Role of xanthine oxidoreductase in the reversal of diastolic heart failure by candesartan in the salt-sensitive hypertensive rat.
The role of angiotensin II and reactive oxygen species in the exacerbation of diastolic heart failure is unknown. We examined the therapeutic effect of angiotensin blockade on hypertensive diastolic heart failure, focusing on the role of xanthine oxidoreductase and reduced nicotinamide-adenine dinucleotide phosphate oxidase, major enzymes producing reactive oxygen species. Dahl salt-sensitive hypertensive rats (DS rats) with established diastolic heart failure were given vehicle, candesartan (an angiotensin II receptor subtype 1 receptor blocker), oxypurinol (a xanthine oxidoreductase inhibitor), apocynin (a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor), or hydralazine (a vasodilator), and their therapeutic effects on diastolic heart failure were compared. Candesartan treatment of DS rats with established diastolic heart failure reversed cardiac remodeling, improved cardiac relaxation abnormality, and prolonged survival, being accompanied by the attenuation of the increase in cardiac superoxide, reduced nicotinamide-adenine dinucleotide phosphate oxidase, and xanthine oxidoreductase activities. Thus, the beneficial effect of candesartan in DS rats appears to be mediated by the inhibition of cardiac reactive oxygen species. Cardiac xanthine oxidoreductase inhibition with oxypurinol significantly reduced cardiac superoxide, prevented the progression of cardiac remodeling, and delayed the mortality in DS rats. Apocynin, which significantly inhibited cardiac reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, prevented the exacerbation of diastolic heart failure more than hydralazine. However, compared with candesartan or oxypurinol, apocynin did not improve cardiac reactive oxygen species, remodeling, and function in DS rats. In conclusion, candesartan slowed the exacerbation of hypertensive diastolic heart failure in DS rats by causing reverse cardiac remodeling. Cardiac xanthine oxidoreductase contributed to these beneficial effects of candesartan.
Yamamoto
Eiichiro
E
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Kataoka
Keiichiro
K
Yamashita
Takuro
T
Tokutomi
Yoshiko
Y
Dong
Yi-Fei
YF
Matsuba
Shinji
S
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000098:Acetophenones / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010117:Oxypurinol / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017382:Reactive Oxygen Species; D013777:Tetrazoles; C056165:acetovanillone; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D020929:Mitogen-Activated Protein Kinase Kinases; D010117:Oxypurinol; C081643:candesartan