Human Pulmonary Circulation Is an Important Site for Both Clearance and Production of Endothelin-1

Abstract

Background Animal studies suggest a major role of the pulmonary circulation in the clearance of circulating endothelin-1 (ET-1). The contribution of the human pulmonary circulation to plasma ET-1 clearance, however, has never been quantified. The absence of an AV gradient in plasma ET-1 has previously been interpreted as evidence that the lungs do not have a role in modulating circulating ET-1 levels. This study was designed to quantify and discern between pulmonary ET-1 clearance and production in humans. Methods and Results We studied 13 subjects by combining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventricular ejection fractions (61±7%, mean±SD) and baseline hemodynamics. Mean pulmonary ET-1 extraction was 47±7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestration rate constant: K seq =0.048±0.019 s −1 . There was no significant difference between irET-1 levels from the pulmonary artery and aorta (0.61±0.29 and 0.68±0.33 pg/mL, respectively; P =.22); the normal lung consequently produces an amount of ET-1 that is quantitatively similar to the amount that has been extracted. Conclusions The human lung is an important site for both clearance and production of ET-1. There is a normal physiological balance of ET-1 across the pulmonary circulation, which explains the absence of difference in AV ET-1 levels despite a 47±7% clearance. Reduced pulmonary clearance or increased production of this peptide may contribute to the increase in circulating levels found in various cardiovascular conditions.