The effect of endothelin-1 on alveolar fluid clearance and pulmonary edema formation in the rat.
BACKGROUND
Endothelin-1 (ET-1) is thought to play a pivotal role in pulmonary edema formation. The underlying mechanisms remain uncertain but may include alterations in capillary pressure and vascular permeability. There are no studies investigating whether ET-1 also affects alveolar fluid clearance which is the primary mechanism for the resolution of pulmonary edema. Therefore, we performed this study to clarify effects of ET-1 on alveolar reabsorption and fluid balance in the rat lung.


METHODS
Alveolar fluid clearance was measured in fluid instilled rat lungs using a 5% albumin solution with or without ET-1 (10(-7) M) and/or amiloride (100 microM). Net alveolar fluid balance, time course of edema formation, pulmonary capillary pressure, and alveolar permeability to albumin were measured in the isolated, ventilated, constant pressure perfused rat lung with or without ET-1 (0.8 nM) added to the perfusate.


RESULTS
In the fluid-instilled lung, ET-1 reduced alveolar fluid clearance by about 65%, an effect that was related to a decrease in amiloride-sensitive transepithelial Na(+) transport (P < 0.001). The ET-1-induced inhibition was completely prevented by the endothelin B receptor antagonist BQ788 (P = 0.006), whereas the endothelin A receptor antagonist BQ123 had no effect (P = 0.663). In the isolated, ventilated, perfused rat lung ET-1 caused a net accumulation of alveolar fluid by about 20% (P = 0.011 vs control), whereas lungs of control rats cleared about 20% of the instilled fluid. ET-1 increased pulmonary capillary pressure (+9.4 cm H(2)O), decreased perfusate flow (-81%), accelerated lung weight gain and reduced lung survival time (P < 0.001). Permeability to albumin was not significantly affected by ET-1 (P = 0.24).


CONCLUSIONS
ET-1 inhibits alveolar fluid clearance of anesthetized rats by inhibition of amiloride-sensitive epithelial Na(+) channels. The inhibitory effect of ET-1 results from activation of the endothelin B receptor. These findings suggest a mechanism by which ET-1, in addition to increasing capillary pressure, contributes to pulmonary edema formation.
Berger
Marc Moritz
MM
Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany. marc_berger@med.uni-heidelberg.d
Rozendal
C Sjula
CS
Schieber
Carolin
C
Dehler
Martin
M
Zügel
Stefanie
S
Bardenheuer
Hubert J
HJ
Bärtsch
Peter
P
Mairbäurl
Heimo
H
D000418:Albumins / Q000378:metabolism; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002199:Capillary Permeability; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism*; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism*; D006874:Hydrostatic Pressure; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011654:Pulmonary Edema / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction
D000418:Albumins; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D026941:Sodium Channel Blockers; C086539:BQ 788; D000584:Amiloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu)