ACTIVATION OF CARDIAC ATP-SENSITIVE K+ CURRENT DURING HYPOXIA - CORRELATION WITH TISSUE ATP LEVELS

Although previous work has implicated activation of ATP-sensitive K+ currents (I(K,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 I(K,ATP) activates in intact cardiac muscle. Accordingly, we correlated changes in tissue high-energy phosphate levels during substrate-free hypoxia with activation of I(K,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-mu-A (P < 0.05, n = 6), and APD decreased from 452 +/- 54 to 292 +/- 56 ms (P < 0.05, n = 6). Glibenclamide (10-mu-M), a specific I(K,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 < 0.05, n = 12), and tissue ATP levels fell from 13.2 +/- 1.3 to 9.7 +/- 0.7-mu-mol/g dry wt (P < 0.05, n = 12). These results directly demonstrate that I(K,ATP) is activated and causes APD shortening during hypoxia in intact cardiac muscle despite only a modest (approximately 25%) decline in tissue ATP content.