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P-sulphophenyltheophyllin e (8-sPT; 40 mg kg(-1) i.v.), whereas the bradycardia was attenuated. The nonxanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]tr iazolo{1,5-c}-quinazin-5-imine (CGS15943A; 3 mg kg(-1) i.v.), also att enuated the bradycardia without affecting the hypotension. 3 The adeno sine A(1) receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antag onized by 8-sPT (40 mg kg(-1)) and CGS15943A (3 mg kg(-1)). 4 The aden osine A(2a) 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)), consiste nt with the response being mediated solely by A(2a) receptors. 5 The m odestly A(2b) receptor-selective agonist, metrifudil, produced a dose- dependent fall in blood pressure and at higher doses a fall in heart r ate. The hypotension induced by metrifudil was not antagonized by eith er 8-sPT (40 mg kg(-1)) or CGS15943A (3 mg kg(-1)) even though the bra dycardia was abolished, suggesting that this agonist activates the put ative A(3) receptor. 6 The non-selective adenosine receptor agonist, N ECA, produced a hypotension and bradycardia that was attenuated by 8-s PT (40 mg kg(-1)), confirming previous work. The non-xanthine antagoni st, CGS15943A (3 mg kg(-1)), also attenuated the hypotension and brady cardia. The bradycardia was blocked to a much greater extent, suggesti ng that NECA may therefore induce hypotension partly by activating the putative A(3) receptor. 7 In conclusion, we have confirmed that the p utative A(3) receptor mediating hypotension in the anaesthetized rat i s not blocked by 8-sPT, and further shown that it is not blocked by CG S15943A. The A(2a) agonists CGS21680 and CV1808 showed no discernible activity at the A(3) receptor, whereas APNEA, NECA, CPA and metrifudil appear to activate this receptor. The adenosine A(1) receptor agonist , GR79236, shows considerable selectivity for the A(1) receptor but ma y activate the A(3) receptor at high doses.