39
Molecular and Cellular Biochemistry 209: 39–46, 2000.
© 2000
K
luwer Academic Publishers. Printed in the Netherlands.
MET-88, a
γγ
γγ
γ-butyrobetaine hydroxylase inhibitor,
improves cardiac SR Ca
2+
uptake activity in rats
with congestive heart failure following myocardial
infarction
Yukio Hayashi,
1
Hideyuki Ishida,
2
Minako Hoshiai,
2
Kiyotaka
Hoshiai,
2
Tsukasa Kirimoto,
1
Tomohiro Kanno,
1
Motoko Nakano,
1
Kiyotaka Tajima,
1
Hidekazu Miyake,
1
Naosuke Matsuura
1
and
Hiroe Nakazawa
2
1
Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., Ebisuno, Hiraishi, Kawauchi-cho, Tokushima;
2
Department of Physiology, School of Medicine, Tokai University, Boseidai, Isehara, Kanagawa, Japan
Received 29 September 1999; accepted 19 January 2000
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 [Ca
2+
]
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 [Ca
2+
]
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 [Ca
2+
]
i
transients. Ca
2+
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 V
max
for SR Ca
2+
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
relaxation in CHF rats is based on the amelioration of [Ca
2+
]
i
transients through increase of SR Ca
2+
uptake activity. (Mol
Cell Biochem 209: 39–46, 2000)
Key words: sarcoplasmic reticulum, SR Ca
2+
-ATPase, [Ca
2+
]
i
transients, cell shortening, γ-butyrobetaine hydroxylase inhibitor,
heart failure
Address for offprints: Y. Hayashi, Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima
771-0194, Japan