Reduction of myocardial infarct size by SM-20550, a novel Na+/H+ exchange inhibitor, in rabbits

Effects of SM-20550, a New Na⁺/H⁺ Exchange Inhibitor, on Survival and Infarct Size in Rat Myocardial Infarction

“…In myocardial ischemia and reperfusion injury, the Na + /H + exchanger has been shown to be involved in arrhythmia, stunning and necrosis in several models, using inhibitors of the Na + /H + exchanger such as ethylisopropyl-amiloride [1], HOE694 [3,6], HOE642 [2,5], EMD85131 [4], and SM-20550 [7,8,10]. Many studies have revealed the effectiveness of inhibitors of the Na + / H + exchanger in attenuating myocardial ischemia and reperfusion injury in rabbit, porcine and canine models with short reperfusion period; however, the present study is the first demonstration of the effect of as inhibitor of Na + /H + exchanger, SM-20550, on survival rate after a long-term reperfusion period in any species.…”

“…2). Previous studies demonstrated the effectiveness of SM-20550 on myocardial necrosis in a canine model where 2 h of ischemia was followed with 5 h of reperfusion [10] and in a rabbit model with 30 min of ischemia and 5 h of reperfusion [8]. The antinecrotic effect of SM-20550 in the present study is consistent with the effects seen previously in canine and rabbit models, although the reperfusion period was longer in this study (14 days) than in the previous ones (5 h).…”

“…Because Ca 2+ overload induces cardiac arrhythmia and necrosis [15,16], the antinecrotic effect of the Na + /H + exchange inhibitor, SM-20550, could result from the prevention of Ca 2+ overload. The involvement of the Na + /H + exchanger during ischemia and at the onset of reperfusion has been demonstrated using inhibitors of the Na + /H + exchanger, such as HOE694 [3], EMD85131 [4] and SM-20550 [8,10], in myocardial ischemia with a few hours of reperfusion. On the other hand, the involvement of the Na + /H + exchanger over days of reperfusion has been less clear.…”

“…In previous studies, we demonstrated that a novel potent Na + /H + exchange inhibitor, SM-20550, which has IC 50 of 10 nmol/l for Na + /H + exchange activity in rat cardiomyocytes and little effect on several channels or receptors [7], has a cardioprotective effect in a rat isolated perfusion model [7], and reduces myocardial necrosis in a rabbit myocardial infarction model [8]. Many studies have shown the involvement of the Na + /H + exchanger in myocardial necrosis in rabbit [1,2], porcine [3] and canine [4] models of cardiac ischemia with short reperfusion period; however, there has been no demonstration of the effect of Na + /H + exchange inhibitors on prognosis after myocardial infarction after a long-term reperfusion period.…”

Inhibitory effect of SM-20550, an Na + /H + exchange inhibitor, on accumulation of leukocytes in ischemia and reperfusion

“…We have recently demonstrated that SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], an Na + /H + exchange inhibitor with an IC 50 of 10 nM and having little effect on several channels or receptors other than Na + /H + exchanger , exerts a cardioprotective effect on the isolated perfused rat heart and reduces myocardial necrosis in the rabbit (Yamada et al 2000). The cardioprotective effect of Na + /H + exchange inhibitors is thought to result from a reduction in intracellular Ca 2+ concentration, "Ca 2+ overload", in the myocardium (Scholz and Albus 1993;Avkiran 1996;Piper et al 1996).…”