Pharmacological characterization of cardiovascular responses induced by endothelin-1 in the perfused rat heart.

Abstract

The effects of the endothelin receptor antagonist TAK-044 (cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-ala nyl-L-alpha-aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl]+ ++disodiu m salt) and BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) were studied in the rat heart to characterize the receptor subtypes responsible for the cardiovascular actions of endothelin-1. Endothelin-1 induced a transient decrease and subsequent increase in perfusion pressure in perfused rat hearts, and increased left ventricular developed pressure. TAK-044 diminished these endothelin-1-induced responses (100 pmol/heart) with IC50 values of 140, 57 and 1.3 nM, respectively. BQ-123 (1-30 mu M) partially inhibited the endothelin-1-induced hypertension (30-40%) in the rat heart, and failed to inhibit the hypotension. The positive inotropic effect of endothelin-1 was abolished by BQ-123. Neither indomethacin (10 mu M) nor Nomega-nitro-L-arginine methyl ester (100 mu M) attenuated the endothelin-1-induced hypotension. TAK-044 and BQ-123 attenuated the positive inotropic effect of endothelin-1 in rat papillary muscles. In rat cardiac membrane fractions, TAK-044 and BQ-123 inhibited [125I]endothelin-1 binding to endothelin ET(A) receptors with IC50 values of 0.39 +/- 0.6 and 36 +/- 9 nM, respectively, whereas only TAK-044 potently blocked the endothelin ET(B) receptor subtype (IC50 value: 370 +/- 180 nM). These results suggest that endothelin-1 modulates cardiovascular functions in the rat heart by activating both endothelin ET(A) and endothelin ET(B) receptors, all of which are sensitive to TAK-044.

• Authors: K Kusumoto, A Fujiwara, S Ikeda, T Watanabe, M Fujino
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 296 Issue 1 Pg. 65-74 (Jan 18 1996) ISSN: 0014-2999 [Print] Netherlands
• PMID: 8720478 (Publication Type: Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Endothelins
• Peptides, Cyclic
• Receptor, Endothelin A
• TAK 044
• cyclo(Trp-Asp-Pro-Val-Leu)

Topics

• Analysis of Variance
• Animals
• Blood Pressure (drug effects)
• Cardiovascular System (drug effects)
• Endothelin Receptor Antagonists
• Endothelins (metabolism, pharmacology)
• Heart (drug effects)
• Male
• Myocardial Contraction (drug effects)
• Papillary Muscles (drug effects, metabolism)
• Peptides, Cyclic (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Endothelin A
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)