Glibenclamide reveals role for endothelin in hypoxia-induced vasoconstriction in rat intrapulmonary arteries.
The present study investigated whether activation of vasodilatory mechanisms masks the involvement of endothelin in hypoxic pulmonary vasoconstriction. Rat intrapulmonary arteries were mounted in microvascular myographs. In arteries with endothelium and contracted with phenylephrine, hypoxia, evoked by exchanging 5% CO2 in air for CO2 in N2, caused a transient contraction followed by a sustained contraction. Hypoxia evoked relaxation in preparations without endothelium. An inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10 microM), blunted hypoxic relaxation in arteries without endothelium and enhanced the sustained hypoxic vasoconstriction in arteries with endothelium. Hypoxic contraction was more pronounced in endothelin compared with phenylephrine-contracted preparations in the absence, but not in the presence of glibenclamide. Antagonism of the endothelin ETA and ETB receptors with SB217242 or the combination of BQ123 and BQ788 inhibited endothelin and hypoxic contraction, but the latter only in the presence of glibenclamide. An inhibitor of nitric oxide (NO) synthase, N-nitro-L-arginine (100 microM), evoked contractions, which were left unaltered by SB217242 in hypoxic conditions. In conclusion, hypoxic contraction is mediated in part by an unknown endothelium-derived contractile factor and incubation with glibenclamide shows endothelin enhances hypoxic contraction in part through inhibition of KATP channels. Moreover, inhibition of NO formation in pulmonary arteries does not change endothelin receptor activation in severe hypoxia.
López-Valverde
Vanesa
V
Department of Pharmacology, University of Aarhus, Aarhus, Denmark. vl@farm.au.dk
Andersen
Charlotte U
CU
Laursen
Britt Elmedal
BE
Mulvany
Michael J
MJ
Simonsen
Ulf
U
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D007189:Indans; D009842:Oligopeptides; D010108:Oxyhemoglobins; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D019335:Nitroarginine; C086539:BQ 788; D020110:Pinacidil; D019001:Nitric Oxide Synthase; C098288:enrasentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D005905:Glyburide