REDUCED PULMONARY METABOLISM OF ENDOTHELIN-1 IN CANINE TACHYCARDIA-INDUCED HEART-FAILURE

Objectives: Plasma endothelin-l (ET-1) increases in congestive heart f ailure (CHF). The pulmonary vascular bed could contribute to this incr ease through a reduced clearance. We evaluated the effect of tachycard ia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of e ndothelial cell functions, we quantified ET-I kinetics in isolated rat lungs under variable pressure and flow-rate conditions. Methods and R esults: Indicator-dilution studies were performed in anesthetized dogs (n=14) before and 3 weeks after rapid ventricular pacing and in isola ted lungs from healthy rats (n=4). In isolated lungs, graded increases in perfusion rate from 5-25 ml/min caused gradual reductions in ET-1 extraction from 60+/-1.5% to 17+/-4.9% (mean+/-S.D.). The capacity to clear ET-1 from the circulation, as computed from the permeability-sur face area product (PS), however did not vary over this range of hows. CHF increased plasma ET-I (11.2+/-11.4 vs. 5.2+/-1.6 fmol/ml, p<0.01), did not affect pulmonary ET-1 extraction (29.4+/-12.5% vs. 29.9+/-12. 9%), but decreased the PS (8.3+/-5.4 cm(3)/s vs. 14.4+/-9.9 cm(3)/s, p =0.038). Contrary to the invariability of the PS in normal isolated ra t lungs, CHF was associated with a positive relationship between the P S and pulmonary plasma flow (r=0.65, p<0.01). ET-1 binding studies in lung tissues showed no significant variations in ETA and ETB receptors densities but revealed a threefold decrease in binding affinity (p<0. 01) that may explain the reduced clearance. Conclusion: CHF causes a r eduction of pulmonary ET-1 clearance that likely contributes to the in creased circulating ET-1 levels and reflects pulmonary metabolic dysfu nction associated with this condition. (C) 1998 Elsevier Science B.V. All rights reserved.