Down-regulation of ETB receptor, but not ETA receptor, in congestive lung secondary to heart failure. Are marked increases in circulating endothelin-1 partly attributable to decreases in lung ETB receptor-mediated clearance of endothelin-1?

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ETA receptors and ETB receptors. We previously reported that an ETA receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ETA receptor mRNA expression but also ETB receptor mRNA expression in the congestive lung because lung ETB receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-I and circulating ET-I levels. The expression of ETB receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ETA receptor mRNA did not differ between the two groups. The protein level of ETB receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ETA receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ETB receptor, but not ETA receptor, occurs in the congestive lung. Since lung ETB receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ETB receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.