1 We have investigated the role of ATP-sensitive potassium (K-ATP) channels in an experimental model of a delayed phase of vascular hyporeactivity induced by lipopolysaccharide (LPS) in rats. 2 After 24 h, from LPS treatment, in anaesthetized rats the bolus injection of phenylephrine (PE) produced an increase in mean arterial pressure (MAP) significantly (P<0.05) reduced in LPS-treated rats compared to the vehicle-treated rats. This reduction was prevented by pre-treatment of rats with glibenclamide (GLB), a selective inhibitor of K-ATP channels. 3 GLB administration did not affect the MAP in vehicle-treated rats but produced an increase of MAP in rats treated with LPS. 4 Cromakalim (CRK), a selective K-ATP channel opener, produced a reduction of MAP that was significantly (P<0.05) higher in LPS- than in vehicle-treated rats. In contrast, the hypotension induced by glyceryl trinitrate (GTN) in LPS-treated rats was not distinguishable from that produced in vehicle-treated rats. 5 Experiments in vitro were conducted on aorta rings collected from rats treated with vehicle or LPS 24 h before sacrifice. The concentration-dependent curve to PE was statistically (P<0.005) reduced in aorta rings collected from LPS- compared to vehicle-treated rats. This difference was totally abolished by tetraethylammonium (TEA), a non-selective inhibitor of K+ channels. 6 CRK produced a relaxation of PE precontracted aorta rings higher in rings from LPS- than in vehicle-treated rats. GLB inhibited CRK-induced relaxation in both tissues, abolishing the observed differences. 7 In conclusion, our results indicate an involvement of K-ATP channels to the hyporesponsiveness of vascular tissue after 24 h from a single injection of LPS in rats. We can presume an increase in the activity of K-ATP channels on vascular smooth muscle cells but we cannot exclude an increase of K-ATP channel number probably due to the gene expression activation.