title: Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats.
abstract: 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 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.
authors.affiliation: Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Seiji
authors.initials: S
authors.lastname: Maeda
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D004095:Dihydropyridines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D008297:Male; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D019332:Endothelin-1; C061004:benidipine