A new endothelin receptor antagonist, TAK-044, shows long-lasting inhibition of both ETA- and ETB-mediated blood pressure responses in rats

S Ikeda, Y Awane, K Kusumoto, M Wakimasu, T Watanabe and M Fujino

Pharmaceutical Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.

The present study describes the pharmacological profile of an endothelin (ET) receptor antagonist, TAK-044, in anesthetized rats. TAK- 044 given 10 min before administration of ET-1 (0.3 nmol/kg i.v.) partially inhibited the ET-1-induced pressor response at 0.1 and 1 mg/kg i.v. and almost completely inhibited the response at a dose of 10 mg/kg. The transient depressor response induced by ET-1 was also inhibited by 1 and 10 mg/kg TAK-044. BQ-123 partially inhibited the pressor response at 0.1-10 mg/kg i.v., whereas it did not inhibit the depressor response except at a dose of 10 mg/kg. These inhibitory effects of TAK-044 were longer lasting than those of BQ-123: 3 hr for TAK-044 and 1 hr for BQ-123 at 10 mg/kg. A selective ETB agonist, sarafotoxin S6c (0.3 nmol/kg i.v.), induced both depressor and pressor responses similar to ET-1. The initial depressor response was inhibited by TAK-044 in a dose-dependent manner (0.1-10 mg/kg i.v.) and by BQ-123 at the highest dose, whereas the sustained pressor response was inhibited only by TAK-044 at a dose of 10 mg/kg. Similar differences between TAK-044 and BQ-123 were observed for sarafotoxin S6c-induced renal vasoconstriction: TAK-044 but not BQ-123 inhibited the response at a dose of 3 mg/kg i.v. We conclude that TAK-044 inhibited both ETA- and ETB-mediated blood pressure responses and that these effects were longer lasting than those of BQ-123. In addition, the ETB-mediated vasoconstriction and pressor responses were inhibited by TAK-044 and not by BQ-123.

Volume 270, Issue 2, pp. 728-733, 08/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				S. Taddei, A. Virdis, L. Ghiadoni, I. Sudano, M. Notari, and A. Salvetti Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension Circulation, October 19, 1999; 100(16): 1680 - 1683. [Abstract] [Full Text] [PDF]

				G. Marano, M. Grigioni, S. Palazzesi, and A. U Ferrari Endothelin and mechanical properties of the carotid artery in Wistar-Kyoto and spontaneously hypertensive rats Cardiovasc Res, March 1, 1999; 41(3): 701 - 707. [Abstract] [Full Text] [PDF]

				M. Ohnishi, A. Wada, T. Tsutamoto, D. Fukai, and M. Kinoshita Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure Cardiovasc Res, September 1, 1998; 39(3): 617 - 624. [Abstract] [Full Text] [PDF]

				W. G. Haynes, C. J. Ferro, K. P. J. O'Kane, D. Somerville, C. C. Lomax, and D. J. Webb Systemic Endothelin Receptor Blockade Decreases Peripheral Vascular Resistance and Blood Pressure in Humans Circulation, May 15, 1996; 93(10): 1860 - 1870. [Abstract] [Full Text]

				M. Sano, K. Fukuda, H. Kodama, J. Pan, M. Saito, J. Matsuzaki, T. Takahashi, S. Makino, T. Kato, and S. Ogawa Interleukin-6 Family of Cytokines Mediate Angiotensin II-induced Cardiac Hypertrophy in Rodent Cardiomyocytes J. Biol. Chem., September 15, 2000; 275(38): 29717 - 29723. [Abstract] [Full Text] [PDF]