Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure.

Abstract

OBJECTIVES:

This study was designed 1) to determine the extent to which endogenous endothelin (ET) affects hemodynamic, hormonal and body fluid balance through ETA and ETB receptors in congestive heart failure (CHF); and 2) to assess the therapeutic benefits and adverse effects of ET receptor antagonists for ETA and ETB on cardiorenal and neurohormonal variables.

BACKGROUND:

ET has two receptors, ETA and ETB, both of which are distributed in various tissues and cells. In vascular beds, ETA receptors mediate vasoconstriction, whereas ETB receptors mediate vasorelaxation. However, ETB receptors also exist in smooth muscle and mediate vasoconstriction.

METHODS:

We administered either the ETA receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETB receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing. The effects of both antagonists on cardiorenal and hormonal functions were studied.

RESULTS:

FR decreased cardiac pressures and the plasma atrial natriuretic peptide (ANP) level and increased cardiac output (CO). Urinary flow rate and urinary sodium excretion increased in association with an increase in the glomerular filtration rate and renal plasma flow (RPF). In contrast, RES increased cardiac pressures and decreased CO. It also decreased the plasma aldosterone level and RPF. Neither antagonist affected plasma norepinephrine levels.

CONCLUSIONS:

Endogenous ETs increase cardiac pressures and the retention of body fluid through ETA receptors in CHF. The vasodilative action through ETB receptors is overall functionally more important than the constrictive action through ETB receptors. ETs may regulate the secretion of ANP and aldosterone. Our findings suggest that selective ETA receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETB receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF.

• Authors: A Wada, T Tsutamoto, D Fukai, M Ohnishi, K Maeda, T Hisanaga, Y Maeda, Y Matsuda, M Kinoshita
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 30 Issue 5 Pg. 1385-92 (Nov 01 1997) ISSN: 0735-1097 [Print] United States
• PMID: 9350944 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azepines
• Endothelin Receptor Antagonists
• Indoles
• Peptides, Cyclic
• FR 139317
• RES 701-1
• Atrial Natriuretic Factor

Topics

• Analysis of Variance
• Animals
• Atrial Natriuretic Factor (blood)
• Azepines (pharmacology)
• Cardiac Output (drug effects)
• Dogs
• Endothelin Receptor Antagonists
• Female
• Heart (drug effects)
• Heart Failure (drug therapy, physiopathology)
• Hemodynamics (drug effects)
• Indoles (pharmacology)
• Kidney (drug effects)
• Male
• Peptides, Cyclic (pharmacology)
• Urodynamics (drug effects)