Effects of nicorandil on cell proliferation and cholesteryl ester accumulation in arterial smooth muscle cells in culture.
Ca2+ regulates a variety of cellular mechanisms in vascular cells as well as in platelets. Nicorandil interacts with the intracellular Ca(2+)-activated processes in vascular smooth muscle cells, while Ca2+ channel blockers such as verapamil and diltiazem block voltage-dependent Ca2+ channels. The effects of nicorandil are due to the hyperpolarization of the membrane, interference with mobilization of Ca2+ from the intracellular storage sites, and blockade of receptor-operated Ca2+ channels. In the present study, the effects of nicorandil on cell proliferation and cholesteryl ester accumulation in rat arterial smooth muscle cells in culture were compared to Ca2+ channel blockers. Smooth muscle cells were prepared from rat thoracic aorta, and the rate of proliferation was determined by measuring the cell number and by [3H]-thymidine incorporation into cellular DNA. The effect of nicorandil on cholesteryl ester content in smooth muscle cells was determined by thin-layer chromatography of the cell extracts. Nicorandil at concentrations of 10(-6) to 10(-4) M, as well as Ca2+ channel blockers (verapamil and diltiazem) inhibited the proliferation and DNA synthesis of cultured smooth muscle cells. The acute inhibitory effects on cell proliferation were observed significantly 16 hours after the addition of the three agents in serum-stimulated cells. These effects were dose dependent, both in acute and in chronic treatment with the three agents. Addition of 10(-5) M nicorandil to medium supplemented with 10% serum resulted in a decrease of the net cholesteryl ester content by 18 +/- 1%, while cellular free cholesterol content was the same as control. Similar results were also obtained in the presence of verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)
Third Department of Internal Medicine, Fukui Medical School, Japan.
R
R
Fujiwara
T
T
Hayashi
Y
Y
Kutsumi
K
K
Oida
T
T
Tamai
T
T
Nakai
S
S
Miyabo
D000818:Animals; D001013:Aorta, Thoracic; D015220:Calcium Channels / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004110:Diltiazem / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D015220:Calcium Channels; D002788:Cholesterol Esters; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D004247:DNA; D002784:Cholesterol; D014700:Verapamil; D004110:Diltiazem