Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure

Abstract

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 (n514) before and 3 weeks after rapid ventricular pacing and in isolated lungs from healthy rats (n54). In isolated lungs, graded increases in perfusion rate from 5-25 ml / min caused gradual reductions in ET-1 extraction from 6061.5% to 1764.9% (mean6S.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 (11.2611.4 vs. 5.261.6 fmol / ml, p,0.01), did not affect 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.

Pulmonary metabolism of endothelin 1 during on-pump and beating heart coronary artery bypass operations

“…11,12 We have previously validated the use of the PS product to evaluate pulmonary removal of tracer ET-1 and demonstrated its stability over a wide range of pulmonary blood flow, despite the expected variations in mean tracer ET extraction. 4 The PS product for ET-1 removal by the pulmonary circulation was computed as follows:…”

Tachycardia‐Induced Cardiomyopathy: A Review of Literature

“…The elevated ET‐1 levels in patients with heart failure result from the reduced pulmonary clearance of ET‐1. In a canine model of pacing‐induced cardiomyopathy, Dupuis et al 45 have demonstrated reductions in ET‐1 extraction in the pulmonary vascular bed due to a reduced binding affinity to the ET‐A and ET‐B receptors. Needless to say that all these various molecules and receptors could become targets for therapeutic intervention in the future.…”

Dual ETA/ETB vs. selective ETA endothelin receptor antagonism in patients with pulmonary hypertension

“…This reduction in pulmonary ET-1 clearance capacity has been related to endothelial ET B receptor down regulation [58], reduced receptor affinity [59] or a disturbed clearance process [60]. The functional relevance of the ET B receptor with respect to pulmonary clearance of ET-1 can be estimated following ET receptor blockade.…”