Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1

doi:10.1016/j.cardiores.2004.03.016

Cardiovascular Research 2004 63(1):41-50; doi:10.1016/j.cardiores.2004.03.016
© 2004 by European Society of Cardiology

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Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1

Thomas G von Lueder^a^,b, Harald Kjekshus^a^,b, Thor Edvardsen^a^,c, Erik Øie^a^,b, Stig Urheim^a^,c, Leif Erik Vinge^a^,b, Muhammed Shakil Ahmed^a^,b, Otto A Smiseth^a^,c and Håvard Attramadal^*^,a^,b

^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 elevatedplasma levels of endothelin-1 (ET-1) in congestive heart failure(CHF). The aims of the present study were to determine the mechanismsof increased secretion of ET-1 from the pulmonary circulationin 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 significantleft ventricular dilatation, increased cardiac filling pressures,and reduced contractility (CHF pigs). Arterial plasma ET-1 levelsin the CHF pigs were increased 4-fold compared to sham pigs(P<0.001). Single-bolus multiple indicator-dilution experimentsrevealed that pulmonary synthesis and release of ET-1 was increasedin CHF, while pulmonary clearance of plasma ET-1 remained unaltereddespite significant reduction of pulmonary fractional extractionof plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol·min^–1·mgprotein^–1) was selectively increased in lower lobe segmentsof CHF pigs (2.0±0.3) compared to lower lobe segmentsof controls (1.1±0.1, P<0.02), and to upper lobe segmentsof CHF pigs (1.1±0.1, P<0.005), and correlated significantlywith 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 segmentswere identified as likely sites of increased synthesis and releaseof ET-1. Conclusions: In rapid pacing-induced CHF, a complexcardiopulmonary interaction revealed by pulmonary congestioncauses increased pulmonary production and secretion of ET-1due to enhanced pulmonary ECE-1 activities. Pulmonary secretionof ET-1 during evolving CHF is an important contributor to elevatedplasma ET-1 levels in the systemic circulation.

KEYWORDS Heart failure; Endothelin; Hemodynamics; Pulmonary circulation

Time for primary review 18 days

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