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 isolated rings from large conduit pulmonary arteries and aorta from rats exposed to either room air (N), 3-week hypoxia (H), or 3-week H followed by 72-h recovery to normoxia (room air). We examined the vasodilatory actions 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). Endothelium-dependent relaxation of N rat pulmonary arteries and aorta to ACh and A23187 was abolished in the presence of L-N(G) nitroarginine methyl ester (L-NAME 10(-4) M) or methylene blue (MB 10(-5) M) but was suppressed 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. Pulmonary 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, (47 +/- 3 vs. 89 +/- 2 and 53 +/- 2 vs. 85 +/- 4%, p < 0.001, respectively) but exhibited similar relaxation to the nonendothelium-dependent vasodilator linsidomine. In contrast, endothelial-relaxation did not differ 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 ACh and ET-3. L-ARG added to the organ bath at a similar concentration had no effect despite a threefold increase in arterial L-ARG. We noted no difference between arterial tissue level Of L-ARG in rats exposed to N, H, or H returned to normoxia (H + N). These data suggest that the impaired endothelium-dependent relaxation that occurs in large conduit pulmonary arteries during chronic hypoxia is not related to global L-ARG depletion depletion despite reversibility of the abnormality after pretreatment with L-ARG.