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Pathophysiological roles of endogenous endothelin-1 in dogs with chronic heart failure produced by rapid right

K Tadano1, J Suzuki, K Hanada

  • 1Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.

The Journal of Pharmacology and Experimental Therapeutics
|July 17, 2001
PubMed

Insights

Congestive heart failure (CHF) in dogs shows an exaggerated endothelin (ET) system. Blocking ET(A)/ET(B) receptors with J-104132 improved cardiovascular and renal function, suggesting a potential CHF treatment.

Area of Science:

  • Cardiovascular Physiology
  • Pharmacology
  • Renal Physiology

Background:

  • The endogenous endothelin (ET) system plays a role in cardiovascular regulation.
  • Congestive heart failure (CHF) is associated with altered ET system activity.
  • ET receptor antagonists are a potential therapeutic strategy for cardiovascular diseases.

Purpose of the Study:

  • To investigate the pathophysiological role of the endogenous ET system in a canine model of CHF.
  • To evaluate the therapeutic efficacy of ET(A)/ET(B) receptor antagonists in CHF.
  • To assess the combined effects of an ET antagonist and enalaprilat in CHF.

Main Methods:

  • A canine model of CHF was created using rapid right ventricular pacing.
  • Concentrations of immunoreactive ET-1 and ET receptor characteristics were measured.
  • Cardiovascular and renal function were assessed after administration of J-104132, an ET(A)/ET(B) receptor antagonist.
  • The additive effects of J-104132 in combination with enalaprilat were examined.

Main Results:

  • CHF induced a significant increase in plasma and ventricular ET-1 concentrations.
  • Administration of J-104132 decreased pulmonary artery pressure, pulmonary capillary wedge pressure, and mean arterial pressure.
  • J-104132 increased cardiac output and renal blood flow without affecting heart rate or contractility.
  • Combination therapy with enalaprilat resulted in further improvements in cardiovascular parameters.

Conclusions:

  • The endogenous ET system is upregulated and contributes to the pathophysiology of CHF.
  • ET(A)/ET(B) receptor antagonism with J-104132 demonstrates beneficial effects on cardiovascular and renal function in CHF.
  • J-104132, alone or in combination with enalaprilat, holds promise for the treatment of human CHF.

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