Abstract 1242: The Ca2+ Channel Blocker Benidipine Promotes Coronary Angiogenesis And Reduces Both Left Ventricular Stiffness And Mortality In Hypertensive Rats
Introduction: Up-regulation of T-type Ca2+ channels (CCs) is associated with heart failure. However, the effects of CC blockers that target T- and L-type channels on diastolic heart failure (DHF) are unknown.
Hypothesis: We examined the hypothesis that benidipine, a blocker of T-and L-type CCs, and nitrendipine, which blocks only L-type channels, would show different effects on DHF.
Methods: Male Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age to induce hypertension and were either left untreated (n = 10) or orally administered benidipine (3 mg/kg per day, n = 10) or nitrendipine (10 mg/kg per day, n = 10) from 10 to 17 weeks of age. Control rats (n = 10) were maintained on a low-salt diet.
Results: The LV ejection fraction was preserved but left ventricular (LV) end-diastolic pressure was increased in untreated rats, indicative of DHF. Benidipine and nitrendipine exhibited similar hypotensive effects and reduced LV weight and cardiomyocyte hypertrophy by similar extents compared with those in the untreated group. Benidipine reduced LV stiffness to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight and mortality relative to those in untreated animals. The extent of interstitial fibrosis, the abundance of mRNAs for β-MHC, TGF-β, ACE, MCP-1, ICAM-1, and collagen type I, as well as the collagen type I/III mRNA ratio in LV tissue were similarly reduced by benidipine and nitrendipine. The amounts of mRNAs for the H and G subunits of T-type CCs were increased in the left ventricle of untreated rats relative to those in control animals, and these increases were similarly reduced by both drugs. Benidipine, but not nitrendipine, both increased capillary density and restored the expression of vascular endothelial growth factor and hypoxia-inducible factor (Hif)-1 at the mRNA and protein levels in LV tissue.
Conclusions: Benidipine promoted coronary angiogenesis through restoration of Hif-1 expression, reduced LV stiffness in a manner independent, at least in part, of a reduction in interstitial fibrosis, and improved survival in this rat model. Blockers of both T- and L-type CCs may thus be more effective than those that target only L-type channels in preventing hypertensive DHF.