Intratracheal adenoviral-mediated delivery of iNOS decreases pulmonary vasoconstrictor responses in rats.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 8502536 Publication Model: Print-Electronic Cited Medium: Print ISSN: 8750-7587 (Print) Linking ISSN: 01617567 NLM ISO Abbreviation: J Appl Physiol (1985) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD : American Physiological Society, c1985-
    • Subject Terms:
      Transduction, Genetic*/methods; Nitric Oxide Synthase/*administration & dosage ; Pulmonary Circulation/*drug effects ; Vasoconstriction/*drug effects; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology ; Adenoviridae ; Animals ; Dose-Response Relationship, Drug ; Exhalation ; Genetic Vectors ; Humans ; Immunologic Techniques ; In Vitro Techniques ; Lung/metabolism ; Male ; Nitric Oxide ; Nitric Oxide Synthase/genetics ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase/pharmacology ; Nitric Oxide Synthase Type II ; Rats ; Rats, Sprague-Dawley ; Staining and Labeling ; Time Factors ; Tissue Distribution ; Trachea ; Vascular Resistance/drug effects ; Vasoconstrictor Agents/pharmacology
    • Abstract:
      We hypothesized that adenovirus-mediated inducible nitric oxide synthase (iNOS) gene transduction of the lung would result in time-dependent iNOS overexpression and attenuate the vascular constrictor responses to a thromboxane mimetic, U-46619. Rats were treated via the trachea with surfactant alone (sham), surfactant containing an adenoviral construct with a cytomegalovirus promoter-regulated human iNOS gene (Adeno-iNOS), or an adenoviral construct without a gene insert (Adeno-Control). Adeno-iNOS-transduced rats demonstrated human iNOS mRNA and increased iNOS protein levels only in the lungs. Immunohistochemistry of lungs from Adeno-iNOS-treated animals demonstrated transgene expression in alveolar wall cells. In the lungs from Adeno-iNOS-transduced rats, the expression of iNOS protein and exhaled nitric oxide concentrations were increased on days 1-4 and 7 but returned to baseline values by day 14. The administration of the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine dihydrochloride (L-NIL) decreased exhaled nitric oxide concentrations to levels found in Adeno-Control-transduced lungs. In a second group of rats, the segmental vasoconstrictor responses to U-46619 were determined in isolated, perfused lungs 3 days after transduction. Lungs from rats transduced with Adeno-iNOS had reduced total, arterial, and venous vasoconstrictor responses to U-46619 compared with sham, Adeno-Control, and control groups. In a third set of experiments, the response to 400 nM U-46619 in the presence of 10 microM L-NIL was not different in the isolated lungs from Adeno-Control- and Adeno-iNOS-transduced rats. We conclude that adenovirus-mediated iNOS gene transduction of the lung results in time-dependent iNOS overexpression, which attenuates the vascular constrictor responses to the thromboxane mimetic U-46619.
    • Grant Information:
      R01 HL057854 United States HL NHLBI NIH HHS; HL-58124 United States HL NHLBI NIH HHS; RR-16480 United States RR NCRR NIH HHS; HL-04050 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Vasoconstrictor Agents)
      31C4KY9ESH (Nitric Oxide)
      76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid)
      EC 1.14.13.39 (NOS2 protein, human)
      EC 1.14.13.39 (Nitric Oxide Synthase)
      EC 1.14.13.39 (Nitric Oxide Synthase Type II)
      EC 1.14.13.39 (Nos2 protein, rat)
    • Publication Date:
      Date Created: 20040720 Date Completed: 20050225 Latest Revision: 20200320
    • Publication Date:
      20231215
    • Accession Number:
      10.1152/japplphysiol.00193.2004
    • Accession Number:
      15258125