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CARDIOVASCULAR

Effects of Adrenomedullin on Cardiac Oxidative Stress and Collagen Accumulation in Aldosterone-Dependent Malignant Hypertensive Rats

Departments of Pharmacology (M.R., A.N., G.-X.Z., Y.-Y.F., S.K., Y.A.) and Cardio-renal and Cerebrovascular Medicine (M.R., P.G., N.H., K.O., M.K.) and Life Science Research Center (Y.N., Y.F.), Kagawa University Medical School, Kagawa, Japan.

We examined the effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. Spontaneously hypertensive rats (SHRs) were treated with one of the following combinations for 4 weeks: tap water and vehicle [0.5% ethanol, subcutaneously (s.c.), n = 5], 1% NaCl in drinking water and vehicle (n = 8), 1% NaCl and aldosterone (0.75 µg/h s.c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 µg/kg/h s.c., n = 8). Systolic blood pressure (SBP) and left ventricular (LV) weight were higher in aldosterone-treated SHRs than vehicle- or vehicle/1% NaCl-treated SHRs. Thiobarbituric acid reactive substances (TBARS) levels and NADPH oxidase activity in LV tissues of aldosterone-treated SHRs were also higher than those of vehicle- or vehicle/1% NaCl-treated SHRs, and these changes were associated with increases in LV mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content. Treatment with adrenomedullin did not alter SBP or LV weight but attenuated aldosterone-induced increases in TBARS levels, NADPH oxidase activity, and mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content in LV tissues. These data suggest that NADPH oxidase-mediated reactive oxygen species production is involved in the pathogenesis of cardiac collagen accumulation in aldosterone-dependent malignant hypertensive rats and that the cardioprotective effects of adrenomedullin are mediated through the suppression of this pathway.

Address correspondence to: Dr. Akira Nishiyama, Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki-cho, Kitagun, Kagawa 761-0793, Japan. E-mail: akira{at}kms.ac.jp

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