ISCHEMIC CARDIOPROTECTION BY ATP-SENSITIVE K-ENERGY PHOSPHATE PRESERVATION( CHANNELS INVOLVES HIGH)

We previously demonstrated that ATP-sensitive K+ channels (K(ATP)) pro tect the guinea pig myocardium against ischemia-reperfusion injury (Co le et al., Circ. Res. 69: 571-581, 1991), but the cellular alterations leading to ischemic injury affected by K(ATP) remain to be defined. T his study investigates the relationship between activation of K(ATP) a nd preservation of high-energy phosphates during global no-flow ischem ia in arterially perfused guinea pig right ventricular walls. Electric al and mechanical activity were recorded via intracellular microelectr odes and a force transducer. Glibenclamide (10 and 50 muM) and pinacid il (10 muM) were used to modulate K(ATP). ATP and creatine phosphate ( CP) levels were determined at the end of no-flow ischemia by enzymatic analysis. Preparations were subjected to 1) 20 min no-flow +/- gliben clamide (10 or 50 muM), 2) 30 min no-flow +/- pinacidil (10 muM) or pi nacidil (10 muM) and glibenclamide (50 muM), or 3) 40 or 50 min of con trol perfusion before rapid freezing in liquid nitrogen. Pinacidil (10 muM) enhanced ischemic shortening of action potential duration (APD) and early contractile failure, prevented ischemic contracture, and inh ibited high-energy phosphate depletion during ischemia. Glibenclamide (50 muM) inhibited the effects of pinacidil (10 muM) on electromechani cal function and preservation of ATP and CP. Glibenclamide (10 muM) al one inhibited the early decline in APD and produced earlier ischemic c ontracture but did not enhance ATP or CP depletion compared with untre ated tissues during 20 min of no-flow. Glibenclamide (50 muM) produced a greater inhibition of APD shortening in early ischemia, further dec reased the latency to ischemic contracture, and caused enhanced ischem ic depletion of ATP. The data indicate the changes in electrical activ ity induced by K(ATP) indirectly preserve high-energy phosphates and r educe injury associated with ischemia. However, the data also suggest the possible presence of additional mechanisms for cardioprotection by K(ATP).