Cardioprotective effect of MCC-135 is associated with inhibition of Ca2+ overload in ischemic/reperfused hearts.
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.
Satoh
Naoya
N
Mitsubishi Pharma Corporation, Research Laboratory II, Cardiovascular Section, 1000 Kamoshida, Aoba-ku, Yokohama 227-0033, Japan. satoh.naoya@ma.m-pharma.co.jp
Kitada
Yoshimi
Y
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008985:Monensin / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001557:Benzenesulfonates; D002316:Cardiotonic Agents; D007476:Ionophores; C434457:MCC 135; D010879:Piperazines; D008985:Monensin; D002118:Calcium