EFFECTS OF AMILORIDE AND AN ANALOGUE ON VENTRICULAR ARRHYTHMIAS, CONTRACTURE AND CELLULAR INJURY DURING REPERFUSION IN ISOLATED AND PERFUSED GUINEA PIG HEART

Abstract

The present study was designed to examine whether activation of Na⁺/H⁺ exchange and subsequent massive Ca²⁺ influx via Na⁺/Ca²⁺ ex-change are involved in the pathogenesis of myocardial reperfusion injury. We tested the effects of 1 mM amiloride, which is known to inhibit both Na⁺/H⁺ and Na⁺/Ca²⁺ exchange, and 3 μM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), which is known to act as a specific inhibitor against Na⁺/H⁺ exchange, on the incidence of ventricular arrhythmias, isovolumic left ventricular function and creatine kinase (CK) release during reperfusion after 15 or 30 min of global ischemia in the isolated and perfused guinea pig heart. Treatment of a normally perfused heart with amiloride decreased heart rate significantly and tended to increase coronary flow and left ventricular developed pressure (LVDP), whereas treatment with EIPA decreased all of these 3 measurements significantly. Treatment with amiloride or EIPA for 15 min before ischemia, and during reperfusion after 15 min of ischemia, under electrical pacing at 240 rpm to eliminate a negative chronotropic effect abolished ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion associated with highly significant inhibition of increases in left ventricular end-diastolic pressure (LVEDP) and CK release. Amiloride or EIPA pretreatment also inhibited the incidence of VF and increases in LVEDP and CK release significantly during reperfusion after 30 min of ischemia. However, amiloride was more effective in preventing these events than EIPA. The treatment with amiloride or EIPA only during reperfusion after 15 or 30 min of ischemia also decreased the incidence of VF and inhibited the increases in LVEDP and CK release significantly, though less effectively than the pretreatment modality. These results suggest that EIPA prevents ventricular arrhythmias, contracture and myocardial cellular injury during reperfusion after 15 min of ischemia by inhibiting Na⁺/H⁺ ex-change, while amiloride exerts more powerful protection against these events than EIPA during reperfusion after 30 min of ischemia by inhibiting both Na⁺/H⁺ and Na⁺/Ca²⁺ exchange.