Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia.

OBJECTIVE: Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF-A) is detected at higher concentrations in plasma from patients with pre-eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre-eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity. DESIGN: Plasma from pre-eclamptic (n = 17) and normotensive (n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique. RESULTS: Pre-eclamptic but not normotensive plasma resulted in a 5.25 ± 0.8-fold acute increase in vascular permeability (P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A (n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF(165) b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF165b (n=6; P<0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma. CONCLUSIONS: These findings suggest that circulating VEGF-A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF165b may be involved in the increased vascular permeability of pre-eclampsia.

Effect of streptomycin on wall-stress-induced arrhythmias in the working rat heart.

OBJECTIVE: To assess whether streptomycin, an inhibitor of mechano-sensitive cation channels, has an effect on arrhythmias-induced by an increase of ventricular wall stress in the rat heart. METHODS: The isolated working rat heart preparation was used. Arrhythmias were induced by increasing the afterload (i.e., aortic pressure) against which the left ventricle (LV) pumped for 20 s. This led to an increase of LV pressure, stretch of the LV and an increase in LV wall stress. The number of ventricular premature beats induced by each afterload step was compared in the absence and presence of streptomycin, a compound known to block mechano-sensitive cation channels in the heart. RESULTS: Perfusion with 200 microM streptomycin caused a significant reduction in wall-stress-induced arrhythmias. The effect of streptomycin on arrhythmias reached steady-state within 10 min of application. In the presence of streptomycin, arrhythmias elicited by a 40 mmHg afterload increase were reduced to 38% of control. Arrhythmias induced by an 80 mmHg afterload increase were reduced to 61% of control. Complex arrhythmias (ventricular tachycardia) induced by an afterload increase were also reduced in the presence of 200 microM streptomycin. There was no change in inotropic state with streptomycin, as assessed either by cardiac output or by maximum developed LV pressure. Streptomycin 50 microM (a typical therapeutic plasma concentration in patients) had no effect on wall-stress-induced arrhythmias. CONCLUSIONS: The results were inconsistent with streptomycin acting by modulating inositol phosphate production, or altering the level of intracellular calcium or inotropic state. The anti-arrhythmic effect of streptomycin appears more consistent with inhibition of mechano-sensitive cation channels, suggesting that these ion channels might be involved in causing wall-stress-induced arrhythmias.