Publication Date:
2012-09-08
Description:
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 (PAEC) 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, 4h 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 30min. In vehicle- and tezosentan/PEG-catalase lambs, PBF did not change further over the 4h study period. PVR fell by 30min in vehicle- and tezosentan-treated lambs, and by 60min in tezosentan/PEG-catalase-treated lambs. In vehicle- and tezosentan/PEG-catalase lambs, PVR did not change further over the 4h study period. In tezosentan-treated lambs, PBF continued to increase and LPVR to decrease over the 4h 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. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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