PARTIAL CONTRIBUTION OF THE ATP-SENSITIVE K+ CURRENT TO THE EFFECTS OF MILD METABOLIC DEPRESSION IN RABBIT MYOCARDIUM

The object of the study was to compare the capability of glibenclamide to block the effects of K+-ATP channel activators on action potential duration and steady state whole cell current to its efficiency in cou nteracting the effects of hypoxia or metabolic poisons in the presence of glycolytic substrate. The modulation of action potential duration by 30 mu M glibenclamide was tested in perfused hearts subjected to hy poxia or to the K+-ATP channel opener pinacidil. Similar protocols wer e used to study the modifications of the steady state whole cell curre nt in isolated ventricular myocytes. It was found that glibenclamide d id not prevent early action potential shortening induced by hypoxia bu t produced a partial recovery after 15 min of exposure. At the steady state the action potential duration had lengthened by 53 +/- 6% at pla teau level and 42 +/- 3% at 95% repolarization. In contrast, action po tential shortening induced by 100 mu M pinacidil was fully reversed by glibenclamide within 2 min. Freshly dispersed ventricular myocytes we re characterized in control conditions as for the properties of the st eady state current. This current, measured at the end of 450 ms long p ulses showed typical inward rectification that was abolished by 50 mu M Ba2+. Cyanide (2 mM), carbonyl-cyanide m-chlorophenylhydrazone (CCCP , 200 nM) and BRL 38227 (30 mu M) produced characteristic increases in time independent outward currents. Glibenclamide abolished the outwar d current induced by BRL 38227 and the concomitant action potential sh ortening. Addition of cyanide in the presence of glibenclamide and BRL 38227 produced a new increase in outward current accompanied by actio n potential shortening. In the absence of K+-ATP channel activators, g libenclamide partly inhibited the CCCP induced current. Our data sugge sted that the delayed onset of glibenclamide action in hypoxic hearts is not due to diffusion barriers. They rather support the view that me chanisms other than K+-ATP channel activation could determine the earl y action potential shortening in whole hearts. The partial recovery ob served under glibenclamide may be due, in part, to channel desensitiza tion but also reflect the contribution of more than one current system to the action potential shortening because the glibenclamide insensit ive fraction of the CCCP induced current is partly blocked by low conc entrations of Ba2+. Differences with other data in the literature are attributed to the degree of metabolic blockade, to species differences , and to the inherent heterogeneities of the whole heart model where n on-muscle cells may modulate the response to hypoxia.