Endothelial "stunning" following a brief exposure to endotoxin: a mechanism to link infection and infarction?

BACKGROUND: There is an association between infection, inflammation and acute cardiovascular events. In an attempt to explore the mechanism of this association we have developed a model to examine the effects on endothelial function of a brief exposure to endotoxin. METHODS AND RESULTS: Endotoxin was instilled into isolated superficial hand veins of healthy volunteers. The vein was isolated by means of two wedges and endotoxin instilled into the isolated segment. After 1 h the contents of the vein were aspirated and the wedges removed. Dose-response curves to bradykinin (a stimulator of nitric oxide synthesis), arachidonic acid (the precursor of prostanoid production) and GTN (a nitric oxide donor) were constructed before and 1 h after endotoxin. Endotoxin caused a glucocorticoid-inhibitable attenuation in the dose-response curves to bradykinin and arachidonic acid (P < 0.05). This effect persisted for 48 h and took 7 days to recover. Exposure of saphenous vein to endotoxin in vitro also caused selective impairment of endothelium-dependent relaxation (P < 0.05) yet microscopy of the vessels exposed to endotoxin showed no endothelial denudation or structural damage. CONCLUSION: The results demonstrate that a brief local exposure to endotoxin caused endothelial dysfunction that persists for 48 h and takes up to 7 days to recover. The endothelial dysfunction is not due to expression of the inducible isoform of nitric oxide synthase and persists for far longer than the effects of endotoxin on vascular smooth muscle function. We have coined the term endothelial "stunning" to describe the transient endothelial dysfunction and suggest it might provide a mechanism underpinning the association between infection or inflammation and increased cardiovascular risk. Endothelial stunning appears to provide a novel, transient, variable and modifiable potential cardiovascular risk factor.