Submitted on October 28, 2005
Accepted on December 16, 2005
The Subdepressor Dose of Benidipine Ameliorates Diabetic Cardiac Remodeling Accompanied by the Normalization of the Upregulated Endothelin System in Rats
Subrina Jesmin1, Yuichi Hattori2, Seiji Maeda1, Sohel Zaedi1, Ichiro Sakuma3, and Takashi Miyauchi1*
1 Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
2 Department of Pharmacology, School of Medicine, University of Toyama, Toyama, Japan
3 Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
* To whom correspondence should be addressed. E-mail: t-miyauc{at}md.tsukuba.ac.jp.
We investigated if 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 weeks with vehicle or benidipine (3 mg/kg/day). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV)tissues compared with non-diabetic controls. Expression of preproET-1, ET converting enzyme, ETA and ETB receptors in LV tissues was also significantly higher in OLETF rats. The two mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase 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 non-diabetic levels when OLETF rats were treated with at 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.
