Calcium (Ca2+) overload is an important pathophysiological factor in
myocardial ischemic/reperfusion injury. We investigated the effects of a cardioprotective
drug,
MCC-135, 5-methyl-2-(1-piperazinyl)
benzenesulfonic acid monohydrate, on (1) cardiac contractile dysfunction and Ca2+ overload induced by
ischemia and reperfusion, and (2) the Na+/Ca2+ exchanger in Langendorff-perfused rat hearts. Low-flow 45-min
ischemia and 30-min reperfusion decreased developed tension and increased ventricular Ca2+ content, effects which were ameliorated by
MCC-135 and
amiloride given after reperfusion. Combination of intracellular Na+ overload induced by
monensin (Na+
ionophore; 5 microM) and zero-flow 15-min
ischemia followed by 30-min reperfusion resulted in a decrease in developed tension and in the intracellular Na+-dependent increase in ventricular Ca2+ content.
MCC-135 and the highest dose of
amiloride given after reperfusion reduced the increase in ventricular Ca2+ content, whereas developed tension was increased only with
MCC-135. These results suggest that the cardioprotective effect of
MCC-135 in
ischemia/reperfusion is associated with suppression of Ca2+ overload and is attributable to inhibition of intracellular Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger.