Reduction of myocardial infarct size by SM-197378, a novel Na+/H+ exchange inhibitor, in rabbits.

The effects of 3-[2-({[amino(imino)methyl]amino}carbonyl)-4-chloro-1H-indol-1-yl]-1-propanesulphonic acid monohydrate (SM-198110), a novel potent Na+/H+ exchange inhibitor, and cariporide (Hoe642), another Na+/H+ exchange inhibitor, were studied in a myocardial ischaemia and reperfusion injury model. Anaesthetized rabbits were subjected to occlusion of the coronary artery for 30 min followed by reperfusion for 5 h. SM-198110 or cariporide was administered before ischaemia and before reperfusion. We also assessed the anti-necrotic effect of SM-198110 when given before reperfusion, both alone and together with glibenclamide, a KATP channel blocker, 5-hydroxydecanoate (5-HD), a mitochondrial KATP channel-selective blocker and 8-(p-sulphophenyl)-theophylline (8-SPT), an adenosine receptor blocker. The infarct size was reduced dose-dependently by i.v. administration of SM-198110 before ischaemia, with a significant reduction in serum creatine phosphokinase activity. Infarct sizes, normalized to the size of the area-at-risk (means±SE) were: vehicle 56.6±3.7%; low-dose SM-198110 39.2±6.3%; mid-dose 32.8±7.4% (PPPP+/H+ exchange inhibition, mitochondrial and/or sarcolemmal KATP channels contribute to the anti-necrotic effect of SM-198110 when the latter is given before reperfusion.