HISTAMINE INCREASES VENULAR PERMEABILITY VIA A PHOSPHOLIPASE-C-NO SYNTHASE-GUANYLATE CYCLASE CASCADE

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (P(a)) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 muM) transiently and progressively increased P(a). The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 muM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 10 muM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 muM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. N(G)-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 muM) augmented P(a) by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.