Endogenous adenosine does not activate ATP-sensitive potassium channels in the hypoxic guinea pig ventricle in vivo.

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Abstract
BACKGROUND: The activation of ATP-sensitive K+ (K+ ATP) channels by K+ ATP openers, eg, pinacidil, hypoxia, and ischemia, is known to shorten 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 vivo in a guinea pig model. METHODS AND RESULTS: Anesthetized animals (n = 37) were subjected to transient acute global hypoxia by ventilation with 100% N2. Monophasic action potentials (MAP) were recorded in ventricular and atrial myocardium by use of custom-made Ag/AgCl electrode catheters. 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 microgram/kg i.v., n = 8), a K+ ATP channel opener, shortened ventricular MAP duration (APD); this effect was reversed by glibenclamide, a potent K+ ATP channel blocker, but not by 8-cyclopentyl-1,3-dimethylxanthine (CPT), a potent A1-selective adenosine antagonist. Global hypoxia shortened atrial and ventricular APD. Glibenclamide but not CPT reversed this effect of hypoxia on ventricular but not atrial MAP. CPT but not glibenclamide reversed the effect of hypoxia on atrial MAP. In addition, CPT delayed the appearance of the atrioventricular (AV) nodal conduction block associated with global hypoxia. Finally, the ability of CPT to selectively attenuate A1-adenosine receptor-mediated effects of adenosine agonists in ventricular and supraventricular tissues was confirmed in 17 animals. CPT reversed the negative dromotropic effect of adenosine on AV nodal conduction and the antiadrenergic effect of N6-cyclopentyladenosine (CPA) mediated by A1-adenosine receptor but not the adenosine-induced decrease in systemic blood pressure caused by the vasodilatory action of the nucleoside mediated by A2-adenosine receptor. CONCLUSIONS: (1) Endogenous adenosine released during global cardiac hypoxia mediates, in part, AV nodal conduction delay and shortening of atrial but not ventricular APD. (2) The action of adenosine on atrial APD is mediated by A1 adenosine receptors, probably via IK,Ado,Ach. (3) Endogenous adenosine apparently does not play an important role in the early stages of acute global hypoxia-induced activation of K+ ATP channels. The present results are consistent with the hypothesis that the shortening of ventricular APD in the hypoxic heart is due, in part, to activation of K+ ATP channels.