Combined therapy utilizing a novel Na+/H+ exchange inhibitor (SM-20220) and THAM for ischemic brain edema

We investigated in the gerbil model whether the therapeutic effect of a novel Na+/H+ exchange inhibitor SM-20220 on ischemic brain edema could be enhanced by improving the decreased intracellular pH with an alkalizing agent, tris (hydroxymethyl) aminomethane (THAM). The left carotid artery of the animals was occluded twice for 10 min at a 5 hr interval. Ischemia-positive animals were selected and classified into the SM-20220- (0.5 mg/kg, i.p.) THAM- (2.0 ml/kg, i.v., 0.3M-THAM), combination of SM-20220 (0.5 mg/kg, i.p.) and THAM (2.0 ml/kg, i.v.), and vehicle- (0.9% saline, i.p.) treatment groups. Each agent was administered at 0, 6, 12 and 36 hr after recirculation following the 2nd episode of ischemia. The brain water, sodium and potassium contents were measured at 12, 24, and 48 hr after recirculation. The water content of the ischemic hemisphere 12 hr after recirculation was significantly lower in the combination-treated group (79.02%; P < 0.05) than in either the SM-20220- (79.28%) or THAM-treated group (79.32%). At 24 hr after recirculation the water content was significantly lower in the combination-treated group (79.83%, P < 0.05) than in the vehicle group (80.95%). At 48 hr after recirculation there were no significant differences in the water content between the vehicle group and any of the other treatment groups. The changes in brain water (delta H2O) and sodium plus potassium (delta Na + delta K) content in the ischemic hemisphere showed a significant correlation in each group. The combined treatment with the novel Na+/H+ exchange inhibitor SM-20220 and THAM is more effective on ischemic brain edema than treatment with a single agent. The results of this study indicate that improvement of intra- and extracellular acidosis by THAM infusion enhanced the activity of the NHE inhibitor SM-20220.