Diltiazem inhibits DNA synthesis and Ca2+ uptake induced by insulin, IGF-I, and PDGF in vascular smooth muscle cells.
Proliferation of vascular smooth muscle cells (VSMC) has been shown to play a key role in the atherosclerotic lesions. It has been demonstrated that serum-derived peptidic growth factors, such as insulin, platelet-derived growth factor (PDGF), or epidermal growth factor (EGF), provide mitogenic signals in VSMC and that the interplay of Ca2+ and other messengers is necessary for triggering proliferation. Since Ca2+ channel blockers act on the voltage-dependent Ca2+ channel to inhibit Ca2+ influx, it is conceivable that they affect the proliferative action of growth factors. In this study we have evaluated the effects of diltiazem, a 1,5-benzothiazepine-derived Ca2+ channel blocker, on [3H]thymidine incorporation into DNA stimulated by insulin, insulinlike growth factor I (IGF-I), or PDGF in cultured VSMC from rat aorta. We have also investigated the effects of insulin, IGF-I, and PDGF on Ca2+ uptake in VSMC. After exposure to insulin (10(-10) to 8 x 10(-6) M) or IGF-I (10(-10) to 10(-7) M) for 48 hours, VSMC incorporated [3H]thymidine to 200-280% of maximum (with insulin or IGF-I alone) compared to control. The effect of IGF-I was approximately 10-100 times more potent than that of insulin. PDGF (0.5-15 ng/ml) also induced an increase in [3H]thymidine incorporation into DNA of VSMC. Additivity is observed between PDGF with insulin or IGF-I, but not between insulin and IGF-I. Sixty minute treatment with insulin (5 x 10(-8) to 10(-6) M), IGF-I (10(-8) to 10(-6) M), or PDGF (1.0-15.0 ng/ml) increased the unidirectional 45Ca2+ uptake during a 5 minute period.(ABSTRACT TRUNCATED AT 250 WORDS)
Fujiwara
R
R
Third Department of Internal Medicine, Fukui Medical School, Japan.
Hayashi
T
T
Nakai
T
T
Miyabo
S
S
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004110:Diltiazem / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013936:Thymidine / Q000378:metabolism
D007328:Insulin; D007329:Insulin Antagonists; D009124:Muscle Proteins; D010982:Platelet-Derived Growth Factor; D007334:Insulin-Like Growth Factor I; D004247:DNA; D004110:Diltiazem; D002118:Calcium; D013936:Thymidine