- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
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 mu g/h s. c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin ( 1.3 mu g/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.
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