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–β1 (TGFβ1) 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 TGFβ1 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 TGFβ1 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.

中文翻译：

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长效钙拮抗剂逆转 OLETF 糖尿病大鼠心脏中 TGFβ1 和内皮素-1 升高的表达

钙通道阻滞剂（CCB）对糖尿病（DM）相关并发症的影响已在临床和基础科学研究中得到充分研究。心血管并发症是2型糖尿病的共同特征，而胰岛素抵抗是2型糖尿病的早期临床表现。CCB 广泛用于治疗糖尿病患者的心血管疾病。在这项研究中，我们使用了自发性 2 型糖尿病大鼠模型，即 Otsuka Long-Evans Tokushima Fatty (OLETF) 大鼠，该大鼠处于高度胰岛素抵抗阶段并伴有中度高血糖。我们检查了转化生长因子-β 的心脏表达1(TGFβ1）和雄性 OLETF 大鼠的内皮素-1 (ET-1)。8 周龄时，OLETF 大鼠接受长效 CCB 贝尼地平（1 mg/kg/天或 3 mg/kg/天，口服，n = 12）和盐酸肼屈嗪（3 mg/kg）治疗 12 周。 /天，po，n = 12），或使用载体（OLETF，n = 12），以及使用年龄匹配的雄性遗传对照Long-Evans Tokushima Otsuka（LETO，n = 12）大鼠。OLETF 大鼠的血压显着高于 LETO 大鼠，并且 OLETF 大鼠的两种剂量的贝尼地平治疗 12 周均未显着降低血压，而肼苯哒嗪治疗则显着降低 OLETF 大鼠的血压。肼屈嗪和贝尼地平的两种剂量均显着降低了 OLETF 大鼠心脏 ET-1 的上调水平。血浆和心脏 TGFβ1与 LETO 大鼠相比，OLETF 大鼠的水平显着升高，并通过贝尼地平（3 mg/kg/天）治疗后恢复正常。我们的结果表明 CCB 可以有效使上调的心脏 TGFβ 正常化1OLETF 大鼠胰岛素抵抗阶段的 ET-1 水平，这可能会改善该大鼠模型的心脏形态和功能，而不改变血压和血糖水平。相比之下，肼屈嗪治疗还可使心脏 ET-1 水平正常化，同时显着降低血压。