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

Abstract

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 ϭ 5], 1% NaCl in drinking water and vehicle (n ϭ 8), 1% NaCl and aldosterone (0.75 g/h s.c., n ϭ 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 g/kg/h s.c., n ϭ 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.

Is Cardiac Hypertrophy in Spontaneously Hypertensive Rats the Cause or the Consequence of Oxidative Stress?

“…This histological feature of the oldest SHR would be related to the higher oxidative stress detected in these rats. This hypothesis is supported by recent investigations in other hypertrophy models (69,70), in which a correlation between ROS production and cardiac collagen accumulation was found. Accumulating evidence has suggested that ROS are capable of directly activating intracellular cascades involved in the regulation of hypertrophic growth (71).…”

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

“…Other studies have further demonstrated that adrenomedulin, a peptide structurally related to CGRP, can act via both CGRP and adrenomedulin receptors to mediate its effects. Adrenomedulin has also been implicated in ROS generation (Yoshimoto et al 1998;Dakhama et al 2004;Rahman et al 2006;Itoh et al 2007;Kim et al 2010). Furthermore, CGRP has been found to play an important role in protecting myocytes, kidney cells, pancreatic B cells, and liver cells from the potentially damaging effects of ROS (She et al 2003;Kroeger et al 2009;Song et al 2009).…”

Angiotensin II Receptor Blocker Reduces Oxidative Stress and Attenuates Hypoxia-Induced Left Ventricular Remodeling in Apolipoprotein E-Knockout Mice

“…NADPH-dependent superoxide production was measured by a lucigenin-enhanced chemiluminescence assay (13,27). Briefly, LV tissues were homogenized with Multi-Beads Shocker (YASUI KIKAI, Osaka, Japan) in modified Krebs-HEPES buffer (pH 7.4, 99.01 mmol/L NaCl, 4.69 mmol/L KCl, 1.87 mmol/L CaCl2, 1.20 mmol/L MgSO4, 1.03 mmol/L K2HPO4, 25 mmol/L Na-HEPES, 11.1 mmol/L glucose) containing 10 mmol/L dithiothreitol (DTT), 1 mmol/L phenylmethylsulfonyl fluoride (PMSF), 3 μmol/L pepstatin and 10 μmol/L leupeptin.…”