Tesfamariam B, Frohlich B H, Gregg R E
Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
J Cardiovasc Pharmacol. 1999 Jul;34(1):95-101. doi: 10.1097/00005344-199907000-00016.
The direct effects of the cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, on vascular smooth muscle responsiveness were examined by incubation of isolated aorta from normocholesterolemic rats with simvastatin, atorvastatin, or pravastatin. The smooth muscle contractions caused by phenylephrine were progressively inhibited with increasing concentrations of simvastatin. Similarly, atorvastatin at the higher concentration caused decreased responses to phenylephrine. In contrast, incubation with pravastatin had no significant effect at all concentrations studied. In Ca2+-free buffer, the transient contraction caused by phenylephrine, which results from intracellular release of Ca2+, also was inhibited by simvastatin and atorvastatin but not by pravastatin. In cultured rat aortic smooth muscle cells loaded with fura-2, increases in intracellular free-Ca2+ concentration ([Ca2+]i) induced by angiotensin II were markedly inhibited in cells incubated with simvastatin and atorvastatin but not pravastatin. The inhibitory effects of simvastatin and atorvastatin were reversed by mevalonate. These findings demonstrate that inhibition of HMG CoA reductase by using simvastatin and atorvastatin, but not pravastatin, has effects on vascular smooth muscle cell responsiveness that involve alteration of Ca2+ homeostasis through a mevalonate-dependent pathway.
通过将正常胆固醇血症大鼠的离体主动脉与辛伐他汀、阿托伐他汀或普伐他汀一起孵育，研究了降胆固醇药物3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂对血管平滑肌反应性的直接影响。随着辛伐他汀浓度的增加，去氧肾上腺素引起的平滑肌收缩逐渐受到抑制。同样，较高浓度的阿托伐他汀也会导致对去氧肾上腺素的反应降低。相比之下，在所有研究浓度下，与普伐他汀一起孵育均无显著影响。在无钙缓冲液中，由细胞内钙释放引起的去氧肾上腺素导致的短暂收缩也受到辛伐他汀和阿托伐他汀的抑制，但不受普伐他汀的抑制。在用fura-2负载的培养大鼠主动脉平滑肌细胞中，与辛伐他汀和阿托伐他汀一起孵育的细胞中，血管紧张素II诱导的细胞内游离钙浓度（[Ca2+]i）升高受到明显抑制，但普伐他汀处理的细胞不受影响。辛伐他汀和阿托伐他汀的抑制作用可被甲羟戊酸逆转。这些发现表明，使用辛伐他汀和阿托伐他汀而非普伐他汀抑制HMG CoA还原酶对血管平滑肌细胞反应性有影响，这种影响涉及通过甲羟戊酸依赖性途径改变钙稳态。
