LOSS OF ENDOTHELIUM-DEPENDENT RELAXATION IN PROXIMAL PULMONARY-ARTERIES FROM RATS EXPOSED TO CHRONIC HYPOXIA - EFFECTS OF IN-VIVO AND IN-VITRO SUPPLEMENTATION WITH L-ARGININE

To explore endothelium-dependent relaxation and the L-arginine (L-ARG) -nitric oxide (NO) pathway during chronic hypoxia, we examined isolate d rings from large conduit pulmonary arteries and aorta from rats expo sed to either room air (N), 3-week hypoxia (H), or 3-week H followed b y 72-h recovery to normoxia (room air). We examined the vasodilatory a ctions of acetylcholine (ACh), ionophore A23187, and endothelin-3 (ET- 3) on extrapulmonary left and right branches of pulmonary arteries and thoracic aorta precontracted by phenylephrine (PE 10(-6) M). Endothel ium-dependent relaxation of N rat pulmonary arteries and aorta to ACh and A23187 was abolished in the presence of L-N(G) nitroarginine methy l ester (L-NAME 10(-4) M) or methylene blue (MB 10(-5) M) but was supp ressed only partially by N(G)-monomethyl-L-arginine (L-NMMA 5 x 10(-4) M). In pulmonary arteries but not in aorta, ET-3 induced endothelium- dependent relaxation that was suppressed by L-NAME, MB, and L-NMMA. Pu lmonary arteries from H rats did not relax with ET-3. As compared with those of N rats, they exhibited less relaxation to ACh and A23187, (4 7 +/- 3 vs. 89 +/- 2 and 53 +/- 2 vs. 85 +/- 4%, p < 0.001, respective ly) but exhibited similar relaxation to the nonendothelium-dependent v asodilator linsidomine. In contrast, endothelial-relaxation did not di ffer between N and H rat aorta. In vivo administration of 300 mg/kg L- ARG to H rats increased plasma levels of L-ARG by 10-fold and arterial tissue level Of L-ARG by sixfold, and fully restored relaxation to AC h and ET-3. L-ARG added to the organ bath at a similar concentration h ad no effect despite a threefold increase in arterial L-ARG. We noted no difference between arterial tissue level Of L-ARG in rats exposed t o N, H, or H returned to normoxia (H + N). These data suggest that the impaired endothelium-dependent relaxation that occurs in large condui t pulmonary arteries during chronic hypoxia is not related to global L -ARG depletion depletion despite reversibility of the abnormality afte r pretreatment with L-ARG.