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 intracellu lar transduction mechanisms in vascular smooth muscle cells and inflam matory cells. We examined the effect of Paf antagonists on expression of inducible NO synthase. 2. A murine macrophage cell line (J774.2) an d rat vascular smooth muscle cells (VSMC) were stimulated with lipopol ysaccharide (LPS), either alone or in combination with Paf or Paf anta gonists, BN 50739 or E-6123. 3. NO synthase activity in J774.2 was mea sured by the conversion of [H-3]L-arginine to [H-3]L-citrulline. Nitri te accumulation was measured in the culture medium of J774.2 and VSM. 4. BN 50739 (10 mu mol/L) and E-6123 (1 mu mol/L) both reduced the exp ression of calcium-independent NO synthase activity and nitrite accumu lation, while Paf alone had no effect. 5. Inhibition of NO synthase in duction by Paf antagonists might afford therapeutic benefits in the ma nagement of septic shock and possibly other cardiovascular disorders.