PLATELET-ACTIVATING-FACTOR MODULATES MICROVASCULAR PERMEABILITY THROUGH NITRIC-OXIDE SYNTHESIS

Biochemical signaling determines the specific action of vasomediators in the control of microvascular permeability and tone. We tested the h ypothesis that nitric oxide (NO) synthesis is involved in the biochemi cal signaling pathway of platelet activating factor (PAF). The cheek p ouch of anesthetized male Syrian hamsters was used as a microvascular model. Vessel diameter [expressed as the ratio of the experimental to the control (e/c) diameter, with control diameter normalized to 1] and extravasation of FITC-dextran 150 by integrated optical intensity (IO I) were determined using intravital fluorescent microscopy and compute r-assisted digital image analysis. N-Nitro-L-arginine methyl ester (L- NAME) at 10(-5) and 10(-6) M and N-nitro-L-monomethyl arginine (L-NMMA ) at 10(-4) and 10(-5) M were used as inhibitors of NO synthase (NOS). Acetylcholine (ACh) and bradykinin were used as indirect indices of N OS activation. L-NAME and L-NMMA attenuated both ACh and bradykinin va sodilatory effects as well as the bradykinin induced increase in vascu lar permeability. Topical PAF (10(-7) M) caused vasoconstriction (mean +/- SEM e/c ratio = 0.3 +/- 0.1) and increased IOI from a normalized baseline of 0 to 67.4 +/- 12.8. Topical administration of L-NAME produ ced differential effects on the series-arranged arterioles but had no effect on postcapillary venular permeability. L-NMMA did not influence the basal arteriolar diameter, but at 10(-5) M it caused a small incr ease in permeability (IOI = 14.3 +/- 4.2). In the presence of NOS inhi bitors, PAF caused a reduced arteriolar constriction (e/c ratio = 0.6 +/- 0.1) relative to PAF alone. Both NOS inhibitors reduced the PAF-st imulated increase in vasopermeability. At 10(-5) M L-NMMA, the PAF-sti mulated IOI mean value was 26.1 +/- 5.2, while at 10(-4) M L-NMMA the PAF-stimulated IOI was 15.2 +/- 2.6 compared to 10(-7) M PAF (67.4 +/- 12.8). These results support our hypothesis that NO synthesis is a st ep in the biochemical signaling pathway of the postcapillary cellular responses to PAF. (C) 1995 Academic Press, Inc.