Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle.

Abstract

Sulfonylurea derivatives glibenclamide and tolbutamide are selective blockers of ATP-sensitive K+ (KATP) channels. However, their ability to prevent cellular K+ loss and shortening of action potential duration during ischemia or hypoxia in the intact heart is modest compared with their efficacy at blocking KATP channels in excised membrane patches. In the isolated arterially perfused rabbit interventricular septum, the increase in unidirectional K+ efflux and shortening of action potential duration during substrate-free hypoxia were effectively blocked by glibenclamide, but only by very high concentrations (100 microM); during hypoxia with glucose present, glibenclamide was only partially effective at reducing K+ loss. During total global ischemia (10 minutes), up to 100 microM glibenclamide or 1 mM tolbutamide attenuated shortening of action potential duration but only reduced [K+]0 accumulation by a maximum of 32 +/- 6%. In isolated patch-clamped guinea pig ventricular myocytes in which the whole-cell ATP-sensitive K+ current was activated by exposure to the metabolic inhibitors, glibenclamide (up to 100 microM) and tolbutamide (10 mM) were only partially effective at blocking the whole-cell ATP-sensitive K+ current (maximum block, 51 +/- 10% and 50 +/- 9%, respectively), especially when ADP was included in the patch electrode solution. In inside-out membrane patches excised from these myocytes, glibenclamide blocked unitary currents through KATP channels with a Kd of 0.5 microM and a Hill coefficient of 0.5 in the absence of ADP at the cytosolic membrane surface, but block was incomplete when 100 microM ADP (+2 mM free Mg2+) was present. ADP had a similar effect on block of KATP channels by tolbutamide. These findings suggest that free cytosolic [ADP], which rises rapidly to the 100 microM range during early myocardial ischemia and hypoxia, may account for the limited efficacy of sulfonylureas at blocking ischemic and hypoxic cellular K+ loss under these conditions.

Amiodarone Inhibits Sarcolemmal but Not Mitochondrial KATP Channels in Guinea Pig Ventricular Cells

“…Another explanation may be that the sarcK ATP channel current activated by metabolic stress might be more resistant to amiodarone. It was demonstrated that sulfonylurea drugs such as glibenclamide and tolbutamide were no longer able to inhibit the opening of sarcK ATP channels during severe metabolic stress although the precise mechanism(s) have not been fully clarified (Venkatesh et al, 1991;Findlay, 1993). The effective concentration to inhibit the sarcK ATP channel current in this study was similar to or less than those needed to inhibit the other channels (Balser et al, 1991;Sato et al, 1994;Mori et al, 1996;Watanabe et al, 1996).…”

Effects of Tolbutamide on ATP‐Sensitive K+ Channels from Human Right Atrial Cardiac Myocytes

“…However, a slight variability of the metabolic state of the individual myocytes in our study could explain the variability of the blocking effects of tolbutamide at millimolar concentrations. The metabolic state of the individual myocytes seems to modulate the sulfonylurea-induced block of cardiac KATP channels, since the blocking effects of sulfonylureas on cardiac KATp channels are lost after metabolic inhibition and cardiac K A T~ channels activated by KCOs are more sensitive towards sulfonylurea-induced block when compared to channels activated by metaboIic inhibition (Venkatesh et al 1991;Findlay 1993;Krause et al 1995).…”

Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts

“…18 Pharmacological agents that increase K ATP channel conductance 9,19 have effects similar to those of ischemia on action potentials and are also arrhythmogenic. 14,16,20,21 The focus on the arrhythmogenic role of K ATP channel activation has been during acute ischemia. 4,14,17 During this period, epicardial muscle that eventually forms the EBZ undergoes more severe electrophysiological alterations than endocardial muscle, 22,23 partly related to greater activation of the K ATP channels.…”

“…14,16,20,21 The focus on the arrhythmogenic role of K ATP channel activation has been during acute ischemia. 4,14,17 During this period, epicardial muscle that eventually forms the EBZ undergoes more severe electrophysiological alterations than endocardial muscle, 22,23 partly related to greater activation of the K ATP channels. 24 During subsequent days, muscle cells in the EBZ undergo changes in ion channels that control repolarization, resting membrane potential, and depolarization and are related to changes in ion channel protein synthesis.…”