INVOLVEMENT OF ENDOTHELIN-1 IN HYPOXIC PULMONARY VASOCONSTRICTION IN THE LAMB

1. Using isolated pulmonary resistance vessels from mature fetal lamb and chronically instrumented lambs (8-17 days old), we have examined w hether hypoxic pulmonary vasoconstriction is sustained by activation o f a constrictor mechanism or suppression of a dilator mechanism. 2. Hy poxia contracted both arteries and veins in vitro, and the contraction was greater with the former. After removing the endothelium, arteries responded faster to hypoxia, but the magnitude of the response remain ed unchanged. 3. Hypoxic arteries, unlike normally oxygenated arteries , did not contract with either indomethacin (2.8 mu M) or N-omega-nitr o-L-areinine methyl ester (L-NAME, 100 mu M). The same vessels relaxed with sodium nitroprusside (SNP, 0.001-10 mu M) but not with bradykini n (0.1-100 nM). 4. Endothelin-1 (ET-1, 0.01-10 nM) contracted isolated arteries and veins under normoxic and hypoxic conditions. In both ves sels, the contraction was fast in onset and subsidence, and was inhibi ted by the ET(A) receptor antagonist BQ123 (1 mu M). The ET-1 precurso r, big ET-1 (100 nM), also contracted arteries and veins, but compared with ET-1 its action was slower in development. Big ET-1 contraction, unlike ET-1 contraction, was curtailed by the inhibitor of the ET-1-c onverting enzyme, phosphoramidon (50 mu M). 5. ET-1 (0.1-10 nM) had no effect on isolated arteries precontracted with a thromboxane A(2) (TX A(2)) analogue (ONO-11113) and treated with BQ123 (10 mu M). Under the same conditions, ET-1 relaxed the veins. Accordingly, in the absence of BQ123 treatment, the selective ET(B) receptor agonist IRL-1620 (0.1 -100 nM) relaxed the contracted veins but not the arteries. 6. BQ123 ( 10 mu M) inhibited the constriction of isolated arteries and veins to hypoxia. likewise, in the conscious lamb a, bolus of BQ123 (1.4 mg kg( -1), injected into the pulmonary artery) curtailed the rise in pulmona ry vascular resistance (R(pa)) brought about by alveolar hypoxia witho ut changing significantly systemic vascular resistance (R(ao)). Under normoxia, R(pa) was insignificantly affected by BandQ123. 7. The resul ts indicate that pulmonary resistance arteries are more susceptible to hypoxia than the veins, and that hypoxic vasoconstriction does not re quire an intact endothelium to occur. Hypoxic tone is ascribed primari ly to intramural generation of ET-1, while removal of the tonic action of a relaxant may only have an accessory role in the response.