Platelet activating factor modulates microvascular permeability through nitric oxide synthesis

Abstract

Biochemical signaling determines the specific action of vasomediators in the control of microvascular permeability and tone. We tested the hypothesis that nitric oxide (NO) synthesis is involved in the biochemical signaling pathway of platelet activating factor (PAF). The cheek pouch 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 (IOI) were determined using intravital fluorescent microscopy and computer-assisted digital image analysis. N-Nitro-L-arginine methyl ester (L-NAME) at 10(-5) and 10(-6) M and N-nitro-L-mono-methyl 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 NOS activation. L-NAME and L-NMMA attenuated both ACh and bradykinin vasodilatory effects as well as the bradykinin-induced increase in vascular 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 produced 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 increase in permeability (IOI = 14.3 +/- 4.2). In the presence of NOS inhibitors, PAF caused a reduced arteriolar constriction (e/c ratio = 0.6 +/- 0.1) relative to PAF alone. Both NOS inhibitors reduced the PAF-stimulated increase in vasopermeability. At 10(-5) M L-NMMA, the PAF-stimulated 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 step in the biochemical signaling pathway of the postcapillary cellular responses to PAF.