Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions.
BACKGROUND
Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors.


METHODS
To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats.


RESULTS
Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1.


CONCLUSIONS
These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.
Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Hong
H
Wang
Tatsuo
T
Shimosawa
Hiromitsu
H
Matsui
Tomoyo
T
Kaneko
Sayoko
S
Ogura
Yuzaburo
Y
Uetake
Katsu
K
Takenaka
Yutaka
Y
Yatomi
Toshiro
T
Fujita
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003971:Diastole; D004195:Disease Models, Animal; D000077545:Eplerenone; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D013113:Spin Labels; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013148:Spironolactone; D000077545:Eplerenone; C001803:tempol