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Chronic T-type Ca2+ channel blockade with mibefradil in hyperinsulinemic, insulin-resistant and hypertensive rats
1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
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.
Insights
Mibefradil, a calcium antagonist, effectively prevents and reverses hyperinsulinemia, hypertriglyceridemia, and hypertension in fructose-hypertensive rats, indicating benefits for metabolic health.
Area of Science:
- Cardiovascular Pharmacology
- Metabolic Syndrome Research
- Animal Models of Disease
Background:
- Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension are key features of metabolic syndrome.
- Fructose-induced hypertension in rats serves as a relevant model for studying these metabolic disturbances.
Purpose of the Study:
- To investigate the long-term effects of the novel calcium channel blocker mibefradil.
- To assess mibefradil's impact on plasma insulin, triglyceride levels, and systolic blood pressure in fructose-hypertensive (FH) rats.
- To evaluate both preventative and reversal effects of mibefradil treatment.
Main Methods:
- Male Sprague-Dawley rats were used in prevention and reversal study protocols.
- Mibefradil was administered orally to fructose-fed rats to induce hyperinsulinemia and hypertension.
- Plasma insulin, triglyceride levels, and systolic blood pressure were monitored throughout the study.
Main Results:
- Fructose feeding led to significant hyperinsulinemia, hypertension, and elevated triglyceride levels.
- Mibefradil treatment prevented the development of hyperinsulinemia and hypertension and attenuated hypertriglyceridemia.
- Mibefradil successfully reversed established hyperinsulinemia, hypertriglyceridemia, and hypertension in FH rats.
Conclusions:
- Mibefradil demonstrates both preventative and reversal efficacy against metabolic and hypertensive abnormalities in FH rats.
- These findings suggest mibefradil has beneficial effects on carbohydrate and lipid metabolism in insulin-resistant states.
- Calcium antagonists like mibefradil may offer therapeutic potential for managing metabolic syndrome components.