Role of Nitric Oxide and Reactive Oxygen Species in Platelet-Activating Factor-Induced Microvascular Leakage

Abstract

Platelet-activating factor (PAF), released during inflammatory responses, increases microvascular permeability to fluid and macromolecules. Previous studies in the hamster cheek pouch microcirculation have shown that PAF-induced increases in permeability can be diminished by pretreatment with a nitric oxide synthase inhibitor indicating that nitric oxide is required for PAF to cause leakage, although nitric oxide itself does not cause leakage. We evaluated the hypothesis that PAF stimulates the production of reactive oxygen species (ROS) that then react with nitric oxide to form a new species that signals the increase in vascular permeability. The hamster cheek pouch microcirculation was used to quantify the leakage of FITC-dextran following topical application of PAF. PAF-induced leakage was markedly inhibited (70%) by prior superfusion of the cheek pouch with superoxide dismutase and catalase. Superfusing the cheek pouch with ROS generated by xanthine oxidase and hypoxanthine produced leakage similar to that observed with PAF. Pretreating the cheek pouch with a nitric oxide synthase inhibitor (N^ω-nitro-L-arginine, L-NA) inhibited ROS-induced leakage by 59% and PAF-induced leakage by 64%. The effects of L-NA and superoxide dismutase plus catalase on PAF-induced leakage were not additive. Systemic administration of mercaptoethylguanidine, a peroxynitrite scavenger, inhibited PAF-induced leakage by 60%. These results suggest that PAF-induced leakage may be mediated by an interaction between ROS and NO, perhaps through the formation of peroxynitrite or one of its products.

Interplay among platelet‐activating factor, oxidative stress, and group I metabotropic glutamate receptors modulates neuronal survival

“…In fact, it has been reported that PAF causes free radical generation and perhaps closely interacts with nitric oxide (Klabunde and Anderson, 2002). Our negative results from SIN-1 and SNP suggest that exogenously administered PAF and nitric oxide are unlikely to cause synergistically more neuronal death in our model.…”

Sphingosine 1-phosphate prevents platelet-activating factor-induced increase in hydraulic conductivity in rat mesenteric venules: pertussis toxin sensitive

“…Fluorescent staining of actin with a fluorochrome conjugated to phalloidin reveals at the cell periphery that thrombin disassembles actin (15), whereas S1P enhances the appearance of actin (5). PAF increases the production of nitric oxide in individually perfused intact microvessels (20), and nitric oxide as well as reactive oxygen species has been reported to mediate the PAF-induced increase in microvascular permeability (12). Interestingly, S1P also stimulates within 5 min the phosphorylation of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide in bovine lung microvascular endothelial cells (16).…”

S-Nitrosation of β-Catenin and p120 Catenin

“…In support of these concepts, we demonstrate that ACh - an agonist that localizes eNOS to Golgi, stimulates production of NO and induces vasodilation 24, 37, 23 - does not cause S-nitrosation. PAF may cause enhanced permeability by formation of peroxynitrite 38 , the reaction product of NO and superoxide anion 39 . In the hamster cheek pouch, SIN-1 (3-morpholinosydnonimine N-ethylcarbamide) 40 , a peroxynitrite generator, induces hyperpermeability 41 .…”