Effects of manidipine on DNA and protein syntheses in cultured vascular smooth muscle and endothelial cells and on proto-oncogene expression.

To elucidate the importance of Ca2+ influx via voltage-dependent Ca2+ channels in the mechanism of vascular remodeling, we investigated effects of a new Ca2+ channel blocker manidipine on DNA and protein syntheses stimulated by several mitogens in cultured rat vascular smooth muscle cells (VSMC) and bovine endothelial cells (EC), and growth-related immediate early proto-oncogenes expression in VSMC. Endothelin-1 (ET-1) induced receptor-mediated phosphoinositide breakdown and increased cytosolic free Ca2+ levels in rat VSMC, with concomitant increases in proto-oncogenes (c-fos c-myc) mRNA levels as well as DNA and protein syntheses. Manidipine dose-dependently (10(-9) M to 10(-6) M) inhibited DNA, and protein syntheses stimulated by 10(-7) M ET-1 in rat VSMC; manidipine was a more potent inhibitor for protein synthesis (IC50: 10(-8) M) than for DNA synthesis (IC50: 10(-7) M). Manidipine also inhibited DNA synthesis stimulated by 10 ng/mL bFGF and 2.5% FCS in rat VSMC and bovine EC; manidipine was more potent in inhibiting DNA synthesis stimulated by bFGF than that by FCS in both cells. The expression of ET-1-induced c-fos and c-myc mRNAs levels was unaffected by manidipine. These results suggest that manidipine has potent inhibitory effects on the ET-1-induced hyperplasia and/or hypertrophy of VSMC, as well as on the bFGF-induced hyperplasias of VSMC and EC, thus implicating its potential usefulness for preventing abnormal VSMC proliferation and angiogenesis associated with hypertension and atherosclerosis.