AJP - Lung Cellular and Molecular Physiology, Vol 267, Issue 3 318-L325, Copyright © 1994 by American Physiological Society

ARTICLES

Tumor necrosis factor-alpha decreases pulmonary artery endothelial nitrovasodilator via protein kinase C

A. Johnson, D. T. Phelps and T. J. Ferro
Research Service, Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.

We postulated that tumor necrosis factor-alpha (TNF) decreases endothelium-derived nitrovasodilator(s) via a protein kinase C (PKC)-dependent pathway. Calf pulmonary artery endothelial monolayers (PAEM) were treated with TNF (10, 100, and 1,000 U/ml) for 15 min or 18 h during an 18-h incubation. At the end of the incubation, the cell lysate and supernatant were harvested. Compared with controls, an 18-h incubation with TNF (100 and 1,000 U/ml) resulted in a decrease in NO2- [the oxidation product of nitric oxide (NO)] in PAEM lysate and supernatant. TNF (100 U/ml) treatment for 15 min did not suppress NO2- levels. The decrease in NO2- and the increase in lipid peroxides in response to TNF were prevented by pretreatment (15 min prior to and throughout the incubation) with either calphostin C (1 microM; a specific PKC inhibitor) or the antioxidants N-acetylcysteine (1 mM), 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron) (10 mM), and superoxide dismutase (10 U/ml). Treatment with phorbol 12-myristate 13-acetate (PMA, 1 microM for 15 min), an activator of PKC, decreased NO2- similarly to TNF. Pretreatment with calphostin C or N-acetylcysteine prior to TNF (10 U/ml) revealed an increase in NO2- levels above control treatment. Treatment with the NO synthase antagonists NG-monomethyl-L-arginine (1 mM) and N-nitroso-L-arginine (1 mM) induced an L-arginine (1 mM)-dependent decrease in NO2- in control but not in TNF-treated PAEM. The induction of NO2- by calcium ionophore (A23187; 500 nM) was not affected by treatment with TNF.(ABSTRACT TRUNCATED AT 250 WORDS)

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