Allopurinol reduces neointimal hyperplasia in the carotid artery ligation model in spontaneously hypertensive rats.
Uric acid and oxidative stress promote cardiovascular diseases, including atherosclerosis and hypertension. Xanthine oxidase, through which uric acid is generated, is a free-radical generating enzyme. The aim of the current study was to investigate whether allopurinol, an inhibitor of xanthine oxidase activity, affects vascular remodeling and vascular smooth muscle cell (VSMC) proliferation. In the carotid artery ligation model using spontaneously hypertensive rats (SHR), treatment with allopurinol induced a reduction in the neointima/media ratio by 27% (38.5+/-34.3% in the control group and 28.1 20.8% in the allopurinol-treated group, respectively, p<0.01) without alterations in vascular circumference at 3 weeks after ligation when compared to the control. Allopurinol lowered the serum uric acid concentration (147.0+/-3.6 micromol/l in the control group and 16.1+/-3.6 micromol/l in the allopurinol-treated group, respectively p<0.01) and xanthine oxidase activity, but not the blood pressure. In an in vitro study, high concentrations of uric acid (100 and 200 micromol/l) stimulated VSMC growth, but there was no stimulation of these cells by a low concentration of uric acid (50 micromol/I) or by any of three concentrations of xanthine (50, 100 and 200 micromol/l). In addition, allopurinol (5 micromol/I) had no effect on the cell growth. In conclusion, uric acid is a potent stimulator of VSMC proliferation, and allopurinol prevented vascular remodeling in SHR at least in part by inhibiting uric acid concentration.
Yamamoto
Yasutaka
Y
Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan. yasutaka@grape.med.tottori-u.ac.jp
Ogino
Kazuhide
K
Igawa
Go
G
Matsuura
Takashi
T
Kaetsu
Yasuhiro
Y
Sugihara
Shinobu
S
Matsubara
Koichi
K
Miake
Junichiro
J
Hamada
Toshihiro
T
Yoshida
Akio
A
Igawa
Osamu
O
Yamamoto
Tetsuya
T
Shigemasa
Chiaki
C
Hisatome
Ichiro
I
D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006339:Heart Rate / Q000187:drug effects; D006965:Hyperplasia / Q000188:drug therapy; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D017540:Tunica Media / Q000187:drug effects*; D014527:Uric Acid / Q000097:blood / Q000494:pharmacology; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000097:blood
D019820:Xanthine; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase