Effects of alpha-lipoic acid on deoxycorticosterone acetate-salt-induced hypertension in rats.
We investigated the potential of natural occurring antioxidant alpha-lipoic acid to prevent hypertension and hypertensive tissue injury induced by deoxycorticosterone acetate (DOCA) and salt in rats. Two weeks after the start of DOCA-salt treatment, the rats were given alpha-lipoic acid (10 or 100 mg/kg/day, s.c.) or its vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as sham-operated controls. In vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3-4 weeks. Daily administration of 100 mg/kg alpha-lipoic acid for 2 weeks suppressed the increase in systolic blood pressure, whereas 10 mg/kg alpha-lipoic acid did not affect the progression of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was morphometrically evaluated at 4 weeks, there were significant increases in media cross-sectional area in vehicle-treated DOCA-salt rats compared with sham-operated rats. The development of vascular hypertrophy was markedly suppressed by alpha-lipoic acid at 100 mg/kg but not at 10 mg/kg. Histopathological examination of the kidney in vehicle-treated DOCA-salt rats revealed fibrinoid-like necrosis in glomeruli and thickening of small arteries. In these animals, creatinine clearance decreased, and fractional excretion of Na(+), urinary excretion of protein and N-acetyl-beta-glucosaminidase increased. Such renal lesions and dysfunctions were ameliorated in DOCA-salt rats given alpha-lipoic acid. In addition, a marked increase in endothelin-1 content in both the aorta and kidney was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. Significant attenuation of this increase occurred in alpha-lipoic acid-treated DOCA-salt rats. These results suggest that administration of alpha-lipoic acid to DOCA-salt hypertensive rats lessens the increased blood pressure and protects against renal and vascular injuries, possibly through the suppression of renal and vascular endothelin-1 overproduction.
Takaoka
M
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. takaoka@oups.ac.jp
Kobayashi
Y
Y
Yuba
M
M
Ohkita
M
M
Matsumura
Y
Y
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D006984:Hypertrophy / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D008063:Thioctic Acid / Q000494:pharmacology*
D019332:Endothelin-1; D003900:Desoxycorticosterone; D008063:Thioctic Acid