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.
Hirata
Y
Y
Department of Medicine-II, Tokyo Medical and Dental University, Japan.
Eguchi
S
S
Tsujino
M
M
D000818:Animals; D015152:Blotting, Northern; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects* / Q000235:genetics*; D016259:Genes, myc / Q000187:drug effects* / Q000235:genetics*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007700:Kinetics; D008934:Mitogens / Q000494:pharmacology; D009124:Muscle Proteins / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009578:Nitrobenzenes; D010879:Piperazines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013268:Stimulation, Chemical
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016232:Endothelins; D008934:Mitogens; D009124:Muscle Proteins; D009578:Nitrobenzenes; D010879:Piperazines; D012333:RNA, Messenger; C054218:manidipine; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA