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

Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia

Submitted 11 January 2005 ; accepted in final form 11 March 2005

Sphingosine 1-phosphate (S1P) is a biologically active lipid. In vitro, S1P tightens the endothelial barrier, as assessed by a rapid increase in electrical resistance and a decrease in solute permeability. We hypothesized that this activity of S1P would also occur in vivo. Hydraulic conductivity (L_p), an assessment of endothelial barrier function, was measured in individually perfused venules in rat mesenteries. S1P (1 µM) decreased basal L_p by 63% when basal L_p was between 3.6 and 4.1 x 10^–7 cm·s^–1·cmH₂O^–1 but showed no effect when basal L_p was below 2 x 10^–7 cm·s^–1·cmH₂O^–1. Under either condition, S1P blocked the sixfold increase in L_p induced by platelet-activating factor (PAF, 10 nM). Perfusion of venules with pertussis toxin (0.1 µg/ml), a specific inhibitor of the inhibitory G protein, G_i, for 3 h did not affect basal L_p or the increased L_p induced by PAF. Pertussis toxin, however, significantly attenuated the inhibitory action of S1P on the PAF-induced increase in L_p, indicating the involvement of the G_i protein. Measurement of endothelial cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) in venules loaded with fura-2 AM showed that S1P alone transiently increased basal endothelial [Ca²⁺]_i (from 89 nM to 193 nM) but had no effect on the magnitude and time course of the PAF-induced increase in endothelial [Ca²⁺]_i. These results indicate that S1P functions in vivo to prevent the PAF-induced increase in microvessel permeability. The inhibitory action of S1P involves the pertussis toxin-sensitive G_i protein and is not mediated by prevention of the PAF-induced increase in endothelial [Ca²⁺]_i.

permeability; endothelium; inhibitory G protein; calcium

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