Renal and systemic effects of chronic blockade of ET(A) or ET(B) receptors in normal rats and animals with experimental heart failure.

Abstract

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

• Authors: Bahaa' Francis, Joseph Winaver, Tony Karram, Aaron Hoffman, Zaid Abassi
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 44 Suppl 1 Pg. S54-8 (Nov 2004) ISSN: 1533-4023 [Electronic] United States
• PMID: 15838359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• A 192621
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Pyrrolidines
• Receptor, Endothelin A
• Receptor, Endothelin B
• Atrasentan

Topics

• Animals
• Atrasentan
• Blood Pressure (drug effects)
• Cardiomegaly (etiology, prevention & control)
• Disease Models, Animal
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (metabolism)
• Heart Failure (complications, drug therapy, metabolism, physiopathology)
• Hemodynamics (drug effects)
• Infusion Pumps, Implantable
• Kidney (drug effects, metabolism, physiopathology)
• Male
• Natriuresis (drug effects)
• Pyrrolidines (administration & dosage, pharmacology)
• Rats
• Rats, Wistar
• Receptor, Endothelin A (metabolism)
• Receptor, Endothelin B (metabolism)
• Time Factors
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)