Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure.
OBJECTIVE
Plasma endothelin-1 (ET-1) increases in congestive heart failure (CHF). The pulmonary vascular bed could contribute to this increase through a reduced clearance. We evaluated the effect of tachycardia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of endothelial cell functions, we quantified ET-1 kinetics in isolated rat lungs under variable pressure and flow-rate conditions.


RESULTS
Indicator-dilution studies were performed in anesthetized dogs (n = 14) before and 3 weeks after rapid ventricular pacing and in isolated 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-surface area product (PS), however did not vary over this range of flows. CHF increased plasma ET-1 (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 cm3/s vs. 14.4 +/- 9.9 cm3/s, p = 0.038). Contrary to the invariability of the PS in normal isolated rat lungs, CHF was associated with a positive relationship between the PS 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.


CONCLUSIONS
CHF causes a reduction of pulmonary ET-1 clearance that likely contributes to the increased circulating ET-1 levels and reflects pulmonary metabolic dysfunction associated with this condition.
Dupuis
J
J
Department of Medicine, Montreal Heart Institute, Quebec, Canada. Dupuisj@icm.umontreal.ca
Moe
G W
GW
Cernacek
P
P
D000704:Analysis of Variance; D000818:Animals; D001783:Blood Flow Velocity; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D006333:Heart Failure / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011485:Protein Binding; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D018709:Statistics, Nonparametric
D019332:Endothelin-1; D017466:Receptors, Endothelin