In septic shock, arginine vasopressin (AVP) is commonly used as a vasopressor to restore blood pressure. Exogenous AVP may have anti-inflammatory effects as well. We investigated whether AVP modulates the effects of tumor necrosis factor-alpha (TNF-alpha) in human aortic endothelial cells (HAECs). TNF-alpha stimulated intercellular adhesion molecule-1 expression, while AVP pretreatment attenuated this effect of TNF-alpha. Upon treatment with AVP, extracellular Ca2+ entered the cells rapidly through L-type calcium channels, which in turn induced cell surface translocation of a disintegrin and metalloprotease 10 (ADAM10) and ectodomain shedding of tumor necrosis factor receptor 1 (TNFR1). On the other hand, siRNA depletion of ADAM10 suppressed AVP-induced ectodomain shedding of TNFR1 and eliminated the inhibitory effect of AVP against TNF-alpha. Depletion of oxytocin receptor also abolished AVP-induced extracellular Ca2+ influx, AVP-induced ectodomain shedding of TNFR1 and the inhibitory effect of AVP against TNF-alpha. These findings suggest that AVP decreases the responsiveness of HAECs to TNF-alpha by inducing ADAM10-dependent ectodomain shedding of TNFR1. Extracellular Ca2+ influx through L-type calcium channels was essential for ADAM10 activation. This effect of AVP was mediated through the oxytocin receptor. (C) 2019 Elsevier Inc. All rights reserved.