K. Tadano et al., Pathophysiological roles of endogenous endothelin-1 in dogs with chronic heart failure produced by rapid right ventricular pacing, J PHARM EXP, 298(2), 2001, pp. 729-736
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
This study was designed to analyze the pathophysiological role of the endog
enous endothelin (ET) system and the therapeutic approach to congestive hea
rt failure (CHF) with ETA/ETB, receptor antagonists in a canine CHF model.
After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrat
ions of immunoreactive ET-1 in dogs increased approximately 2-fold in plasm
a and in the left and right ventricles but not in the lung. There were no m
eaningful 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 endoge
nous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg
/kg i.v.), an ETA/ETB receptor antagonist, on cardiovascular and renal func
tion in dogs with CHF. Compared with vehicle, J-104132 at both doses signif
icantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedg
e 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 ad
ditive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) admin
istered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MA
P, PCWP and PAP, and further increases in CO, resulting in further decrease
s in total peripheral resistance. These results indicate that the endogenou
s ET system is exaggerated in CHF and has a detrimental effect on cardiac f
unction. Therefore, J-104132 given alone or as combination therapy may play
a beneficial role in the treatment of CHF in humans.