Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure.
Endothelin (ET)-1 increases in plasma during congestive heart failure (CHF). Some ET antagonists improve hemodynamics, suggesting its potential benefits in the treatment of CHF. We examined the acute and chronic effects of a new ET receptor antagonist, T-0201 (Tanabe Seiyaku Co. Ltd., Japan), in CHF. To confirm the in vivo effects of T-0201, we observed the inhibitory effects of T-0201 (1-100 micrograms/kg) on the response of blood pressure to exogenously administered ET-1 (0.75 nmol/kg) in conscious normal dogs. Pretreatment with T-0201 significantly inhibited the ET-1-induced initial hypotension that is mediated by ETB receptors, and attenuated the subsequent hypertension, which is primarily mediated by ETA receptors. Thus, T-0201 at a dose of 100 micrograms/kg not only works as a potent ETA antagonist but also shows antagonist activity for ETB receptors in dogs. To evaluate the chronic therapeutic effects of T-0201, we administered T-0201 (0.3 mg/kg/day; n = 5) orally to dogs with CHF induced by rapid right ventricular pacing (22 days, 270 beats/min) for 15 days, beginning 8 days after pacing. T-0201 significantly prevented the deterioration of cardiorenal function during the development of CHF, expressed as a decrease in cardiac pressure and an increase in cardiac and urine output. These results suggest that chronic antagonism of both ET receptors prevents the progressive exacerbation of CHF.
Ohnishi
M
M
First Department of Internal Medicine, Shiga University of Medical Science, Japan.
Wada
A
A
Tsutamoto
T
T
Fukai
D
D
Sawaki
M
M
Maeda
Y
Y
Kinoshita
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D002908:Chronic Disease; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1