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HEART

Reversal of Elevated Cardiac Expression of TGFß₁ and Endothelin-1 in OLETF Diabetic Rats by Long-Acting Calcium Antagonist

Subrina Jesmin^*, Sohel Zaedi^*, Seiji Maeda^*, Chishimba N. Mowa, Ichiro Sakuma and Takashi Miyauchi^*,1

^* Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan; Department of Biology, Appalachian State University, Boone, North Carolina 28607; and Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, 060-8638 Japan

To whom requests for reprints should be addressed at ¹ Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. E-mail: t-miyauc{at}md.tsukuba.ac.jp

Abstract

The effects of calcium channel blockers (CCBs) on complications associated with diabetes mellitus (DM) have been well studied in clinical and basic science investigations. Cardiovascular complications are a common feature of type 2 DM, and insulin resistance is an early clinical manifestation of type 2 DM. CCBs are widely used to treat cardiovascular diseases in patients with DM. In this study, we used a spontaneous type 2 diabetic rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, at a highly insulin-resistant stage with modest hyperglycemia. We examined cardiac expression of transforming growth factor–ß₁ (TGFß₁) and endothelin-1 (ET-1) in male OLETF rats. At 8 weeks of age, OLETF rats were treated for 12 weeks with the long-acting CCB benidipine (1 mg/kg/day or 3 mg/kg/day, po, n = 12), with hydralazine hydrochloride (3 mg/kg/day, po, n = 12), or with vehicle (OLETF, n = 12), and male age-matched genetic control Long-Evans Tokushima Otsuka (LETO, n = 12) rats were used. Blood pressure was significantly higher in OLETF rats than in LETO rats, and benidipine treatment at both dosages in OLETF rats for 12 weeks did not significantly reduce blood pressure, whereas hydralazine treatment significantly lowered blood pressure in OLETF rats. Hydralazine and both dosages of benidipine significantly reduced upregulated cardiac ET-1 levels in OLETF rats. Plasma and cardiac TGFß₁ levels were remarkably higher in OLETF rats compared with LETO rats and were normalized by treatment with benidipine (3 mg/kg/day). Our results suggest that CCBs are effective in normalizing upregulated cardiac TGFß₁ and ET-1 levels at the insulin-resistant stage in OLETF rats, which may improve cardiac morphology and function in this rat model without altering blood pressure and plasma glucose levels. In contrast, hydralazine treatment also normalizes cardiac ET-1 levels while significantly reducing blood pressure.

Key Words: insulin resistance • heart • TGFß₁ • endothelin-1 • calcium channel blocker • hydralazine