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

Summary: 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 IO-6M). Endothelium-dependent relaxation of N rat pulmonary arteries and aorta to ACh and A23187 was abolished in the presence of l-NGnitroarginine methyl ester (l-NAME 10-4M) or methylene blue (MB 10-5M) but was suppressed only partially by NGmonoethlyl-l-arginine(l-NMMA 5 x 10-4M). 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 nonendotheliumdependent 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 endotheliumdependent 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