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 (KV) 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-N-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.