Abstract
This study was designed to analyze the pathophysiological role of the endogenous endothelin (ET) system and the therapeutic approach to congestive heart failure (CHF) with ETA/ETB receptor antagonists in a canine CHF model. After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrations of immunoreactive ET-1 in dogs increased approximately 2-fold in plasma and in the left and right ventricles but not in the lung. There were no meaningful changes in the density and affinity of total ET receptors, or in the ratio of ETA to ETB receptors. To clarify the functional role of endogenous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg/kg i.v.), an ETA/ETBreceptor antagonist, on cardiovascular and renal function in dogs with CHF. Compared with vehicle, J-104132 at both doses significantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP), and increased cardiac output (CO) and renal blood flow. J-104132 had no effects on heart rate and cardiac contractility. In addition, we examined whether J-104132 has an additive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) administered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MAP, PCWP and PAP, and further increases in CO, resulting in further decreases in total peripheral resistance. These results indicate that the endogenous ET system is exaggerated in CHF and has a detrimental effect on cardiac function. Therefore, J-104132 given alone or as combination therapy may play a beneficial role in the treatment of CHF in humans.
Footnotes
- Abbreviations:
- ET
- endothelin
- CHF
- congestive heart failure
- TIVCC
- thoracic inferior vena cava constriction
- irET-1
- immunoreactive endothelin-1
- ALDO
- aldosterone
- ANP
- atrial natriuretic peptide
- NE
- norepinephrine
- PRA
- plasma renin activity
- LVEDP
- left ventricular end-diastolic pressure
- MAP
- mean arterial blood pressure
- PAP
- pulmonary arterial pressure
- PCWP
- pulmonary capillary wedge pressure
- CO
- cardiac output
- LV
- left ventricle
- RBF
- renal blood flow
- GFR
- glomerular filtration rate
- HR
- heart rate
- TPR
- total peripheral resistance
- PVR
- pulmonary vascular resistance
- LVEDD
- left ventricular end-diastolic inner diameter
- LVPWD
- left ventricular posterior wall diameter
- LVESD
- left ventricular end-systolic diameter
- FS
- fractional shortening
- EIA
- enzyme immunoassay
- BSA
- bovine serum albumin
- +dp/dt
- positive first derivative of left ventricular pressure
- RV
- right ventricle
- ECE
- endothelin-converting enzyme
- Received December 8, 2000.
- Accepted April 9, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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