Inotropes inhibit endothelial cell surface adhesion molecules induced by interleukin-1 beta

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Objectives Leukocyte-endothelial cell interactions play a critical role in sepsis-induced multiple organ system failure and acute respiratory distress syndrome. Increased cyclic adenosine 3 prime,5 prime-monophosphate (cAMP) has been previously reported to inhibit expression of the cytokine-stimulated endothelial cell adhesion molecules, E-selectin, and vascular cell adhesion molecule-1 (VCAM-1). We hypothesized that clinically relevant concentrations of inotropes, such as amrinone and dopamine, which increase cAMP, could inhibit cytokine-stimulated upregulation of endothelial adhesion proteins.Design Prospective, controlled in vitro study.Setting Leukocyte biology laboratory.Subjects Human umbilical vein endothelial cells isolated from neonatal umbilical cord specimens and whole blood obtained from normal human adult volunteers were used in this study.Interventions Endothelial cell monolayers were pretreated with increasing concentrations of amrinone or dopamine, or left untreated as controls, followed by exposure to recombinant human interleukin (IL)-1 beta for 6 hrs. Monolayers were then incubated with monoclonal antibodies to E-selectin, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1), fluorescence labeled, and assessed for mean fluorescence intensity by flow cytometry as a measure of surface adhesion molecule concentrations. Whole blood neutrophils were pretreated with or without inotropes, then stimulated with n-formyl methyl leucine phenylalanine. Stimulated neutrophils were incubated with antibodies against the neutrophil adherence protein CD11b and assessed by flow cytometry.Measurements and Main Results IL-1 beta markedly increased E-selectin (p = .01), VCAM-1 (p < .01), and ICAM-1 (p < .001) concentrations (n = 6). Pretreatment with amrinone significantly decreased endothelial E-selectin surface values at all concentrations (p < .001 by analysis of variance, n = 5), including therapeutic concentration ranges. Amrinone also inhibited upregulation of ICAM-1 (p < .001) at therapeutic concentrations, and VCAM-1 (p < .001) at higher concentrations. Dopamine inhibited only E-selectin at relevant concentrations. Neutrophil pretreatment with inotropes did not prevent CD11b upregulation.Conclusions Pretreatment with amrinone, and to a lesser degree, with dopamine, at clinically relevant concentrations inhibits in vitro IL-1 alpha-induced increases in human umbilical vein endothelial cell adhesion molecule concentrations. Future studies are necessary to investigate the mechanisms of these effects and to determine in vivo efficacy of inotropes as anti-inflammatory agents.(Crit Care Med 1997; 25:303-308)

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