Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction.
OBJECTIVE
To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs.


METHODS
In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n=13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist). Hemodynamic and gas-exchange variables were monitored. Pulmonary capillary pressure, used for calculation of upstream and downstream vascular resistance, was assessed by the pulmonary vascular occlusion technique.


RESULTS
Pulmonary veins were more sensitive than arteries to endothelin-1 both in vitro and in vivo. This difference was more pronounced with sarafotoxin, where almost no arterial effects were noted. In vivo and in vitro exposure to phenylephrine resulted in selective arterial constriction. Endotoxin infusion resulted in pulmonary hypertension with a clear downstream dominance. The latter changes including the increase in capillary pressure were totally abolished by intervention with the dual endothelin receptor antagonist tezosentan.


CONCLUSIONS
The endothelin system is extensively involved in endotoxemic pulmonary venous hypertension, an effect possibly mediated by the endothelin B receptor.
Rossi
Patrik
P
Section of Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institutet Solna, 17176 Stockholm, Sweden. patrik.rossi@ki.se
Persson
Björn
B
Boels
Piet J M
PJ
Arner
Anders
A
Weitzberg
Eddie
E
Oldner
Anders
A
D000818:Animals; D002939:Ciprofloxacin / Q000031:analogs & derivatives; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply*; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000503:physiopathology*; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D008070:Lipopolysaccharides; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; D002939:Ciprofloxacin; C120582:tezosentan; C047224:sarafloxacin