Effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats.
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 microg/h s.c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 microg/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.
Rahman
Matlubur
M
Department of Pharmacology, Kagawa University Medical School, Kitagun, Kagawa 761-0793, Japan.
Nishiyama
Akira
A
Guo
Peng
P
Nagai
Yukiko
Y
Zhang
Guo-Xing
GX
Fujisawa
Yoshihide
Y
Fan
Yu-Yan
YY
Kimura
Shoji
S
Hosomi
Naohisa
N
Omori
Koji
K
Abe
Youichi
Y
Kohno
Masakazu
M
D053607:Adrenomedullin; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012964:Sodium / Q000652:urine
D002316:Cardiotonic Agents; D005353:Fibronectins; D010455:Peptides; D012333:RNA, Messenger; D053607:Adrenomedullin; D000450:Aldosterone; D003094:Collagen; D012964:Sodium; D019255:NADPH Oxidases; D011188:Potassium