A(2)-PURINOCEPTOR-MEDIATED RELAXATION IN THE GUINEA-PIG CORONARY VASCULATURE - A ROLE FOR NITRIC-OXIDE

1 The Langendorff heart preparation was used to investigate the mechan ism of action of the endothelium-dependent vasodilatation evoked by ad enosine and its analogues in the guinea-pig coronary vasculature. 2 Th e relative order of potency of adenosine and its analogues in causing a reduction in perfusion pressure was D-5'-(N-ethylcarboxamide)adenosi ne (NECA) = l)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21 680)>R-N6-(2-phenylisopropyl)adenosine (R-PIA) = adenosine = 2-chloroa denosine (2-CA)>S-N6-(2-phenylisopropyl)adenosine (S-PIA) = N6-cyclope ntyl-adenosine (CPA); thus suggesting the presence of A2-purinoceptors in this preparation. 3 8-(p-Sulphophenyl)theophylline (8-PSPT; 3 x 10 (-5) M) significantly reduced both the maximum amplitude and area of t he vasodilatation produced in response to adenosine (5 x 10(-10)-5 x 1 0(-8) mol) without having any effect on the response to the P2-purinoc eptor agonist, 2-methylthioATP. The relaxation induced by adenosine (5 x 10(-12)-5 x 10(-8) mol) was unaffected by the selective A1-purinoce ptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10(-8) M). This antagonist profile suggests that only A2-purinoceptors are presen t in the guinea-pig coronary vasculature. 4 The areas of the vasodilat or response to adenosine (5 x 10(-10)-5 x 10(-7) mol), NECA (5 x 10(-1 2)-5 x 10(-7) mol) and CGS 21680 (5 x 10(-12)-5 x 10(-10) mol) were si gnificantly reduced by N(G)-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-5) M). The amplitude of the responses to low concentrations of ad enosine (5 x 10(-10)-5 x 10(-9) mol), NECA (5 x 10(-11) mol) and CGS 2 1680 (5 x 10(-11)-5 x 10(-9) mol) were significantly reduced by L-NAME (3 x 10(-5) M). 5 L-Arginine (1.5 x 10(-3) M) significantly reversed the inhibition, by L-NAME (3 x 10(-5) M), of the relaxant response to adenosine (5 x 10(-8) mol), NECA (5 x 10(-9) mol) and CGS 21680 (5 x 1 0(-11) mol). 6 Indomethacin (10(-6) M) did not inhibit the response to adenosine, except at low doses (5 x 10(-11)-5 x 10(-10) mol). 7 It is concluded that in the guinea-pig coronary vasculature, while a major part of the vasodilator action of adenosine is probably directly via A 2-receptors on the smooth muscle, activation of a subpopulation of A2- purinoceptors on endothelial cells by adenosine and its analogues indu ces relaxation via production of nitric oxide; prostanoids appear to p lay a minimal role in the relaxation induced by adenosine as in most o ther preparations.