Pulmonary endothelinergic system in experimental congestive heart failure

Objectives: Endothelin-1 (ET-1), plays an important role in the pathophysio logy of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure. Methods and results: We use d rats with coronary artery ligation as an experimental model of either com pensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung , the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that E T-1 overexpression is regulated at a transcriptional level (P<0.01). In con trast, there was no change in ET-1 mRNA expression in aortae, left ventricu lar myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ETB receptor mR NA in the congestive lung was significantly lower than in control and compe nsated HF rats (P<0.0001), while the expression of ETA receptor mRNA did no t differ between groups. The lung and plasma ET-1 peptide levels were respe ctively 4.2 and 9 fold higher in the rats with decompensated HF than in con trol rats (P<0.05; P<0.0001). Organoculture experiments showed that the lun g ET-1 peptide secretion level in rats with decompensated HF was higher tha n that in control rats (P<0.01). In contrast, there was no change in ET-1 p eptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET -1 was 22%. ET-1 peptide was also present in the pleural effusion of decomp ensated heart failure. Plasma ET-1 concentration was significantly correlat ed with upstream markers of left ventricular diastolic dysfunction, with th e expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 con centration and with the expression ratio of ET-1/ETB receptor mRNA. Conclus ion: Taken together, these data suggest that overexpression of ET-1 and dow n-regulation of ETB receptors in the lung are determinants of circulating e ndothelin in CHF. As a corollary, increased plasma endothelin may provide e vidence of pulmonary endothelial dysfunction in CHF. (C) 2001 Elsevier Scie nce B.V. All rights reserved.