Effects of salt status and blockade of mineralocorticoid receptors on aldosterone-induced cardiac injury.
The mineralocorticoid aldosterone regulates sodium and water homeostasis in the human body. The combination of excess aldosterone and salt loading induces hypertension and cardiac damage. However, little is known of the effects of aldosterone on blood pressure and cardiac pathophysiology in the absence of salt loading. We have now investigated the effects of salt status and blockade of mineralocorticoid receptors (MRs) on cardiac pathophysiology in uninephrectomized Sprague-Dawley rats implanted with an osmotic minipump to maintain hyperaldosteronism. The rats were fed a low-salt (0.0466% NaCl in chow) or high-salt (0.36% NaCl in chow plus 1% NaCl in drinking water) diet in the absence or presence of treatment with a subdepressor dose of the MR antagonist spironolactone (SPL). Aldosterone excess in the setting of low salt intake induced substantial cardiac remodeling and diastolic dysfunction without increasing blood pressure. These effects were accompanied by increased levels of oxidative stress and inflammation as well as increased expression of genes related to the renin-angiotensin and endothelin systems in the heart. All of these cardiac changes were completely blocked by the administration of SPL. On the other hand, aldosterone excess in the setting of high salt intake induced hypertension and a greater extent of cardiac injury, with the cardiac changes being only partially attenuated by SPL in a manner independent of its antihypertensive effect. The combination of dietary salt restriction and MR antagonism is thus a promising therapeutic option for the management of hypertensive patients with hyperaldosteronism or relative aldosterone excess.
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Takuya
T
Hattori
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Tamayo
T
Murase
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
Yukino
Y
Sugiura
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
Kai
K
Nagasawa
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Keiji
K
Takahashi
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Masafumi
M
Ohtake
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Mayuko
M
Ohtake
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Masaaki
M
Miyachi
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Toyoaki
T
Murohara
Department of Pathophysiological Laboratory Sciences, Nagoya University School of Medicine, Nagoya, Japan.
Kohzo
K
Nagata
D000450:Aldosterone; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000502:physiology; D004039:Diet, Sodium-Restricted; D004452:Echocardiography; D016232:Endothelins / Q000502:physiology; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism*; D006334:Heart Function Tests; D006929:Hyperaldosteronism / Q000503:physiopathology; D006973:Hypertension / Q000175:diagnosis / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009205:Myocarditis / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009392:Nephrectomy; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology
D016232:Endothelins; D000451:Mineralocorticoid Receptor Antagonists; D013481:Superoxides; D000450:Aldosterone; D012964:Sodium