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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 14, 2006; DOI: 10.1124/jpet.106.105106

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Received for publication March 23, 2006.
Revised June 12, 2006.
Accepted for publication June 13, 2006.

Effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats

Matlubur Rahman 1, Akira Nishiyama 1*, Peng Guo 1, Yukiko Nagai 1, Guo-Xing Zhang 1, Yoshihide Fujisawa 2, Yu-Yan Fan 2, Shoji Kimura 1, Naohisa Hosomi 1, Koji Omori 1, Youichi Abe 1, Masakazu Kohno 1

1 Kagawa University Medical School 2 KagawaUniversity Medical School

* Address correspondence to: E-mail: akira{at}kms.ac.jp

Abstract

We examined the effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. Spontaneously hypertensive rats (SHR) were treated with one of the following combinations for 4 weeks: tap water and vehicle (0.5% ethanol, SC, n=5); 1% NaCl in drinking water and vehicle (n=8); 1% NaCl and aldosterone (0.75 µg/h, SC, n=8); and 1% NaCl, aldosterone and adrenomedullin (1.3 µg/kg/h, SC, n=8). Systolic blood pressure (SBP) and left ventricular (LV) weight were higher in aldosterone-treated SHR than vehicle- or vehicle/1%NaCl-treated SHR. Thiobarbituric acid reactive substances (TBARS) levels and NADPH oxidase activity in LV tissues of aldosterone-treated SHR were also higher than those of vehicle- or vehicle/1%NaCl-treated SHR, 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.


Key words: NADPH oxidase, adrenomedullin, aldosterone, collagen, left ventricle, reactive oxygen species


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