A2‐purinoceptor‐mediated relaxation in the guinea‐pig coronary vasculature: a role for nitric oxide

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Abstract
1 The Langendorff heart preparation was used to investigate the mechanism of action of the endothelium-dependent vasodilatation evoked by adenosine and its analogues in the guinea-pig coronary vasculature. 2 The relative order of potency of adenosine and its analogues in causing a reduction in perfusion pressure was d-5′-(N-ethylcarboxamide)adenosine (NECA) = 2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680)>R-N6-(2-phenylisopropyl)adenosine (R-PIA) = adenosine = 2-chloroadenosine (2-CA)>S-N6-(2-phenylisopropyl)adenosine (S-PIA) = N6-cyclopentyl-adenosine (CPA); thus suggesting the presence of A2-purinoceptors in this preparation. 3 8-(p-Sulphophenyl)theophylline (8-PSPT; 3 × 10−5 m) significantly reduced both the maximum amplitude and area of the vasodilatation produced in response to adenosine (5 × 10−10 − 5 × 10−8 mol) without having any effect on the response to the P2-purinoceptor agonist, 2-methylthioATP. The relaxation induced by adenosine (5 × 10−12 − 5 × 10−8 mol) was unaffected by the selective A1-purinoceptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10−8 m). This antagonist profile suggests that only A2-purinoceptors are present in the guinea-pig coronary vasculature. 4 The areas of the vasodilator response to adenosine (5 × 10−10 − 5 × 10−7 mol), NECA (5 × 10−12 − 5 × 10−7 mol) and CGS 21680 (5 × 10−12 − 5 × 10−10 mol) were significantly reduced by NG-nitro-l-arginine methyl ester (l-NAME; 3 × 10−5 m). The amplitude of the responses to low concentrations of adenosine (5 × 10−10 − 5 × 10−9 mol), NECA (5 × 10−11 mol) and CGS 21680 (5 × 10−11 − 5 × 10−9 mol) were significantly reduced by l-NAME (3 × 10−5 m). 5 l-Arginine (1.5 × 10−3m) significantly reversed the inhibition, by l-NAME (3 × 10−5m), of the relaxant response to adenosine (5 × 10−8 mol), NECA (5 × 10−9 mol) and CGS 21680 (5 × 10−11 mol). 6 Indomethacin (10−6 m) did not inhibit the response to adenosine, except at low doses (5 × 10−11 − 5 × 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 A2-receptors on the smooth muscle, activation of a subpopulation of A2-purinoceptors on endothelial cells by adenosine and its analogues induces relaxation via production of nitric oxide; prostanoids appear to play a minimal role in the relaxation induced by adenosine as in most other preparations.