Candesartan and amlodipine combination therapy provides powerful vascular protection in stroke-prone spontaneously hypertensive rats.
The vascular protective effects of placebo, candesartan (1 mg kg(-1) per day) monotherapy, candesartan (1 mg kg(-1) per day) and amlodipine (1 mg kg(-1) per day) combination therapy, and candesartan (1 mg kg(-1) per day) and hydrochlorothiazide (HCTZ) (10 mg kg(-1) per day) combination therapy for 2 weeks were compared in stroke-prone, spontaneously hypertensive rats. Candesartan monotherapy significantly reduced blood pressure, and both combination therapies were equally and significantly lower than the monotherapy. Acetylcholine-induced vascular relaxation was significantly stronger in all therapeutic groups than in the placebo-treated group. Furthermore, the relaxation was significantly stronger in the candesartan plus amlodipine-treated group than in the candesartan-treated group; however, there was no significant difference between the candesartan- and candesartan plus HCTZ-treated groups. Vascular gene expressions of the NADPH oxidase subunits p22(phox), gp91(phox), NOX1 and NOX4 were significantly attenuated in all therapeutic groups compared with the placebo-treated group, and there were no significant differences among those groups. However, a significant augmentation of vascular superoxide dismutase activity was observed in the candesartan plus amlodipine-treated group, but not in other groups. Malondialdehyde levels in the vascular tissues were significantly attenuated in all therapeutic groups. Compared with the candesartan-treated group, significant attenuation was observed in the candesartan plus amlodipine-treated group, but not in the candesartan plus HCTZ-treated group. Immunohistological analysis showed that areas positive for 4-hydroxy-2-nonenal were significantly reduced in all therapeutic groups, but this reduction was significantly greater for the candesartan plus amlodipine-treated group than for the candesartan-treated group. Thus, candesartan and amlodipine combination therapy could have a powerful protective effect in vascular tissues via the reduction of oxidative stress.
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
Shinji
S
Takai
Denan
D
Jin
Takashi
T
Shimosato
Hiroshi
H
Sakonjo
Mizuo
M
Miyazaki
D000109:Acetylcholine / Q000494:pharmacology; D017311:Amlodipine / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001808:Blood Vessels / Q000187:drug effects* / Q000503:physiopathology; D004232:Diuretics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D006852:Hydrochlorothiazide / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000037:antagonists & inhibitors; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D020521:Stroke / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D013777:Tetrazoles; D014665:Vasodilator Agents; D006852:Hydrochlorothiazide; D017311:Amlodipine; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D000109:Acetylcholine; C081643:candesartan