Direct vascular effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
1. We have examined the effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet-derived growth factor (PDGF)-induced migration and fetal calf serum (FCS)-induced proliferation of rabbit smooth muscle cells (SMC) were investigated. 2. Probucol, at 10 micro mol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 micro mol/L, HR780 significantly (P = 0.010) inhibited X/XO-induced EC injury. 3. HR780 dose-dependently inhibited PDGF-induced SMC migration and FCS-induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG-CoA reductase inhibitor, simvastatin (0.1-100 micro mol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1-100 micro mol/L) did not show any effects. 4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.
Wajima
Teruaki
T
Pharmacology, Aventis Pharma Ltd, Minamidai, Kawagoe, Saitama, Japan. teruaki.wajima@aventis.com
Makita
Shigeki
S
Oshima
Kenichi
K
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005312:Fetal Blood / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D011341:Probucol / Q000008:administration & dosage / Q000493:pharmacokinetics; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology; D013552:Swine; D019820:Xanthine / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism; D014969:Xanthine Oxidase / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; C062437:HR 780; D019820:Xanthine; D019821:Simvastatin; D007770:L-Lactate Dehydrogenase; D014969:Xanthine Oxidase; D017035:Pravastatin; D011341:Probucol; D008798:Mevalonic Acid