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Am J Physiol Heart Circ Physiol 290: H2146-H2154, 2006. First published December 30, 2005; doi:10.1152/ajpheart.01142.2005
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Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

Subrina Jesmin,1 Yuichi Hattori,2 Seiji Maeda,1 Sohel Zaedi,1 Ichiro Sakuma,3 and Takashi Miyauchi1

1Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan; 2Department of Pharmacology, School of Medicine, University of Toyama, Toyama, Japan; and 3Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Submitted 28 October 2005 ; accepted in final form 16 December 2005

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg·kg–1·day–1). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ETA and ETB receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

insulin resistance; Otsuka Long-Evans Tokushima Fatty rat heart; calcium channel blocker


Address for reprint requests and other correspondence: T. Miyauchi, Cardiovascular Div., Dept. of Internal Medicine, Institute of Clinical Medicine, Univ. of Tsukuba, Tsukuba, Ibaraki 305-8575 Japan (e-mail: t-miyauc{at}md.tsukuba.ac.jp)






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