MET-88 a gamma-butyrobetaine hydroxylase inhibitor, improves cardiac SR Ca2+ uptake activity in rats with congestive heart failure following myocardial infarction

We previously reported that MET-88, 3-(2,2,2-trimethylhydrazinium) propiona te, improved left ventricular diastolic dysfunction induced by congestive h eart failure (CHF) in rats. The present study was designed to investigate t he mechanism by which MET-88 improved the cardiac relaxation impaired in CH F rats. The left coronary artery of the animals was ligated, and the rats w ere then orally administered vehicle (control), MET-88 at 50 or 100 mg/kg o r captopril at 20 mg/kg for 20 days. Myocytes were isolated from the non-in farcted region in the left ventricle, and cell shortening and [Ca2+](i) tra nsients were measured with a video-edge detector and by fluorescence analys is, respectively. In CHF control rats, the diastolic phase of cell shorteni ng was prolonged compared with that of the sham-operated (sham) rats. This prolongation was prevented by treatment with MET-88 at 100 mg/kg or captopr il at 20 mg/kg. CHF control rats also showed an increase in the decay time of [Ca2+](i) transients compared with sham rats. MET-88 at 100 mg/kg and ca ptopril at 20 mg/kg attenuated the increase in decay time of [Ca2+](i) tran sients. Ca2+ uptake activity of the sarcoplasmic reticulum (SR) isolated fr om the non-infarcted region in the left ventricle was measured, and Linewea ver-Burk plot analysis of the activity was performed. CHF control rats reve aled a decrease in the V-max for SR Ca2+ uptake activity without alteration in Kd. MET-88 at 100 mg/kg significantly prevented the decrease in V-max, but had no effect on Kd. Also, treatment with MET-88 at 100 mg/kg improved myocardial high-energy phosphate levels impaired in CHF rats. These results suggest that one of the mechanisms by which MET-88 improved cardiac relaxa tion in CHF rats is based on the amelioration of [Ca2+](i) transients throu gh increase of SR Ca2+ uptake activity.