Acute effects of endothelin-1 and TAK-044 (ETA and ETB receptor antagonist) in rats with dilated cardiomyopathy

The hemodynamic effects of endothelin (ET)-1 and TAK-044 (ET, and ET, recep tor 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 NO, N0.3, N3 and N30; each group, n = 4). ET- 1 concentrations in plasma and myocardium were measured, and immunohistoche mical detection of ET-1 in the left ventricle from the remaining rats (grou ps 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 exam ined. The plasma and myocardial ET-1 concentrations were significantly high er 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 o f both groups of rats. Although the ET-1-induced increase in the mean arter ial 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 F 60, ET-1-induced hypertension was blocked incompletely. These results indic ate that the heart may be a major ET-1-producing organ, and a higher dose o f ET-1 antagonist is needed to block the effect of ET-1 in rats with dilate d cardiomyopathy.