Effect of Short-Term Treatment of SHR With the Novel Calcium Channel Antagonist Mibefradil on Function of Small Arteries

Abstract

Treatment of spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) for at least 12 weeks with calcium channel antagonists is associated with regression of structural hypertensive changes in the heart and in conduit and small arteries. To establish whether structural or functional changes of small arteries could be corrected with shorter periods of specific antihypertensive treatment, SHR and WKY were treated for 4 weeks with the novel calcium channel blocker mibefradil. Blood pressure rise was significantly reduced by mibefradil treatment in SHR to 165 ± 1 mm Hg compared to a systolic blood pressure of 183 ± 2 mm Hg in untreated SHR ( P < .01). Aortic hypertrophy in SHR was slightly reduced by treatment, but small artery hypertrophy in 4 vascular beds (mesenteric, renal, coronary, and femoral) was unaffected by administration of mibefradil for 4 weeks. Mibefradil treatment resulted in normalization of endothelium-dependent relaxation in mesenteric small arteries, with disappearance of acetylcholine-induced contractions, although hypertrophy and remodeling of these small arteries were not significantly affected by treatment. In WKY rats, treatment had no effect on either structure or function of small arteries. These results demonstrate that treatment with the calcium antagonist mibefradil may induce an improvement in altered endothelial function even before regression of cardiovascular hypertrophy and remodeling takes place under treatment, indicating that normalization of abnormal small artery endothelial function in SHR under antihypertensive therapy may be independent of correction of altered small artery structure.