Evidence for oxygenation-induced endothelin release from isolated lungs of chronically hypoxic rats

In lungs from chronically hypoxic (CH, 3 weeks at 10% inspired O2) rats, oxygenation (20% O2, 5% CO2, 75% N2; PO2 121 mmHg) of the perfusate increases pulmonary perfusion pressure (PPP) and lung weight (LW). Hypoxic perfusate (95% N2, 5% CO2; PO2 5.5 mmHg) had no effect on PPP in lungs from CH rats. Indomethacin and nitro-L-arginine (L-NOARG) augmented the oxygen-induced increase in PPP. In contrast, the free radical scavengers superoxide dismutase (SOD) plus catalase delayed the onset of oxygen-induced vasoconstriction, while the endothelin (ET)B receptor antagonist BQ788 inhibited it. The ET(A) receptor antagonist BQ123 did not affect the PPP changes. This suggests a role for endogenous endothelins and ET(B) receptors in mediating the oxygenation-induced pulmonary vasoconstriction. Indomethacin had no effect on oxygen-induced lung weight (LW) changes while BQ788 and L-NOARG reduced the LW increase. This evidence shows that ET(B) receptor activation and NO generation are involved in the LW changes. In conclusion, oxygenation of the perfusate in isolated lungs from CH rats leads to pulmonary vasoconstriction which involves endothelins and activation of ET(B) receptors. In addition, increased NO production associated with ET(B) receptor activation is the prime stimulus for observed LW increase.