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) signi®cantly (P50.05) 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 aect 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 signi®cantly (P50.05) 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 sacri®ce. The concentration-dependent curve to PE was statistically (P50.005) reduced in aorta rings collected from LPS-compared to vehicle-treated rats. This dierence 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 dierences. 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.

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One of the major problems related to the percutaneous transluminal coronary angioplasty technique is the renarrowing of the vessel, a phenomenon known as restenosis. NO and nonsteroidal anti-inflammatory drugs have been shown to play a role in this pathology. The main problem with the use of conventional NO donors is that they affect blood pressure and flow, and for these reasons, they cannot be used safely in clinical practice. The aim of this study was to evaluate, with the use of a rat model of balloon angioplasty, whether a structural derivative of flurbiprofen, containing an added NO-releasing moiety (HCT-1026), is able to reduce or prevent neointimal formation. Rats were treated for 14 days with equimolar doses of flurbiprofen (2, 7, and 21 mg/kg) or HCT-1026 (3, 10, and 30 mg/kg). After this 14-day treatment, HCT-1026 but not flurbiprofen significantly modified the neointima/media ratio. The reduction in the neointimal proliferation obtained with HCT-1026 was well correlated with an increase in nitrite/nitrate plasma levels and a reduced cell proliferation. Neither HCT-1026 nor flurbiprofen affected inducible NO synthase induction in injured vessels. In conclusion, HCT-1026 caused a significant reduction in restenosis that appears to be directly related to NO release. HCT-1026 may prove to be beneficial in preventing or delaying restenosis in humans.

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 LPStreated 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 À1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 Â 10 6 U kg À1 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 (Po0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg À1 i.p.). 5 GLB-induced hypertension (40 mg kg À1 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 LPStreated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.