PT  - JOURNAL ARTICLE
AU  - Kiyoshi Tadano
AU  - Jun Suzuki
AU  - Kayoko Hanada
AU  - Mizuki Nakao
AU  - Rumi Nakao
AU  - Sayuri Uehara
AU  - Hisashi Ohta
AU  - Takashi Miyauchi
AU  - Masaru Nishikibe
TI  - Pathophysiological Roles of Endogenous Endothelin-1 in Dogs with Chronic Heart Failure Produced by Rapid Right Ventricular Pacing
DP  - 2001 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 729--736
VI  - 298
IP  - 2
4099  - http://jpet.aspetjournals.org/content/298/2/729.short
4100  - http://jpet.aspetjournals.org/content/298/2/729.full
SO  - J Pharmacol Exp Ther2001 Aug 01; 298
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics