Chronic T-type Ca2+ channel blockade with mibefradil in hyperinsulinemic, insulin-resistant and hypertensive rats.
OBJECTIVE
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.
Verma
S
S
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Bhanot
S
S
Hicke
A
A
McNeill
J H
JH
D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D005632:Fructose; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control*; D007333:Insulin Resistance; D008297:Male; D020748:Mibefradil; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D001562:Benzimidazoles; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D020748:Mibefradil; D005632:Fructose