© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure
aDepartment of Medicine, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec H1T 1C8, Canada
bSt. Michaels Hospital, Toronto, Ontario, Canada
* Corresponding author. Tel.: +1-514-376-3330 ext. 3542; Fax: +1-514-376-1355; E-mail: Dupuisj@icm.umontreal.ca
Objectives: 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. Methods and 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. Conclusion: 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.
KEYWORDS Endothelin; Pulmonary circulation; Pacemaker; Endothelial function; Heart failure
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