Bicarbonate-dependent superoxide release and pulmonary artery tone

Abstract

Pulmonary vasoconstriction is influenced by inactivation of nitric oxide (NO) with extracellular superoxide ([Formula: see text]). Because the short-lived [Formula: see text] anion cannot diffuse across plasma membranes, its release from vascular cells requires specialized mechanisms that have not been well delineated in the pulmonary circulation. We have shown that the bicarbonate [Formula: see text] anion exchange protein (AE2) expressed in the lung also exchanges [Formula: see text] for [Formula: see text]. Thus we determined whether [Formula: see text] release involved in pulmonary vascular tone depends on extracellular [Formula: see text]. We assessed endothelium-dependent vascular reactivity and [Formula: see text] release in the presence or absence of [Formula: see text] in pulmonary artery (PA) rings isolated from normal rats and those exposed to hypoxia for 3 days. Lack of extracellular [Formula: see text] in normal PA rings significantly attenuated endothelial [Formula: see text] release, opposed hypoxic vasoconstriction, and enhanced acetylcholine-mediated vasodilation. Release of [Formula: see text] was also inhibited by an AE2 inhibitor (SITS) and abolished in normoxia by an NO synthase inhibitor ( NG-nitro-l-arginine methyl ester). In contrast, hypoxia increased PA AE2 protein expression and [Formula: see text] release; the latter was not affected by NG-nitro-l-arginine methyl ester or other inhibitors of enzymatic [Formula: see text] generation. Enhanced [Formula: see text] release by uncoupling NO synthase with geldanamycin was attenuated by hypoxia or by [Formula: see text] elimination. These results indicate that [Formula: see text] produced by endothelial NOS in normoxia and unidentified sources in hypoxia regulate pulmonary vascular tone via AE2.