Hiroshi Kamiyama

A Na+–H+ exchange inhibitor (SM-20550) protects from microvascular deterioration and myocardial injury after reperfusion

Na+-H+ exchange inhibitors may reduce myocardial damage after reperfusion. However, their effects on microvascular deterioration are not known. We examined the potency of a novel Na+-H+ exchange inhibitor, SM-20550 [ N-(Aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonate], and its effects on microvascular damage after reperfusion. In an in vitro study, the Na+-H+ exchange inhibiting activity of SM-20550 was about 10 times greater than that of ethylisopropyl amiloride. In in vivo experiments, we occluded the left circumflex coronary artery in 29 dogs for 2 h and then reperfused for 5 h. SM-20550 was administered either before ischemia (n = 11) or before reperfusion (n = 7). Another 11 dogs served as controls. We found that SM-20550 not only improved coronary vasodilator responses to acetylcholine and adenosine after reperfusion, but also reduced infarct size (P < 0.01). Intramyocardial bleeding, which should reflect microvascular damage, was not found in dogs with SM-20550 treatment. Infarct size was correlated inversely with collateral blood flow in control (both, P < 0.01) but not in SM-20550-treated animals. Furthermore, SM-20550 significantly suppressed ventricular fibrillation during both ischemia and reperfusion. These results suggest that protective effects of Na+-H+ exchange inhibitors on reperfused myocardium are due at least in part to microvascular protection.

The Effect of N,N,N-Trimethylsphingosine on Reperfusion Injury

The paradoxical phenomenon of the exacerbation of myocardial injury after reintroduction of blood into the ischemic tissue of the heart is well known. It has been reported that in the relatively short time from 15 to 30 min of reperfusion, a supply of neutropenic blood reduced myocardial infarct size in ischemia-reperfusion canine models. The neutrophils play a major role in the exacerbation of myocardial injury[1][2], N, N,N-Trimethylsphingosine(TMS) derived from sphingosine strongly inhibits oxidative burst and phagokinetic migration of neutrophils, due to its inhibitory effect on protein kinase C (Kimura S, Hakomori S, Igarashi Y, et al., submitted). Based on this finding, the possible protective effect of TMS on reperfusion injury in dog heart was studied.