Endothelium-mediated coronary dilatation by adenosine does not depend on endothelial adenylate cyclase activation: studies in isolated guinea pig hearts.
Adenosine, applied to the coronary system of guinea pigs at up to 10(-6) M, elicits dilatation solely via an endothelium-mediated process. We investigated the role of coronary A2 receptors in this dilation, since the coronary endothelium possesses adenosine A2-receptors with a stimulatory action on the adenylate cyclase. In situ, A2 receptor stimulation can be assessed by prelabeling the coronary endothelial adenine nucleotide pool with 3H-adenosine and subsequently determining the rate of release of radiolabeled cAMP induced by A2 agonists. Thus, perfusion of isolated hearts with 5'-N-ethylcarboxamidoadenosine (NECA) dose-dependently increased coronary flow and the release of 3H-cAMP from the endothelium. In the presence of 50 microM 2',5'-dideoxyadenosine (ddA), a P-site agonist which inhibits the catalytic activity of adenylate cyclase, coronary flow increases induced by both adenosine and NECA were unaffected. In contrast, ddA reduced the release of labeled cAMP in response to NECA by about 60%. In cultured endothelial cells, ddA likewise inhibited cAMP accumulation due to NECA by about 70%. Moreover, ddA antagonized the adenylate cyclase mediated flow response due to the PGI2 analogue, iloprost, as well as the positive chronotropic and inotropic actions of isoproterenol. The dissociation elicited by ddA between the coronary flow response and the release of cAMP strongly indicates that the endothelial A2 receptors which are linked to adenylate cyclase are not causally involved in endothelium-dependent coronary dilatation induced by adenosine.
Newman
W H
WH
Department of Pharmacology, Medical University of South Carolina, Charleston 29425.
Becker
B F
BF
Heier
M
M
Nees
S
S
Gerlach
E
E
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives*; D015224:Dideoxynucleosides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000502:physiology; D004789:Enzyme Activation; D011464:Epoprostenol / Q000494:pharmacology; D006168:Guinea Pigs; D016285:Iloprost; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D015224:Dideoxynucleosides; D011942:Receptors, Adrenergic, alpha; D019830:Adenosine-5'-(N-ethylcarboxamide); D016048:Dideoxyadenosine; C021008:2',5'-dideoxyadenosine; D011464:Epoprostenol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D016285:Iloprost; D000241:Adenosine; D007545:Isoproterenol