Endothelin-1-induced pulmonary vasoreactivity is regulated by ET(A) and ET(B) receptor interactions.
BACKGROUND
Roles of endothelin (ET) receptors (R) and of the endothelium on ET-1-induced pulmonary vasoreactivity are subjects of debate. This stems from endothelial ET(B)-R that can release both vasodilators and vasoconstrictors. The aim of this study was to evaluate the roles of the endothelium and of ET-Rs on ET-1-induced pulmonary vasoreactivity.


METHODS
Pharmacological experiments were performed in isolated rat lungs and in pulmonary resistance arteries.


RESULTS
In isolated lungs, ET-1 and the selective ET(B)-R agonist sarafotoxin 6c (S6c) induced a similar vasoconstriction. ET-1 constriction was reduced by a selective ET(A)-R antagonist; however, the selective ET(B)-R antagonist had no significant effect. In preconstricted lungs, ET(B)-R stimulation caused mild vasodilation at low concentrations but severe vasoconstriction at higher concentrations. In isolated arteries, responses to ET-1 and S6c were not different and unaffected by removal of endothelium. Interestingly, concentrations of ET(A)-R and ET(B)-R antagonists that only mildly reduced ET-1 vasoconstriction when used alone, prevented maximal constriction and greatly reduced vascular sensitivity to ET-1 when used in combination.


CONCLUSIONS
In rat lungs, both ET(A)-R and ET(B)-R contribute to ET-1-induced pulmonary vasoconstriction with evidence of interaction between receptors. A mild vasodilator role of the endothelial ET(B)-R is evident only at low agonist concentration and when baseline vascular tone is increased.
Sauvageau
Stéphanie
S
Research Center, Montreal Heart Institute, Montreal, Que., Canada.
Thorin
Eric
E
Caron
Alexandre
A
Dupuis
Jocelyn
J
D000818:Animals; D000077868:Atrasentan; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D010477:Perfusion; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology
C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077868:Atrasentan