Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1.
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.
von Lueder
Thomas G
TG
Institute of Surgical Research, Rikshospitalet University Hospital, University of Oslo, Norway.
Kjekshus
Harald
H
Edvardsen
Thor
T
ØIe
Erik
E
Urheim
Stig
S
Vinge
Leif Erik
LE
Ahmed
Muhammed Shakil
MS
Smiseth
Otto A
OA
Attramadal
Håvard
H
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000097:blood; D019332:Endothelin-1 / Q000032:analysis / Q000096:biosynthesis / Q000097:blood*; D000072396:Endothelin-Converting Enzymes; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000737:chemistry / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000378:metabolism; D008666:Metalloendopeptidases; D023421:Models, Animal; D011652:Pulmonary Circulation; D013552:Swine
D019332:Endothelin-1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes