ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.

Abstract

The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels, respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion, or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV, action potential duration at 90% repolarization (APD90) decreased by 62%, and developed tension fell by greater than 95%, but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion, but during ischemia, resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent, but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia), and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects, albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues, resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles, tachyarrhythmias, and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function, but at 10 microM it had a negative inotropic effect, decreasing APD90 and developed tension by 5% and 18%, respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil, and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM, respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

“…Role of K ATP channels in nitrite-induced cardioprotection in vitro K ATP channels, highly expressed in myocardial sarcolemma and thought to be expressed in myocardial mitochondria, have been found to serve as triggers and mediators of cardioprotection [18][19][20]. To investigate a role for K ATP channels in mediating nitrite-induced cardioprotection, rats were treated with and without nitrite (4 mg/kg) 15 minutes prior to 30 minutes regional myocardial ischemia and 120 minutes reperfusion.…”

Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans

“…Under ischaemic conditions the opening of cardiovascular K ATP channels triggers endogenous cardioprotective mechanisms which prevent a further ATP depletion by shortening of action potential with a decrease in contraction [7] and by vasodilation which results in an increased oxygen supply [8]. These mechanisms protect the myocardium against ischaemia and reperfusion damage and improve mechanical function during reperfusion [9]. The protective effects of ischaemic preconditioning have also been suggested to be mediated by opening of cardiovascular K ATP channels [10,11].…”

Gadolinium limits myocardial infarction in the rat: Dose–response, temporal relations and mechanisms

“…These channels, highly expressed in myocardial sarcolemmal and thought to be expressed in myocardial mitochondria, have been found to serve as mediators of cardioprotection (17)(18)(19). Gadolinium is known to exert effects on a broad range of ion channels in the heart.…”