Downregulation of endothelin B receptors in cardiomyopathic hamsters.

The mechanisms responsible for abnormal fluid retention in congestive heart failure (CHF) are unclear. Studies were conducted to elucidate how endothelin (ET) may contribute to salt and water retention. Cardiomyopathic (CM) hamsters with moderate heart failure were employed for in vivo and in vitro trials. Clearance methods were used to compare the level of renal function in CM hamsters and control animals. Radioligand binding studies were also performed to determine ET receptor distribution in the inner medullary collecting ducts. CM hamsters exhibited an attenuated response to ANF infusion (FENa: 2.7 +/- 0.5 vs. 5.9 +/- 0.8%, p < 0.01; FEH2O: 1.7 +/- 0.3 vs. 3.2 +/- 0.4%, p < 0.01; UcGMP: 11.2 +/- 2.3 vs. 16.6 +/- 2.0 pmol/min, p < 0.05) and a decrease in total ET receptor density (532 +/- 77 vs. 959 +/- 154 fmol/mg protein, p < 0.005). Particularly ETB receptors were significantly reduced (214 +/- 26 vs. 483 +/- 88 fmol/mg protein, p < 0.003). Enalapril therapy simultaneously restored the natriuretic and diuretic effects of ANF and ET receptor density in the diseased animals. These studies suggest that the renin-angiotensin-aldosterone system and ET hormonal system act together, via ETB receptor downregulation, to promote the abnormal fluid retention observed in CHF.