GLIBENCLAMIDE REDUCES THE CORONARY VASOACTIVITY OF ADENOSINE RECEPTORAGONISTS

Experiments in guinea pig heart Langendorff preparations assessed the effect of K-ATP channel blockade on the coronary vasoactivity of adeno sine and 17 analogs chosen to represent a variety of purine and ribose modifications. Although glibenclamide is a functional antagonist that acts at the level of an effector rather than at a receptor, it caused parallel rightward shifts of agonist dose-response curves. The size o f the shift of EC(50) differed according to the kind of analog: the ra nking was, generally, N-6-phenethyladenosines > 2-aryl-aminoadenosines = 2-(1-alkyn-1-yl)adenosines > N-6-cycloalkyladenosines = adenosine-5 '-uronamides. The coronary vasoactivity ranking of agonists in the pre sence of supramaximal concentrations of glibenclamide was 2-(1-alkyn-1 -yl)adenosines = 2-aralkoxyadenosines > 2-aralkylaminoadenosines > 2-a rylaminoadenosines > N-6-substituted adenosines. Glibenclamide did not affect the vasoactivity of adenosine itself, perhaps because avid upt ake by endothelial cells prevented penetration of the agonist to recep tors deeper in the vascular wall. The results exclude a model consisti ng of one kind of receptor acting exclusively through a K-ATP channel, argue against one kind of receptor coupled to a K-ATP channel as well as to an additional effector but is consistent with two kinds of vaso dilatory adenosine receptors, one of which activates a K-ATP channel. The identity of the adenosine receptor coupled to the K-ATP channel is uncertain; the other receptor has the pharmacological profile of an A (2a)-adenosine receptor.