Published Online
on June 10, 2002

A more recent version of this article appeared on July 1, 2002

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Submitted on February 19, 2002
Revised on March 7, 2002

Long-Term Adrenomedullin Infusion Improves Survival in Malignant Hypertensive Rats

Yosuke Mori; Toshio Nishikimi^*; Naohiko Kobayashi; Hidehiko Ono; Kenji Kangawa; and Hiroaki Matsuoka

From the Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine (Y.M., T.N., N.K., H.O., H.M.), Mibu, Tochigi; and the Research Institute National Cardiovascular Center (K.K.), Suita, Osaka, Japan.

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

Abstract—Previous studies have demonstrated that adrenomedullin has inhibitory effects on the proliferation and DNA synthesis of mesangial cells and vascular smooth muscle cells in vitro and that plasma adrenomedullin levels are markedly elevated in malignant hypertension. This study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in malignant hypertensive rats. We studied the following 3 groups: control Wistar Kyoto rats, deoxycorticosterone acetate--salt spontaneously hypertensive rats, and adrenomedullin-treated deoxycorticosterone acetate--salt spontaneously hypertensive rats. Chronic adrenomedullin infusion using an osmotic minipump was started simultaneously with deoxycorticosterone acetate--salt treatment. After 3 weeks of the treatment, malignant hypertensive rats were characterized by higher blood pressure, kidney weight, urinary protein excretion, glomerular injury score, plasma renin concentration, aldosterone level, endogenous rat plasma adrenomedullin level, renal cortical tissue angiotensin II level, angiotensin-converting enzyme mRNA level, and transforming growth factor-ß1 mRNA level in the renal cortex, and by lower creatinine clearance, compared with the control rats. Chronic adrenomedullin infusion significantly improved these parameters (kidney weight -6.5%, urinary protein excretion -63.8%, glomerular injury score -38.3%, plasma renin concentration -52.4%, aldosterone -23.2%, rat adrenomedullin -28.6%, renal angiotensin II -28.1%, renal angiotensin-converting enzyme mRNA -38.3%, renal transforming growth factor-ß1 mRNA -56.2%, and creatinine clearance +20.5%) without significant reduction of mean arterial pressure (-4%). Kaplan-Meier survival analysis showed that adrenomedullin infusion significantly prolonged survival time. These results suggest that subdepressor dose of chronic adrenomedullin infusion has renoprotective effects in this malignant hypertension model, at least in part, via inhibition of the circulating and intrarenal renin-angiotensin system.

Key words: adrenomedullin • hypertension, malignant • renal disease • renin-angiotensin system • renal circulation

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