© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1
aInstitute for Surgical Research, Rikshospitalet University Hospital, University of Oslo, Norway
bMSD Cardiovascular Research Center, Rikshospitalet University Hospital, University of Oslo, Norway
cDepartment of Cardiology, Rikshospitalet University Hospital, University of Oslo, Norway
*Corresponding author. MSD Cardiovascular Research Center, Institute for Surgical Research A3.1013, Rikshospitalet University Hospital, Sognsvannsveien 20, N-0027 Oslo, Norway. Tel.: +47-23073520; fax: +47-23073530. Email address: havard.attramadal{at}klinmed.uio.no
Objective: The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF. Methods: Juvenile pigs were subjected to sham operation (n=9) or rapid cardiac pacing-induced CHF (215–240 bpm, n=15). Results: Three weeks of rapid pacing led to significant left ventricular dilatation, increased cardiac filling pressures, and reduced contractility (CHF pigs). Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while pulmonary clearance of plasma ET-1 remained unaltered despite significant reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol·min–1·mg protein–1) was selectively increased in lower lobe segments of CHF pigs (2.0±0.3) compared to lower lobe segments of controls (1.1±0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1±0.1, P<0.005), and correlated significantly with the wet/dry weight ratios of the pulmonary tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion. Furthermore, alveolar macrophages in congested lobe segments were identified as likely sites of increased synthesis and release of ET-1. Conclusions: In rapid pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary congestion causes increased pulmonary production and secretion of ET-1 due to enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving CHF is an important contributor to elevated plasma ET-1 levels in the systemic circulation.
KEYWORDS Heart failure; Endothelin; Hemodynamics; Pulmonary circulation
Time for primary review 18 days
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