endothelin-1 and Pleural-Effusion

We focused on neurohumoral activity and its clinical correlates early and late after fenestrated, lateral intra-atrial total cavopulmonary connection (TCPC). Between 2007 and 2010, we prospectively studied 28 early and 48 late postoperative TCPC patients. Plasma concentrations of vasopressin, endothelin-1, proBNP, proANP were determined. We reviewed clinical data to determine relationship between neurohumoral activation and clinical status after TCPC. There was a significant influence of preoperative ventricular end-diastolic pressure (VEDP) (P=0.008) and vasopressin concentration (P=0.02) on the appearance of prolonged pleural effusions. A significant correlation between a combined predictor (a product of preoperative vasopressin concentration and VEDP) and time of effusions (r=0.59, P=0.006) was found. The mean respiratory equivalent of carbon dioxide at peak exercise (VE/VCO(2peak)) was significantly lower in patients operated before the second year of life compared to patients operated after two years of age (27.5±1.39 vs. 48.6±3.86; P=0.039). There was a significant correlation of endothelin-1 (r=0.84; P=0.008) and proBNP (r=0.88; P=0.02) concentrations with VE/VCO(2peak). The prolonged postoperative pleural effusions can be predicted based on the product of preoperative vasopressin concentration and VEDP. Exercise performance is related to the age at TCPC. Endothelin-1 and proBNP can be useful for identification of high-risk Fontan patients.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Child, Preschool; Endothelin-1; Exercise Tolerance; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Infant; Length of Stay; Logistic Models; Male; Natriuretic Peptide, Brain; Pleural Effusion; Poland; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vasopressins; Ventricular Pressure

Endothelin-1 (ET-1), plays an important role in the pathophysiology 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.. We used rats with coronary artery ligation as an experimental model of either compensated 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 ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ET(B) receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ET(A) receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide 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 decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ET(B) receptor mRNA.. Taken together, these data suggest that overexpression of ET-1 and down-regulation of ET(B) receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF.

Topics: Analysis of Variance; Animals; Aorta; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Gene Expression; Heart Failure; Heart Ventricles; Lung; Male; Metalloendopeptidases; Muscle, Skeletal; Organ Culture Techniques; Pleural Effusion; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

Alpha-naphthylthiourea when injected intraperitoneally to rats (10 mg kg-1 i.p.) produced lung oedema as indicated by an increase in lung weight/body ratio and pleural effusion reaching a maximum within 4 hours. Prior intravenous single bolus injection of endothelin-1 elicited a significant and dose-dependent inhibition in both parameters. However, prior i.v. injection of angiotensin II using relatively higher doses did not alter the oedema-producing effect of alpha-naphthylthiourea indicating a characteristic for endothelin-1. The inhibitory effect of endothelin-1 on pleural effusion is more prominent than lung weight/body weight ratio. The resolution of lung oedema by single bolus i.v. injection of endothelin-1 is probably due to the acute long-lasting and potent vasoconstrictor effect of the peptide and its large accumulation in lung tissue. Phosphoramidon, an inhibitor of endothelin converting enzyme, did not alter the oedema producing effect of alpha-naphthylthiourea indicating the lack of the participation of endothelin-peptide cascade to this pathological event. Bosentan, a non-selective receptor blocker of endothelin-1, did not inhibit the preventive effect of the peptide against alpha-naphthylthiourea-induced lung oedema. Possible mechanisms of the acute effect of endothelin-1 on lung oedema are discussed.

Topics: Angiotensin II; Animals; Aspartic Acid Endopeptidases; Body Weight; Bosentan; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Male; Metalloendopeptidases; Organ Size; Pleural Effusion; Protease Inhibitors; Pulmonary Edema; Rats; Sulfonamides; Thiourea