ENDOGENOUS ADENOSINE DOES NOT ACTIVATE ATP-SENSITIVE POTASSIUM CHANNELS IN THE HYPOXIC GUINEA-PIG VENTRICLE IN-VIVO

Background The activation of ATP-sensitive K+ (K-ATP(+)) channels by K -ATP(+) openers, eg, pinacidil, hypoxia, and ischemia, is known to sho rten the ventricular action potential. Since adenosine is released in increased amounts during cardiac hypoxia and ischemia, the hypothesis that endogenous adenosine activates K-ATP(+) channels was tested in vi vo in a guinea pig model. Methods and Results Anesthetized animals (n= 37) were subjected to transient acute global hypoxia by ventilation wi th 100% N-2. Monophasic action potentials (MAP) were recorded in ventr icular and atrial myocardium by use of custom-made Ag/AgCl electrode c atheters. In addition, right atrial and left ventricular electrograms as well as systemic arterial blood pressure were monitored throughout the experiments. Under normoxic conditions, pinacidil (1.8 mu g/kg IV, n=8), a K-ATP(+) channel opener, shortened ventricular MAP duration ( APD); this effect was reversed by glibenclamide, a potent K-ATP(+) cha nnel blocker, but not by 8-cyclopentyl-1,3-dimethylxanthine (CPT), a p otent A(1)-selective adenosine antagonist. Global hypoxia shortened at rial and ventricular APD. Glibenclamide but not CPT reversed this effe ct of hypoxia on ventricular but not atrial MAP. CPT but not glibencla mide reversed the effect of hypoxia on atrial MAP. In addition, CPT de layed the appearance of the atrioventricular (AV) nodal conduction blo ck associated with global hypoxia. Finally, the ability of CPT to sele ctively attenuate A(1)-adenosine receptor-mediated effects of adenosin e agonists in ventricular and supraventricular tissues was confirmed i n 17 animals. CPT reversed the negative dromotropic effect of adenosin e on AV nodal conduction and the antiadrenergic effect of N-6-cyclopen tyladenosine (CPA) mediated by A(1)-adenosine receptor but not the ade nosine-induced decrease in systemic blood pressure caused by the vasod ilatory action of the nucleoside mediated by A(2)-adenosine receptor. Conclusions (1) Endogenous adenosine released during global cardiac hy poxia mediates, in part, AV nodal conduction delay and shortening of a trial but not ventricular APD. (2) The action of adenosine on atrial A PD is mediated by A(1) adenosine receptors, probably via I-K,I-Ado,I-A ch. (3) Endogenous adenosine apparently does not play an important rol e in the early stages of acute global hypoxia-induced activation of K- ATP(+) channels. The present results are consistent with the hypothesi s that the shortening of ventricular APD in the hypoxic heart is due, in part, to activation of K-ATP(+) channels.