Bicarbonate-dependent superoxide release and pulmonary artery tone.
Pulmonary vasoconstriction is influenced by inactivation of nitric oxide (NO) with extracellular superoxide (O2-*). Because the short-lived O2-* 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 (HCO3-)-chloride anion exchange protein (AE2) expressed in the lung also exchanges O2-* for HCO3-. Thus we determined whether O2-* release involved in pulmonary vascular tone depends on extracellular HCO3-. We assessed endothelium-dependent vascular reactivity and O2-* release in the presence or absence of HCO3- in pulmonary artery (PA) rings isolated from normal rats and those exposed to hypoxia for 3 days. Lack of extracellular HCO3- in normal PA rings significantly attenuated endothelial O2-* release, opposed hypoxic vasoconstriction, and enhanced acetylcholine-mediated vasodilation. Release of O2-* 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 O2-* release; the latter was not affected by NG-nitro-l-arginine methyl ester or other inhibitors of enzymatic O2-* generation. Enhanced O2-* release by uncoupling NO synthase with geldanamycin was attenuated by hypoxia or by HCO3- elimination. These results indicate that O2-* produced by endothelial NOS in normoxia and unidentified sources in hypoxia regulate pulmonary vascular tone via AE2.
Nozik-Grayck
Eva
E
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710,USA. grayc001@mc.duke.edu
Huang
Yuh-Chin T
YC
Carraway
Martha Sue
MS
Piantadosi
Claude A
CA
D000818:Animals; D027321:Anion Transport Proteins; D017920:Antiporters; D001639:Bicarbonates / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D064606:SLC4A Proteins; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*
D027321:Anion Transport Proteins; D017920:Antiporters; D001639:Bicarbonates; D008565:Membrane Proteins; D012333:RNA, Messenger; D064606:SLC4A Proteins; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat