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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H2146    most recent 01142.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jesmin, S. Articles by Miyauchi, T. Search for Related Content PubMed PubMed Citation Articles by Jesmin, S. Articles by Miyauchi, T.

Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

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 ET_A and ET_B receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38^MAPK, 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