Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF

PURPOSE. To explore the effects of brief intravenous (TV) infusion of vascu lar endothelial growth factor (VEGF) on vascular albumin permeability, bloo d flow, and vascular conductance (blood flow normalized to arterial blood p ressure) in ocular tissues and brain and to assess the role of nitric oxide in mediating these changes. METHODS. A quantitative, double-tracer, radiolabeled albumin permeation met hod was combined with radiolabeled microspheres for assessment of changes i n vascular permeability and blood flow, respectively, induced in ocular tis sues by TV infusion of recombinant human VEGF(165) for 20 minutes (80-450 p icomoles/kg body weight). An inhibitor of nitric oxide synthase (NOS), N-G- monomethyl-L-arginine (L-NMMA; 50 micromoles/kg body weight infused simulta neously with VEGF), was used to explore the role of nitric oxide in mediati ng the vascular changes induced by VEGF. RESULTS. Infusion of VEGF(165) in thiopental-anesthetized rats dose-depende ntly increased I-125-albumin permeation in the retina, anterior uvea, and c horoid/sclera and in brain, aorta, lung, kidney, small intestine, and perip heral nerve. Mean arterial blood pressure, cardiac output, and stroke volum e were decreased only at the highest dose of VEGF, whereas heart rate remai ned unchanged. Blood flow was increased in the anterior uvea, and vascular conductance was increased in retina, anterior uvea, choroid/sclera, and bra in at the highest dose of VEGF. The NOS inhibitor, L-NMMA, blocked VEGF-ind uced vascular hyperpermeability in all ocular and nonocular tissues, preven ted the increase in vascular conductance in all ocular tissues, and blocked the decrease in mean arterial blood pressure, cardiac output, and stroke v olume. Infusion of L-NMMA alone decreased vascular conductance in choroid/s clera and kidney, slightly increased mean arterial blood pressure, and in g eneral, did not affect I-125-albumin permeation. (L-NMMA slightly decreased albumin permeation in the retina and increased it in the brain.) CONCLUSIONS. Intravenous infusion of VEGF can acutely impair endothelial ce ll barrier functional integrity and relax resistance arterioles in ocular t issues and brain through a mechanism involving activation of NOS.