Fig. 3. This schematic diagram depicts the role of the endothelium in the regulation of vascular tone and illustrates important early events known to occur in systemic inflammatory response syndrome (SIRS) at the level of the endothelium. The endothelium regulates local vascular tone and adapts organ blood flow to metabolic needs, by altering the balance of 4 key mediators: nitric oxide (NO), prostacyclin (PGI²), thromboxane (TXA²), and endothelin (ET). Endotoxin (lipopolysaccharide [LPS]) binds to macrophages to release cytokines, which bind to and activate the endothelium. This increases production of these vasoactive agents, in particular NO, by up-regulating the inducible form of NO synthase (iNOS). This alters the dynamic balance of these 4 vasoactive agents over time and appears to play a central role in the hemodynamic sequelae of SIRS. cNOS = constitutive form of NOS; COX-1 = cyclooxygenase 1; COX-2 = cyclooxygenase 2; PLA²= phospholipase 2; AA = arachidonic acid; l-ARG = l-arginine; pro-ET = proendothelin; ECE = endothelin-converting enzyme.