Edaravone, a radical scavenger, may enhance or produce antiproliferative effects of fluvastatin, amlodipine, ozagrel, GF109203X and Y27632 on cultured basilar artery smooth muscle cells.
Proliferation of vascular smooth muscle cells stimulated by reactive oxygen species (ROS) may play a pivotal role in the pathogenesis of atherosclerosis. To clarify mechanisms by which ROS promote vascular atherogenesis, effects of fluvastatin, amlodipine, ozagrel (thromboxane synthetase inhibitor), GF109203X (a protein kinase C inhibitor) and Y27632 (a ROCK inhibitor) on the proliferation of guinea-pig basilar artery smooth muscle cells (GBa-SM3) in a 5% FBS culture medium were studied over 3 d in the presence or absence of a free radical scavenger, edaravone. Viability of cells at the end of incubation was measured by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test. Results demonstrated that fluvastatin and amlodipine by themselves possess antiproliferative effects on the GBa-SM3 cells at 10-100 microM and 0.1-1 microM, respectively. While edaravone possessed no antiproliferative effect by itself at 100 microM, it significantly (p<0.05) augmented the antiproliferative effects of fluvastatin and amlodipine. In addition, ozagrel, GF109203X and Y27632 possessed no appreciable effects on the cell growth by themselves. However, coincubation of edaravone at 100 microM with these agents elicited significant antiproliferative effects for ozagrel, GF109203X and Y27632 at 10-100 microM, 1-10 microM and 0.1-1 microM, respectively. In conclusion, edaravone may have clinically beneficial interactions with fluvastatin, amlodipine and ozagrel regarding the prevention of vascular atherosclerosis. The interactions between edaravone and the inhibitors of protein kinase C and ROCK were suggestive of possible contributions of ROS-triggered intracellular signals associated with these enzymes to vascular atherogenesis, but further studies are required for confirmation.
Yamaguchi
Tomoaki
T
Departments of Hospital Pharmacy, Nakano General Hospital, Tokyo, Japan. nghph@nakanosogo.or.jp
Oishi
Kazuhiko
K
Uchida
Masaatsu
M
Echizen
Hirotoshi
H
D000577:Amides / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D001488:Basilar Artery / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077553:Edaravone; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008689:Methacrylates / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles
D000577:Amides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D016166:Free Radical Scavengers; D007211:Indoles; D008301:Maleimides; D008689:Methacrylates; D011725:Pyridines; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C108830:Y 27632; D017311:Amlodipine; D000077340:Fluvastatin; C022616:thiazolyl blue; C034364:ozagrel; C070515:bisindolylmaleimide I; D000077553:Edaravone; D000983:Antipyrine