Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP-sensitive potassium channels activity

1 Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. 2 Previously we showed that ATP-sensitive potassium (K-ATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. 3 We evaluated the effect of dexamethasone (DEX 8 mg kg(-1) i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 10(6) U kg(-1) i.p.)-induced endotoxemia in urethane-anaesthetised rats. 4 DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg(-1) i.p.). 5 GLB-induced hypertension (40 mg kg(-1) i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. 6 Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. 7 In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with K-ATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.