title: Tezosentan increases nitric oxide signaling via enhanced hydrogen peroxide generation in lambs with surgically induced acute increases in pulmonary blood flow.
abstract: We have previously shown that acute increases in pulmonary blood flow (PBF) are limited by a compensatory increase in pulmonary vascular resistance (PVR) via an endothelin-1 (ET-1) dependent decrease in nitric oxide synthase (NOS) activity. The mechanisms underlying the reduction in NO signaling are unresolved. Thus, the purpose of this study was to elucidate mechanisms of this ET-1-NO interaction. Pulmonary arterial endothelial cells were acutely exposed to shear stress in the presence or absence of tezosentan, a combined ET(A) /ET(B) receptor antagonist. Shear increased NO(x) , eNOS phospho-Ser1177, and H(2) O(2) and decreased catalase activity; tezosentan enhanced, while ET-1 attenuated all of these changes. In addition, ET-1 increased eNOS phospho-Thr495 levels. In lambs, 4 h of increased PBF decreased H(2) O(2) , eNOS phospho-Ser1177, and NO(X) levels, and increased eNOS phospho-Thr495, phospho-catalase, and catalase activity. These changes were reversed by tezosentan. PEG-catalase reversed the positive effects of tezosentan on NO signaling. In all groups, opening the shunt resulted in a rapid increase in PBF by 30 min. In vehicle- and tezosentan/PEG-catalase lambs, PBF did not change further over the 4 h study period. PVR fell by 30 min in vehicle- and tezosentan-treated lambs, and by 60 min in tezosentan/PEG-catalase-treated lambs. In vehicle- and tezosentan/PEG-catalase lambs, PVR did not change further over the 4 h study period. In tezosentan-treated lambs, PBF continued to increase and LPVR to decrease over the 4 h study period. We conclude that acute increases in PBF are limited by an ET-1 dependent decrease in NO production via alterations in catalase activity, H(2) O(2) levels, and eNOS phosphorylation.
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pediatrics, University of California, San Francisco CA 94143.|Cardiovascular Research Institute, University of California, San Francisco CA 94143.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Oishi
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Yali
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Pediatrics, University of California, San Francisco CA 94143.
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Datar
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Surgery, University of California, San Francisco CA 94143.
authors.forename: Anthony
authors.initials: A
authors.lastname: Azakie
authors.affiliation: Department of Pediatrics, University of California, San Francisco CA 94143.|Cardiovascular Research Institute, University of California, San Francisco CA 94143.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Health Sciences University, Augusta GA 30912.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D042783:Endothelial Cells; D019332:Endothelin-1 / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000166:cytology; D011725:Pyridines / Q000008:administration & dosage*; D044022:Receptor, Endothelin A / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D034561:Sheep, Domestic / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D019332:Endothelin-1; D011725:Pyridines; D044022:Receptor, Endothelin A; D013777:Tetrazoles; D009569:Nitric Oxide; C120582:tezosentan; D006861:Hydrogen Peroxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III