A2-purinoceptor-mediated relaxation in the guinea-pig coronary vasculature: a role for nitric oxide.
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 x 10(-5) M) significantly reduced both the maximum amplitude and area of the vasodilatation produced in response to adenosine (5 x 10(-10) -5 x 10(-8) mol) without having any effect on the response to the P2-purinoceptor agonist, 2-methylthioATP. The relaxation induced by adenosine (5 x 10(-12) -5 x 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 x 10(-10) -5 x 10(-7 mol), NECA (5 x 10(-12) -5 x 10(-7) mol) and CGS 21680 (5 x 10(-12) -5 x 10(-10) mol) were significantly reduced by NG-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-5) M). The amplitude of the responses to low concentrations of adenosine (5 x 10-10-5 x 10-9mol), NECA (5 x 1011 mol) and CGS 21680 (5 x 1011-5 x 10-9mol)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 I0- mol) and CGS 21680 (5 x 10-11 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 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.
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Department of Anatomy and Developmental Biology, University College London.
Burnstock
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D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
D000959:Antihypertensive Agents; D010627:Phenethylamines; D011453:Prostaglandins; D011983:Receptors, Purinergic; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D009569:Nitric Oxide; C031433:8-(4-sulfophenyl)theophylline; D001120:Arginine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin