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(Circulation. 1999;99:570-577.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure

Comparison of Effects With Those of Endothelin A Receptor Antagonism

Atsuyuki Wada, MD; Takayoshi Tsutamoto, MD; Masato Ohnishi, MD; Masahide Sawaki, MD; Daisuke Fukai, MD; Yukiharu Maeda, MD; Masahiko Kinoshita, MD

From the First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.

Correspondence to Atsuyuki Wada, MD, First Department of Internal Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan, 520-2192. E-mail wada{at}belle.shiga-med.ac.jp

Background—Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist.

Methods and Results—CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05).

Conclusions—An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.

Key Words: endothelin • heart failure • enzymes • receptors • hormones

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