Nitric oxide opposes phorbol ester-induced increases in pulmonary microvascular permeability in dogs.

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 microg/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 x 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 microM), 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.

• Authors: R S Sprague, A H Stephenson, L Mcmurdo, A J Lonigro
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 284 Issue 2 Pg. 443-8 (Feb 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9454782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Nitric Oxide
• Arginine
• Nitric Oxide Synthase
• Tetradecanoylphorbol Acetate
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Arginine (pharmacology)
• Capillary Permeability (drug effects)
• Cardiac Output (drug effects)
• Dogs
• Enzyme Inhibitors (pharmacology)
• Lung (blood supply)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide (pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Pulmonary Edema (physiopathology)
• Tetradecanoylphorbol Acetate (pharmacology)