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 counteracting the effects of hypoxia or metabolic poisons in the presence of glycolytic substrate. The modulation of action potential duration by 30 microM glibenclamide was tested in perfused hearts subjected to hypoxia or to the K(+)-ATP channel opener pinacidil. Similar protocols were used to study the modifications of the steady state whole cell current in isolated ventricular myocytes. It was found that glibenclamide did not prevent early action potential shortening induced by hypoxia but produced a partial recovery after 15 min of exposure. At the steady state the action potential duration had lengthened by 53 +/- 6% at plateau level and 42 +/- 3% at 95% repolarization. In contrast, action potential shortening induced by 100 microM pinacidil was fully reversed by glibenclamide within 2 min. Freshly dispersed ventricular myocytes were characterized in control conditions as for the properties of the steady state current. This current, measured at the end of 450 ms long pulses showed typical inward rectification that was abolished by 50 microM Ba2+. Cyanide (2 mM), carbonylcyanide m-chlorophenylhydrazone (CCCP, 200 nM) and BRL 38227 (30 microM) produced characteristic increases in time independent outward currents. Glibenclamide abolished the outward current induced by BRL 38227 and the concomitant action potential shortening. Addition of cyanide in the presence of glibenclamide and BRL 38227 produced a new increase in outward current accompanied by action potential shortening. In the absence of K(+)-ATP channel activators, glibenclamide partly inhibited the CCCP induced current. Our data suggested that the delayed onset of glibenclamide action in hypoxic hearts is not due to diffusion barriers. They rather support the view that mechanisms other than K(+)-ATP channel activation could determine the early action potential shortening in whole hearts. The partial recovery observed under glibenclamide may be due, in part, to channel desensitization but also reflect the contribution of more than one current system to the action potential shortening because the glibenclamide insensitive fraction of the CCCP induced current is partly blocked by low concentrations 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 non-muscle cells may modulate the response to hypoxia.