Role of endothelin in deterioration of heart failure due to cardiomyopathyin hamsters - Increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function

Background-We previously reported that chronic endothelin (ET) receptor blo ckade ameliorated the survival rate and cardiac hemodynamics in rats with c hronic heart failure (CHF) due to myocardial infarction. However, it remain s unclear whether ET-1 is involved in the pathophysiology of cardiomyopathy , which is one of the major causes of CHF. Accordingly, we investigated the production of ET-I in the heart and the effect of chronic ETA receptor blo ckade on survival rate and cardiac function in the Bio 14.6 hamster, which is an idiopathic model of CHF caused by cardiomyopathy. Methods and Results-We used 52-week-old Bio 14.6 cardiomyopathic hamsters a nd age-matched F1b normal hamsters. The expression of preproET-1 mRNA and t he ET-1 level in the hearts were markedly higher in the cardiomyopathic ham sters than in the normal hamsters. The cardiomyopathic hamsters showed seve re CHF, illustrated by lower left ventricular (LV) +dP/dt/P-max and right v entricular (RV) +dP/dt/P-max and by higher LV end-diastolic pressure (EDP), RVEDP, and central venous pressure compared with the normal hamsters. Long -term (9 weeks) treatment with an ETA antagonist (TA-0201, 1.3 mg.kg(-1).d( -1)) markedly increased survival of cardiomyopathic hamsters (untreated, 16 %; TA-0201-treated, 65.2%; P<0.001). After 6 weeks of treatment, LV +dP/dt/ P-max and RV +dP/dt/P-max were significantly higher and LVEDP and RVEDP wer e lower in the TA-0201-treated group than in the untreated group, suggestin g that chronic TA-0201 treatment effectively prevented deterioration of car diac dysfunction. Conclusions-In the cardiomyopathic hamsters with CHF, the production of ET- 1 in the heart was markedly increased, and chronic ETA receptor blockade gr eatly ameliorated survival and cardiac dysfunction. These results suggest t hat ET-1 plays an important role in the deterioration of CHF caused by card iomyopathy, and ETA antagonists may exert therapeutic effects in CHF due to cardiomyopathy.