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

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ET(A) receptors and ET(B) receptors. We previously reported that an ET(A) 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 ET(A) receptor mRNA expression but also ET(B) receptor mRNA expression in the congestive lung because lung ET(B) receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-1 and circulating ET-1 levels. The expression of ET(B) receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ET(A) receptor mRNA did not differ between the two groups. The protein level of ET(B) 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 ET(A) 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 ET(B) receptor, but not ET(A) receptor, occurs in the congestive lung. Since lung ET(B) receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ET(B) 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.