Effects of diazoxide and glyburide on ATP-sensitive K+ channels from hypertrophied ventricular myocytes

Abstract

Hyperpolarizing vasodilators that specifically activate ATP-sensitive K+ currents (IK(ATP] in smooth muscle have been suggested as promising antihypertensive (if potentially arrhythmogenic and/or hyperglycemic) therapy. To date, however, the effects of agents presumed to influence these channels have not been characterized in hypertrophied cardiac muscle secondary to chronic hypertension. We used standard intracellular and patch clamp, single-channel recording techniques to study the effects of diazoxide, a presumed activator, as well as the sulfonylurea glyburide on IK(ATP) in cardiac muscle from control (WKY) and spontaneously hypertensive rats (SHR). Intracellular recordings were obtained from isolated left ventricles at 37 degrees C; unitary currents were recorded in excised, inside-out membrane patches with symmetrical transmembrane K+ at 21-23 degrees C. Diazoxide (5-100 microM) caused a decrease in action potential duration in both WKY and SHR ventricles. Glyburide (5-25 microM) produced dramatic dose-dependent increases in action potential duration approaching 100% in both groups. Action potential amplitude and resting membrane potential were unaffected by either agent. Before drug administration, unitary currents in hypertrophied myocytes exhibited a greater open state probability upon depolarization than those from control myocytes, although conductance, mean single-channel open time, and the number of channels per patch were not significantly different. Under patch clamp, both diazoxide (25 and 100 microM) and glyburide (50 microM) decreased IK(ATP) activity in cells from WKY and SHR in the absence of ATP. In both groups, the response reflected an overall decrease in open state probability. These data indicate that although IK(ATP) characteristics are altered in hypertension and myocardial hypertrophy, the effects of agents specific to this current are not significantly different in cells from SHR relative to control. On the other hand, the effects of diazoxide may be linked to temperature or to the metabolic state of the cell.