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

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Abstract

We previously reported that MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, improved left ventricular diastolic dysfunction induced by congestive heart failure (CHF) in rats. The present study was designed to investigate the mechanism by which MET-88 improved the cardiac relaxation impaired in CHF rats. The left coronary artery of the animals was ligated, and the rats were then orally administered vehicle (control), MET-88 at 50 or 100 mg/kg or captopril at 20 mg/kg for 20 days. Myocytes were isolated from the non-infarcted region in the left ventricle, and cell shortening and [Ca2+]i transients were measured with a video-edge detector and by fluorescence analysis, respectively. In CHF control rats, the diastolic phase of cell shortening 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 captopril 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 captopril at 20 mg/kg attenuated the increase in decay time of [Ca2+]i transients. Ca2+ uptake activity of the sarcoplasmic reticulum (SR) isolated from the non-infarcted region in the left ventricle was measured, and Lineweaver-Burk plot analysis of the activity was performed. CHF control rats revealed a decrease in the Vmax for SR Ca2+ uptake activity without alteration in Kd. MET-88 at 100 mg/kg significantly prevented the decrease in Vmax, 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 relaxation in CHF rats is based on the amelioration of [Ca2+]i transients through increase of SR Ca2+ uptake activity.

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Authors and Affiliations

  1. Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan

    Yukio Hayashi

  2. Department of Physiology, School of Medicine, Tokai University, Boseidai, Isehara, Kanagawa, 259-1100, Japan

    Hideyuki Ishida, Minako Hoshiai, Kiyotaka Hoshiai & Hiroe Nakazawa

  3. Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan

    Tsukasa Kirimoto, Tomohiro Kanno, Motoko Nakano, Kiyotaka Tajima, Hidekazu Miyake & Naosuke Matsuura

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Hayashi, Y., Ishida, H., Hoshiai, M. et al. MET-88 a γ-butyrobetaine hydroxylase inhibitor, improves cardiac SR Ca2+ uptake activity in rats with congestive heart failure following myocardial infarction. Mol Cell Biochem 209, 39–46 (2000). https://doi.org/10.1023/A:1007093926315

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