Abstract-Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H 2 O 2 ), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H 2 O 2 -related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombininduced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca 2ϩ levels, or the H 2 O 2 -stimulated, thrombin-stimulated, or Escherichia coli hemolysin-stimulated Ca 2ϩ increase. ADM diminished thrombin-and H 2 O 2 -related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome. (Circ Res. 2002;91:618-625.)Key Words: adrenomedullin Ⅲ cultured endothelial cells Ⅲ endothelial permeability Ⅲ endothelial barrier dysfunction T he incidence of sepsis and ensuing multiple organ failure has increased over the past two decades and has caused multiple deaths in intensive care units. The development of adult respiratory distress syndrome (ARDS) characterized by noncardiogenic pulmonary edema contributes substantially to a fatal outcome. 1 Increased microvascular permeability is a hallmark of an inflammatory reaction, including ARDSrelated pulmonary edema formation. Circumstantial evidence has suggested that endothelial hyperpermeability is related to alterations of the cellular cytoskeleton. 2 Endothelial cells have been shown to contain an elaborate microfilament system allowing active actin-and myosin-based cell contraction. Activation of cell contraction and disturbance of junctional organization subsequently result in the induction of interendothelial gaps followed by enhanced paracellular endothelial permeability. [2][3][4][5][6] Major initiators of this process are polymorphonuclear leukocyte-derived oxygen metabolites, 7-9 pore-forming bacterial exotoxins, 9,10 and endogenous proinflammatory mediators, such as thrombin. 5,9,11 Exposure of endothelial cells to hydrogen peroxide (H 2 O 2 ) results in the activat...

Abstract-Seroepidemiological