Activation of cardiac ATP-sensitive K+ current during hypoxia: correlation with tissue ATP levels

Abstract

Although previous work has implicated activation of ATP-sensitive K+ currents (IK,ATP) in action potential duration (APD) shortening and increased cellular K+ efflux during hypoxia, ischemia, and metabolic inhibition, no prior study has directly assessed the tissue levels of ATP at which IK,ATP activates in intact cardiac muscle. Accordingly, we correlated changes in tissue high-energy phosphate levels during substrate-free hypoxia with activation of IK,ATP in intact voltage-clamped rabbit papillary muscles. During 10 min of hypoxia, the outward K+ current measured in response to a voltage-clamp pulse step from -50 to 0 mV increased from 8.57 +/- 0.27 to 15.67 +/- 1.41 microA (P less than 0.05, n = 6), and APD decreased from 452 +/- 54 to 292 +/- 56 ms (P less than 0.05, n = 6). Glibenclamide (10 microM), a specific IK,ATP blocker, prevented both of these changes. In a parallel set of experiments, papillary muscles were freeze-clamped and assayed for tissue ATP. In these muscles, 10 min of hypoxia resulted in a comparable degree of APD shortening (441 +/- 24 to 297 +/- 18 ms, P less than 0.05, n = 12), and tissue ATP levels fell from 13.2 +/- 1.3 to 9.7 +/- 0.7 mumol/g dry wt (P less than 0.05, n = 12). These results directly demonstrate that IK,ATP is activated and causes APD shortening during hypoxia in intact cardiac muscle despite only a modest (approximately 25%) decline in tissue ATP content.

The effect of glibenclamide on frog skeletal muscle: evidence for K+ATP channel activation during fatigue.

“…475.3 498 between 3 and 6 min and a maximal effect in 10-13 min. (Gasser & Vaughan-Jones, 1990;Deutch, Klitzner, Lamp & Weiss, 1991). However, one must assume that glibenclamide does not affect the K+ delayed rectifier.…”

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

“…4 The increase in conductance that results causes efflux of potassium into the extracellular space 4,14 and shortening of repolarization. [2][3][4] It was originally hypothesized that the shortening of repolarization acts as a protective mechanism by limiting calcium entry, although more recent studies ascribe the protective role to mitochondrial ATP channels. 15 Activation of the K ATP channels during acute ischemia is arrhythmogenic 16,17 ; the extracellular potassium accumulation and shortening of the refractory period favor the occurrence of reentrant excitation.…”

“…T he K ATP channel 1 is activated by a reduction in ATP that occurs during acute ischemia 2 and has been implicated in early ischemic changes in electrophysiology, contractility, 3 and rhythm 4 that result from an acute coronary artery occlusion. Occlusion of a coronary artery eventually results in infarction, but some ischemic cells may survive to form infarct border zones.…”

The therapeutic agents that target ATP-sensitive potassium channels

“…Under normal conditions, the cardiac sarcolemmal K ATP channel is predominately closed (33). The channel activates during various forms of metabolic stress, including ischaemia, hypoxia, hyperglycemia, hypoglycaemia and inhibition of glycolysis and/or oxidative phosphorylation (34,35).…”