Fujiwara R, Hayashi T, Nakai T, Miyabo S
Third Department of Internal Medicine, Fukui Medical School, Japan.
Cardiovasc Drugs Ther. 1994 Dec;8(6):861-9. doi: 10.1007/BF00877405.
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)
血管平滑肌细胞（VSMC）的增殖在动脉粥样硬化病变中起关键作用。已证明血清衍生的肽类生长因子，如胰岛素、血小板衍生生长因子（PDGF）或表皮生长因子（EGF），在VSMC中提供促有丝分裂信号，并且Ca2+与其他信使的相互作用对于触发增殖是必要的。由于Ca2+通道阻滞剂作用于电压依赖性Ca2+通道以抑制Ca2+内流，可以设想它们会影响生长因子的增殖作用。在本研究中，我们评估了1,5 - 苯并硫氮杂䓬衍生的Ca2+通道阻滞剂地尔硫䓬对大鼠主动脉培养的VSMC中由胰岛素、胰岛素样生长因子I（IGF - I）或PDGF刺激的[3H]胸苷掺入DNA的影响。我们还研究了胰岛素、IGF - I和PDGF对VSMC中Ca2+摄取的影响。在暴露于胰岛素（10^(-10)至8×10^(-6) M）或IGF - I（10^(-10)至10^(-7) M）48小时后，与对照相比，VSMC将[3H]胸苷掺入量达到最大值的200 - 280%（单独使用胰岛素或IGF - I时）。IGF - I的作用比胰岛素强约10 - 100倍。PDGF（0.5 - 15 ng/ml）也诱导VSMC的DNA中[3H]胸苷掺入量增加。观察到PDGF与胰岛素或IGF - I之间具有相加性，但胰岛素和IGF - I之间没有。用胰岛素（5×10^(-8)至10^(-6) M）、IGF - I（10^(-8)至10^(-6) M）或PDGF（1.0 - 15.0 ng/ml）处理60分钟会增加5分钟内的单向45Ca2+摄取。（摘要截断于250字）
