This study investigates the role of endogenous platelet-activating factor (PAF) in the production of nitric oxide (NO) by constitutive and inducible isoforms of NO synthase (NOS) in endotoxin shock. In anesthetized rats, 3 hours of endotoxemia resulted in a fall in mean arterial blood pressure (MAP) from 127±5 (control) to 61±7 mm Hg and a reduction of the pressor responses to norepinephrine (NE, 1 μg · kg-1) from 33±3 (control) to 17±2 mm Hg. Endotoxemia for 3 hours also resulted in a significant reduction in the contractile effects of NE (10-8 to 10-6 mol/L) in thoracic aortas ex vivo. This hyporeactivity to NE was due to an enhanced formation of NO, for it was restored by the NOS inhibitor NG-nitro-L-arginine methyl ester. Animals pretreated with the PAF receptor antagonist WEB 2086 maintained higher MAP (MAP at 180 minutes, 98±6 mm Hg) and exhibited more pronounced pressor responses to NE at 180 minutes after LPS injection. Moreover, WEB 2086 attenuated by 58% the lipopolysaccharide (LPS)-induced hyporeactivity of the rat aortic rings ex vivo. At 3 hours after LPS injection, calcium-independent NOS activity was induced in the lung. The activity of inducible NOS was significantly lower (by 31%) in lungs of rats pretreated with WEB 2086. The hypothesis that WEB 2086 attenuates the induction of NOS in vivo was substantiated in vitro by the finding that pretreatment with WEB 2086 for 30 minutes inhibited the LPS-stimulated NO production in cultured murine macrophages. In anesthetized rats, PAF itself caused a biphasic (transient immediate and sustained delayed) fall in MAP, which was attenuated by the NOS inhibitor NG-methyl-L-arginine. PAF also caused induction of calcium-independent NOS activity in the lung, an effect that was prevented by WEB 2086 and dexamethasone. Thus, PAF contributes to the induction of the calcium-independent isoform of NOS by LPS administration in vitro and in vivo. In addition, PAF activated the constitutive isoform of NOS to produce NO. Thus, inhibition of NOS induction and activation may contribute to the beneficial effects of PAF antagonists in endotoxemia.
- Endotoxin shock
- Tumor necrosis factor
- WEB 2086
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine