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.