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OtherPULMONARY PHARMACOLOGY

Nitric Oxide Opposes Phorbol Ester-Induced Increases in Pulmonary Microvascular Permeability in Dogs

Randy S. Sprague, Alan H. Stephenson, Lorraine Mcmurdo and Andrew J. Lonigro
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 443-448;
Randy S. Sprague
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Alan H. Stephenson
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Lorraine Mcmurdo
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Andrew J. Lonigro
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Abstract

In addition to its effects on vascular tone, nitric oxide (NO) has been suggested to function as a participant in fluid homeostasis affecting interactions between the endothelium and circulating inflammatory cells. The role of NO in the increased microvascular permeability of acute lung injury, however, remains controversial. We investigated the hypothesis that NO opposes increases in pulmonary vascular permeability after phorbol myristate acetate administration, i.e., in a model of neutrophil-dependent acute lung injury. In anesthetized dogs, phorbol myristate acetate (10 μg/kg, i.v.) had no effect on pulmonary arterial pressure (Ppa) or extravascular lung water. After pretreatment with the NO synthesis inhibitor, NG-nitro-l-arginine methyl ester (10 mg/kg, i.v.; 5 mg/kg/hr), an identical dose of phorbol myristate acetate resulted in a 20 ± 8 mm Hg (P < .01) increase in pulmonary arterial pressure and a 186 ± 86% (P < .01) increase in extravascular lung water. To determine if the pulmonary edema was related to increases in microvascular pressure or to changes in the microvascular permeability coefficient, experiments were performed in isolated blood-perfused dog lungs. The addition of phorbol myristate acetate (4.2 × 10−8 M) to the perfusate was without effect on microvascular pressure or pulmonary capillary filtration coefficient. However, after NG-nitro-l-arginine methyl ester (100 μM), phorbol myristate acetate resulted in increases in both microvascular pressure and permeability coefficient that were prevented by pretreatment with l-arginine (1 mM). These data support the hypothesis that endogenous NO opposes increases in pulmonary vascular permeability as well as microvascular pressure in this neutrophil-dependent model of acute lung injury resulting in preservation of the endothelial barrier to the passage of water and solutes and prevention of the formation of pulmonary edema.

Footnotes

  • Send reprint requests to: Dr. R. S. Sprague, Saint Louis University School of Medicine, 1402 Grand Blvd., St. Louis, MO 63104.

  • ↵1 This work was supported by National Institutes of Health, National Heart, Lung and Blood Institute Grants HL51298 and HL52675 and by the American Heart Association, Missouri Affiliate.

  • Abbreviations:
    PMA
    phorbol myristate acetate
    PMN
    polymorphonuclear leukocyte
    ALI
    acute lung injury
    Ppa
    mean pulmonary arterial pressure
    Psa
    mean systemic arterial pressure
    Pla
    mean left atrial pressure
    Pmv
    microvascular pressure
    EVLW
    extravascular lung water
    L-NAME
    - NG-nitro-l-arginine methyl ester
    TPP
    transpulmonary pressure
    Kfc
    pulmonary capillary filtration coefficient
    ECV
    ethchlorvynol
    DMSO
    dimethyl sulfoxide
    NO
    nitric oxide
    ECV
    ethchlorvynol
    ARDS
    adult respiratory distress syndrome
    • Received June 2, 1997.
    • Accepted October 3, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherPULMONARY PHARMACOLOGY

Nitric Oxide Opposes Phorbol Ester-Induced Increases in Pulmonary Microvascular Permeability in Dogs

Randy S. Sprague, Alan H. Stephenson, Lorraine Mcmurdo and Andrew J. Lonigro
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 443-448;

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OtherPULMONARY PHARMACOLOGY

Nitric Oxide Opposes Phorbol Ester-Induced Increases in Pulmonary Microvascular Permeability in Dogs

Randy S. Sprague, Alan H. Stephenson, Lorraine Mcmurdo and Andrew J. Lonigro
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 443-448;
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