HUMAN PULMONARY CIRCULATION IS AN IMPORTANT SITE FOR BOTH CLEARANCE AND PRODUCTION OF ENDOTHELIN-1

Background Animal studies suggest a major role of the pulmonary circul ation in the clearance of circulating endothelin-1 (ET-1). The contrib ution of the human pulmonary circulation to plasma ET-1 clearance, how ever, has never been quantified. The absence of an AV gradient in plas ma 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 co mbining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventric ular ejection fractions (61 +/- 7%, mean +/- SD) and baseline hemodyna mics. Mean pulmonary ET-1 extraction was 47 +/- 7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestr ation rate constant: K-seq = 0.048 +/- 0.019 s(-1). There was no signi ficant 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); th e normal lung consequently produces an amount of ET-1 that is quantita tively similar to the amount that has been extracted. Conclusions The human lung is an important site for both clearance and production of E T-2. There is a normal physiological balance of ET-1 across the pulmon ary circulation, which explains the absence of difference in AV ET-1 l evels despite a 47 +/- 7% clearance. Reduced pulmonary clearance or in creased production of this peptide may contribute to the increase in c irculating levels found in various cardiovascular conditions.