ETA, mixed ETA/ETB receptor antagonists, and protein kinase C inhibitor prevent acute hypoxic pulmonary vasoconstriction: influence of potassium channels.
The aims of this study were to investigate the effects of a selective ETA (BQ-123), a selective ETB (BQ-788), and a specific mixed ETA/ETB receptor antagonist (bosentan) on the pulmonary vasoconstriction induced by hypoxia in the isolated perfused rat lung, and the role of nitric oxide, adenosine triphosphate-sensitive (KATP), large conductance Ca+-activated (BKCa) and 4-aminopyridine-sensitive voltage-gated K channels (K+) in the relaxant effects of the selective ETA receptor antagonist BQ-123 and a protein kinase C inhibitor, bisindolylmaleimide I. K+ channels were inhibited by glibenclamide, charybdotoxin, and 4-aminopyridine and nitric oxide synthase by L-NG-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response (+57%, p < 0.001). BQ-123, bosentan, and bisindolylmaleimide I induced a concentration-dependent decrease of the hypoxic pressure response (p < 0.001), whereas BQ-788 did not exhibit any inhibitory effect against hypoxic pressure response. Glibenclamide, charybdotoxin, and 4-aminopyridine partially opposed the inhibitory effects elicited by BQ-123 (p < 0.05), but L-NAME did not modify these effects. The effects of bisindolylmaleimide I on hypoxic pressure response were unaffected by glibenclamide, charybdotoxin, or 4-aminopyridine. The authors conclude that (a) ETA receptors and protein kinase C are involved in the modulation of hypoxic pulmonary vasoconstriction; and (b) the ETA antagonist BQ-123 opposes hypoxic pulmonary vasoconstriction through KATP, KV, and BKCa channels, differing in this from the protein kinase C inhibitor bisindolylmaleimide I. These results suggest that BQ-123 operates through a mechanism independent of bisindolylmaleimide I-inhibited protein kinase C isoforms.
Goirand
Françoise
F
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Faculté de Médecine, Dijon, France. Francoise.Goirand@u-bourgogne.fr
Bardou
Marc
M
Guerard
Pascal
P
Dumas
Jean-Paul
JP
Rochette
Luc
L
Dumas
Monique
M
D000818:Animals; D000077300:Bosentan; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D000860:Hypoxia / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D065128:Endothelin Receptor Antagonists; D007211:Indoles; D008301:Maleimides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D015221:Potassium Channels; D013449:Sulfonamides; C086539:BQ 788; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)