Acute effects of endothelin-1 and TAK-044 (ET(A) and ET(B) receptor antagonist) in rats with dilated cardiomyopathy.

Abstract

The hemodynamic effects of endothelin (ET)-1 and TAK-044 (ET(A) and ET(B) receptor antagonist) were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Six weeks after immunization, survived Lewis rats (30/43 = 70%) were randomly allocated into five groups to be given 0, 0.3, 3, 30 and 60 mg/kg/day (groups F0, F0.3, F3, F30 and F60; each group, n = 4) of TAK-044 using an osmotic pump subcutaneously. Age-matched normal Lewis rats (n = 26) were also randomly divided into four groups to be given 0, 0.3, 3 and 30 mg/kg/day (groups N0, N0.3, N3 and N30; each group, n = 4). ET-1 concentrations in plasma and myocardium were measured, and immunohistochemical detection of ET-1 in the left ventricle from the remaining rats (groups F and N) was performed. After administration of TAK-044 for 7 days, 2, 4, 11, 21 and 42 ng/min ET-1 every 20 min was infused using a pump, and the change in mean arterial pressure of each group during the infusion was examined. The plasma and myocardial ET-1 concentrations were significantly higher in group F than group N (12.3 +/- 1.5 vs. 5.4 +/- 0.2 pg/ml and 426 +/- 31 vs. 98 +/- 6 pg/g tissue; both p < 0.01). Strong positive signals for ET-1 were found to be widely distributed in the left ventricular myocardium of both groups of rats. Although the ET-1-induced increase in the mean arterial pressure was abolished in group N30, the maximal dose of ET-1 produced a 34% increase in the mean arterial pressure in group F30. Even in group F60, ET-1-induced hypertension was blocked incompletely. These results indicate that the heart may be a major ET-1-producing organ, and a higher dose of ET-1 antagonist is needed to block the effect of ET-1 in rats with dilated cardiomyopathy.

• Authors: K Watanabe, Y Ohta, T Kouda, T Sekiguchi, S Sato, M Nakazawa, G Hasegawa, M Naito, K Fuse, M Ito, S Hirono, N Tanabe, H Hanawa, K Kato, M Kodama, Y Aizawa
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 36 Suppl 2 Pg. S49-54 ( 2000) ISSN: 0160-2446 [Print] United States
• PMID: 11206720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin Receptor Antagonists
• Endothelin-1
• Peptides, Cyclic
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin
• TAK 044

Topics

• Animals
• Blood Pressure (drug effects)
• Cardiomyopathy, Dilated (physiopathology)
• Endothelin Receptor Antagonists
• Endothelin-1 (pharmacokinetics, pharmacology)
• Heart Rate (drug effects)
• Immunohistochemistry
• Male
• Peptides, Cyclic (pharmacology)
• Rats
• Rats, Inbred Lew
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin (physiology)