Published Online
on May 16, 2005

A more recent version of this article appeared on June 1, 2005

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Submitted on November 9, 2004
Revised on November 27, 2004

Dual ECE/NEP Inhibition on Cardiac and Neurohumoral Function During the Transition From Hypertrophy to Heart Failure in Rats

Noriaki Emoto^*; Sunu Budhi Raharjo; Daiji Isaka; Shigeru Masuda; Suko Adiarto; Arco Y. Jeng; and Mitsuhiro Yokoyama

From the Division of Cardiovascular and Respiratory Medicine (N.E., S.B.R., D.I., S.M., S.A., M.Y.), Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; and the Novartis Institutes for BioMedical Research (A.Y.J.), Novartis Pharmaceutical Corp, East Hanover, NJ.

^* To whom correspondence should be addressed. E-mail: emoto{at}med.kobe-u.ac.jp.

Abstract--CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.

Key words: endothelin • heart failure • hypertension • hypertrophy

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