Published Online
on February 3, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on July 30, 2002
Revised on August 23, 2002

Ventricular Adrenomedullin System in the Transition From LVH to Heart Failure in Rats

Toshio Nishikimi^*; Kazuyoshi Tadokoro; Yosuke Mori; Xin Wang; Kazumi Akimoto; Fumiki Yoshihara; Naoto Minamino; Kenji Kangawa; and Hiroaki Matsuoka

From the Department of Hypertension and Cardiorenal Medicine (T.N., K.T., Y.M., X.W., H.M.) and the Laboratory of Molecular and Cellular Biology (K.A.), Dokkyo University School of Medicine, Mibu, Tochigi; and the National Cardiovascular Center Research Institute (F.Y., N.M., K.K.), Suita, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: nishikim{at}dokkyomed.ac.jp.

Abstract--We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (r=0.72, r=0.79, and r=0.70, respectively; all P<0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model.

Key words: adrenomedullin • hypertension, sodium dependent • hypertrophy, left ventricular • heart failure • rats, Dahl

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