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      Pulmonary vascular dysfunction secondary to pulmonary arterial hypertension: insights gained through retrograde perfusion

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          Abstract

          Here, we tested the hypothesis that severe pulmonary arterial hypertension impairs retrograde perfusion. To test this hypothesis, pulmonary arterial hypertension was induced in Fischer rats using a single injection of Sugen 5416 followed by 3 wk of exposure to 10% hypoxia and then 2 wk of normoxia. This Sugen 5416 and hypoxia regimen caused severe pulmonary arterial hypertension, with a Fulton index of 0.73 ± 0.07, reductions in both the pulmonary arterial acceleration time and pulmonary arterial acceleration to pulmonary arterial ejection times ratio, and extensive medial hypertrophy and occlusive neointimal lesions. Whereas the normotensive circulation accommodated large increases in forward and retrograde flow, the hypertensive circulation did not. During forward flow, pulmonary artery and double occlusion pressures rose sharply at low perfusion rates, resulting in hydrostatic edema. Pulmonary arterial hypertensive lungs possessed an absolute intolerance to retrograde perfusion, and they rapidly developed edema. Retrograde perfusion was not rescued by maximal vasodilation. Retrograde perfusion was preserved in lungs from animals treated with Sugen 5416 and hypoxia for 1 and 3 wk, in lungs from animals with a milder form of hypoxic hypertension, and in normotensive lungs subjected to high outflow pressures. Thus impaired retrograde perfusion coincides with development of severe pulmonary arterial hypertension, with advanced structural defects in the microcirculation.

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          Author and article information

          Journal
          Am J Physiol Lung Cell Mol Physiol
          Am. J. Physiol. Lung Cell Mol. Physiol
          ajplung
          Am J Physiol Lung Cell Mol Physiol
          AJPLUNG
          American Journal of Physiology - Lung Cellular and Molecular Physiology
          American Physiological Society (Bethesda, MD )
          1040-0605
          1522-1504
          1 May 2018
          18 January 2018
          1 May 2019
          : 314
          : 5
          : L835-L845
          Affiliations
          [1] 1Department of Physiology and Cell Biology, University of South Alabama , Mobile, Alabama
          [2] 2Department Pharmacology, University of South Alabama , Mobile, Alabama
          [3] 3Department of Internal Medicine, University of South Alabama , Mobile, Alabama
          [4] 4Department of Pediatrics, University of South Alabama , Mobile, Alabama
          [5] 5Center for Lung Biology, University of South Alabama , Mobile, Alabama
          Author notes
          Address for reprint requests and other correspondence: T. Stevens, Dept. of Physiology and Cell Biology, Center for Lung Biology, College of Medicine, Univ. of South Alabama, Mobile, AL 36688 (e-mail: tstevens@ 123456southalabama.edu ).
          Article
          PMC6008136 PMC6008136 6008136 L-00201-2017 L-00201-2017
          10.1152/ajplung.00201.2017
          6008136
          29345199
          158d63d2-a245-4395-8c49-443ab29c574b
          Copyright © 2018 the American Physiological Society
          History
          : 3 May 2017
          : 8 December 2017
          : 15 January 2018
          Funding
          Funded by: NIH
          Award ID: HL66299
          Award ID: HL60024
          Categories
          Research Article

          plexiform lesions,vascular resistance,semaxanib (Sugen 5416),pulmonary hypertension,edema

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