Reduced pulmonary clearance of endothelin-1 contributes to the increase of circulating levels in heart failure secondary to myocardial infarction

Background-The pulmonary vascular bed is a major site for endothelin-l (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. Methods and Results-Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with I-125-labeled ET-I. Infarct rats developed MF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63 +/- 1.5% to 41 +/- 4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-I levels correlated closely and inversely with ET-1 extraction (P<0.001). Conclusions-HF is associated with reduced pulmonary ET-I clearance that contributes to the increase in circulating levels.