Mechanism of hypoxic pulmonary vasoconstriction involves ET(A) receptor-mediated inhibition of K(ATP) channel.
There is controversy on the role of endothelin (ET)-1 in the mechanism of hypoxic pulmonary vasoconstriction (HPV). Although HPV is inhibited by ET-1 subtype A (ET(A))-receptor antagonists in animals, it has been reported that ET(A)-receptor blockade does not affect HPV in isolated lungs. Thus we reassessed the role of ET-1 in HPV in both rats and isolated blood- and physiological salt solution (PSS)-perfused rat lungs. In rats, the ET(A)-receptor antagonist BQ-123 and the nonselective ET(A)- and ET(B)-receptor antagonist PD-145065, but not the ET(B)-receptor antagonist BQ-788, inhibited HPV. Similarly, BQ-123, but not BQ-788, attenuated HPV in blood-perfused lungs. In PSS-perfused lungs, either BQ-123, BQ-788, or the combination of both attenuated HPV equally. Inhibition of HPV by combined BQ-123 and BQ-788 in PSS-perfused lungs was prevented by costimulation with angiotensin II. The ATP-sensitive K(+) (K(ATP))-channel blocker glibenclamide also prevented inhibition of HPV by BQ-123 in both lungs and rats. These results suggest that ET-1 contributes to HPV in both isolated lungs and intact animals through ET(A) receptor-mediated suppression of K(ATP)-channel activity.
Sato
K
K
Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Morio
Y
Y
Morris
K G
KG
Rodman
D M
DM
McMurtry
I F
IF
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001769:Blood; D065128:Endothelin Receptor Antagonists; D005905:Glyburide / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D026902:Potassium Channel Blockers; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D026902:Potassium Channel Blockers; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D012965:Sodium Chloride; D000255:Adenosine Triphosphate; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D005905:Glyburide