title: Additive amelioration of oxidative stress and cardiac function by combined mineralocorticoid and angiotensin receptor blockers in postinfarct failing hearts.
abstract: Reactive oxygen species are exacerbating factors in failing hearts. We examined whether spironolactone, a mineralocorticoid receptor antagonist, provides additional effects to olmesartan, an angiotensin II receptor blocker, on oxidative stress in postinfarct failing hearts. Congestive heart failure due to myocardial infarction (MI) was induced by the coronary artery ligation in rats. Three weeks later, the rats were divided into 4 groups: an untreated MI group, spironolactone (100 mg·kg·d)-treated MI group, olmesartan (10 mg·kg·d)-treated MI group, and combination-treated (spironolactone and olmesartan) MI group. After 7 weeks of MI, monotherapy improved left ventricular dilatation and function, and suppressed myocardial lipid peroxidation, in association with an attenuation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent and mitochondrial superoxide production. Moreover, combination therapy caused a synergistic improvement in these indices. In experiments using cultured myocytes, aldosterone (100 nmole/L) and angiotensin II (100 nmole/L) enhanced both sources of superoxide production, although these humoral factors affected NADPH oxidase subunits (p47phox and gp91phox) differently. In conclusion, aldosterone and angiotensin II increase NADPH oxidase-dependent and mitochondrial superoxide production in myocytes, and the combination of an angiotensin II receptor blocker and mineralocorticoid receptor antagonist has a synergistic attenuation of cardiac oxidative stress, leading to an improvement in cardiac function in postinfarct failing hearts.
authors.affiliation: Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Noda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Junichi
authors.initials: J
authors.lastname: Hamada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshifuji
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D013777:Tetrazoles; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; C437965:olmesartan; D019255:NADPH Oxidases