Mibefradil reduces blood glucose concentration in db/db mice

OBJECTIVE: Numerous recent studies suggest that abnormal intracellular calcium concentration ([Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic β-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes, but the mechanism remains unknown. METHODS: We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection. RESULTS: Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92±20.46 mg/dl to 285.20±5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced by NNC 55-0396, a compound structurally similar to mibefradil but more selective for T-type Ca2+ channels, but not by the specific L-type Ca2+ channel blocker nicardipine. Mibefradil did not show such hypoglycemic effects in heterozygous animals. In addition, triglycerides, basal insulin and food intake were significantly decreased by mibefradil treatment in the db/db mice but not in the controls. Western blot analysis, immunohistochemistry and immunofluorescence staining showed a significantly increased expression of T-type Ca2+ channel α-subunits Cav3.1 and Cav3.2 in liver and brain tissues from db/db mice compared to those from heterozygous animals. CONCLUSIONS: Collectively, these results suggest that T-type Ca2+ channels are potential therapeutic targets for antidiabetic drugs. .

Blood pressure response to antihypertensive agents related to baseline blood pressure.

Prevalence of white-coat hypertension varies approximately 20 per cent among mild hypertensives. When white-coat hypertensives are prescribed antihypertensive medication, there is usually a decrease in clinic blood pressure (BP), but little or no change in 24 hours blood pressure (ABPM). The objective of the study was to test the hypothesis that efficacy of medication therapy for hypertension is identical in any grading of severity of baseline blood pressure. The authors retrospectively analysed ABPM data from mild to moderate hypertensive patients. Efficacy in decreasing blood pressure by antihypertensives has linear relation to baseline blood pressure. Response to antihypertensive agents in white-coat hypertension is minimal but a significant effect still persists and the possibility of hypotensive adverse events from medication in the case cannot be overlooked.