ALLEVIATION OF CONTRACTILE DYSFUNCTION IN ISCHEMIC HEARTS BY SLOWLY INACTIVATING NA+ CURRENT BLOCKERS

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (V-max), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at greater than or equal to 10 nM but reduced V-max only at greater than or equal to 1 mu M. R-56865 (10 nM-10 mu M) failed to affect V-max but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (>10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia. Our results indicate that these drugs can selectively attenuate the Nat window current without affecting the fast peak of the Na+ current and that the slow component of Na+ current may constitute a pathway of early Na+ loading in the ischemic myocyte.