OBJECTIVES:To determine the effects of calcium antagonists on hyperinsulinemia, hypertriglyceridemia and hypertension, we examined the long-term effects of a new calcium channel blocker, mibefradil, on plasma insulin levels, plasma triglyceride levels and systolic blood pressure in insulin-resistant and hyperinsulinemic fructose-hypertensive (FH) rats. To this aim, both prevention and reversal protocols were employed.

METHODS:Prevention study: Male Sprague-Dawley rats were procured at 6 weeks of age and were divided into: control (C, n = 6), control-treated (CT, n = 5), fructose (F, n = 7) and fructose-treated (FT, n = 6). Baseline measurements of plasma glucose, insulin and systolic blood pressure were conducted in all groups. At week 7, chronic mibefradil treatment (30 mg/kg/day, orally for 6 weeks) was initiated in the CT and FT groups. At week 8, the rats in the F and FT groups were started on a 66% fructose diet to induce hyperinsulinemia and hypertension. Weekly measurements of plasma insulin, plasma triglycerides and systolic blood pressure were conducted for the following 4 weeks. Reversal protocol: In a separate study, 8-week-treated FH rats and their age-matched controls were used to examine the effects of mibefradil on reversing fructose-induced hyperinsulinemia and hypertension.

RESULTS:The F group exhibited hyperinsulinemia (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml, P < 0.05), hypertension (148 +/- 3 vs. C 121 +/- 1 mmHg, P < 0.002) and elevated triglyceride levels (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM, P < 0.05). Chronic mibefradil treatment prevented the development of hyperinsulinemia (1.6 +/- 0.08 ng/ml, P < 0.004 vs. F) and hypertension (123 +/- 1 mmHg. P < 0.001 vs. F) and attenuated the development of hypertriglyceridemia. In the reversal study, mibefradil treatment reversed the development of hyperinsulinemia, hypertriglyceridemia and elevated BP in FH rats. Treatment did not affect the plasma glucose levels in any group (prevention or reversal).

CONCLUSIONS:Long-term treatment with the calcium antagonist, mibefradil, both prevents and reverses the development of hyperinsulinemia, hypertriglyceridemia and hypertension in FH rats. These data indicate beneficial effects of mibefradil on carbohydrate and lipid metabolism in hyperinsulinemic and insulin-resistant states.

译文

目的 : 为了确定钙拮抗剂对高胰岛素血症,高甘油三酯血症和高血压的影响,我们检查了新型钙通道阻滞剂mibefradil对血浆胰岛素水平的长期影响,胰岛素抵抗和高胰岛素性果糖高血压 (FH) 大鼠的血浆甘油三酸酯水平和收缩压。为此,采用了预防和逆转方案。
方法 : 预防研究: 雄性Sprague-Dawley大鼠在6周龄时被购买,并分为: 对照组 (C,n = 6),对照处理 (CT,n = 5),果糖 (F,n = 7) 和果糖处理 (FT,n = 6)。所有组均进行了血糖,胰岛素和收缩压的基线测量。在第7周时,CT和FT组开始了慢性mibefradil治疗 (30 mg/kg/天,口服6周)。在第8周,F和FT组的大鼠开始66% 果糖饮食以诱导高胰岛素血症和高血压。在接下来的4周内,每周测量血浆胰岛素,血浆甘油三酸酯和收缩压。逆转方案: 在一项单独的研究中,使用8周治疗的FH大鼠及其年龄匹配的对照组来检查米贝拉地对逆转果糖诱导的高胰岛素血症和高血压的作用。
结果 : F组表现为高胰岛素血症 (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml,P <0.05),高血压 (148 +/- 3 vs. C 121 +/- 1 mmHg,P <0.002) 和甘油三酯水平升高 (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM,P <0.05)。慢性米贝拉地尔治疗可防止高胰岛素血症 (1.6 +/- 0.08 ng/ml,P <0.004 vs. F) 和高血压 (123 +/- 1 mmHg。P <0.001 vs. F) 的发展,并减轻高甘油三酯血症的发展。在逆转研究中,米贝拉地尔治疗逆转了FH大鼠高胰岛素血症,高甘油三酯血症和BP升高的发展。治疗不会影响任何组的血浆葡萄糖水平 (预防或逆转)。
结论 : 钙拮抗剂mibefradil的长期治疗都可以预防和逆转FH大鼠的高胰岛素血症,高甘油三酯血症和高血压。这些数据表明mibefradil在高胰岛素血症和胰岛素抵抗状态下对碳水化合物和脂质代谢的有益作用。

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