Abstract
In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca2+]i) and the secretion of von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs) and on relaxation of rat aorta in response to histamine. At 10 μM concentration, VAS2870 suppressed the [Ca2+]i rise induced by histamine. Inhibition was not competitive, with IC50 3.64 and 3.22 μM at 1 and 100 μM concentrations of histamine, respectively. There was no inhibition of [Ca2+]i elevation by VAS2870 in HUVECs in response to the agonist of type 1 protease-activated receptor SFLLRN. VAS2870 attenuated histamine-induced secretion of vWF and did not inhibit basal secretion. VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. We suggest that NOX inhibitors might be used as a tool for preventing thrombosis induced by histamine release from mast cells without affecting vasorelaxation.
Highlights
Histamine plays an important role as chemical mediator in multiple physiological and pathophysiological processes in central and peripheral tissues
We studied the effect of VAS2870 on [Ca2+ ]i elevation induced by histamine
3.22 μM at 1 and 100 μM concentrations of histamine, respectively. These results suggest the existence of a specific mechanism of histamine-induced [Ca2+ ]i mobilization in human umbilical vein endothelial cells (HUVECs)
Summary
Histamine plays an important role as chemical mediator in multiple physiological and pathophysiological processes in central and peripheral tissues. We demonstrated an involvement of two-pore channels in an H2 O2 -induced increase in the level of calcium ions in the cytoplasm of human umbilical vein endothelial cells (HUVECs) [34] This could be coupled with exocytosis of the von Willebrand factor (vWF) in these cells in response to H2 O2 [35]. We studied the role of NOX in histamine-induced Ca2+ rise and vWF secretion in HUVECs and NOX involvement in rat aorta relaxation in response to histamine. To solve these questions, we used VAS2870 as a tool inhibitor of NOXs [36]. VAS2870 belongs to the triazolopyrimidines, which are regarded as the most specific inhibitors of NOXs [37]
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