Paf antagonists block induction of nitric oxide synthase in cultured macrophages and vascular smooth muscle cells.
1. Nitric oxide (NO) synthase inhibitors and Paf antagonists abrogate hypotension in septic shock. The latter may act by blocking intracellular transduction mechanisms in vascular smooth muscle cells and inflammatory cells. We examined the effect of Paf antagonists on expression of inducible NO synthase. 2. A murine macrophage cell line (J774.2) and rat vascular smooth muscle cells (VSMC) were stimulated with lipopolysaccharide (LPS), either alone or in combination with Paf or Paf antagonists, BN 50739 or E-6123. 3. NO synthase activity in J774.2 was measured by the conversion of [3H]L-arginine to [3H]L-citrulline. Nitrite accumulation was measured in the culture medium of J774.2 and VSM. 4. BN 50739 (10 mumol/L and E-6123 (1 mumol#L) both reduced the expression of calcium-independent NO synthase activity and nitrite accumulation, while Paf alone had no effect. 5. Inhibition of NO synthase induction by Paf antagonists might afford therapeutic benefits in the management of septic shock and possibly other cardiovascular disorders.
Arthur
J F
JF
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Shahin
S
S
Dusting
G J
GJ
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002956:Citrulline / Q000032:analysis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D008070:Lipopolysaccharides; D009573:Nitrites; D010972:Platelet Activating Factor; D014230:Triazoles; C064509:BN 50739; C068033:E 6123; D002956:Citrulline; D001120:Arginine; D019001:Nitric Oxide Synthase