1 Endotoxaemia causes an enhanced formation of reactive oxygen species (ROS) which contribute to the multiple organ dysfunction syndrome (MODS) in septic shock. Here we investigate (i) the e ects of endotoxin on the expression of two isoforms of superoxide dismutase (SOD), namely Cu/Zn-SOD (cytosol) and Mn-SOD (mitochondria) in the rat kidney, and (ii) the e ects of the radical scavenger tempol on the MODS caused by lipopolysaccharide (LPS, E. coli, 6 mg kg 71 i.v.) in the rat. 2 Endotoxaemia resulted in a rapid, but transient, decline in the expression of both mRNA and protein of Cu/Zn-SOD as well as an increase in the expression of the mRNA of Mn-SOD in the kidney. Endotoxaemia for 6 h also caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of nitrite/nitrate. 3 Pretreatment of rats with tempol (100 mg kg 71 i.v. bolus injection, 15 min prior to LPS followed by an infusion of 30 mg kg 71 i.v., n=9) did not a ect the circulatory failure, but attenuated the renal dysfunction and the hepatocellular injury/dysfunction caused by LPS. Tempol did not a ect the rise in nitrite/nitrate caused by endotoxin. 4 These results imply that an enhanced formation of ROS (including superoxide anions) in conjunction with inadequate defences against such ROS contributes to the injury and dysfunction of the kidney and the liver in endotoxic shock.

Abstract-The cardioprotective effects of E-type prostaglandins (EPs) have been attributed to vasodilatation, inhibition of platelet and neutrophil function (EP 2 mediated), and an unknown "cytoprotective effect." We have hypothesized that selective activation of EP 3 receptors may cause cardioprotection. The prostanoid derivative ONO-AE-248 selectively binds to murine EP 3␣ receptors expressed in Chinese hamster ovary (CHO) cells (K i , 15 nmol/L) and prevents the rise in cAMP caused by forskolin in CHO cells (IC 50 Ϸ1 nmol/L) in which the EP 3␣ receptor had been expressed. In anesthetized rats subjected to regional myocardial ischemia for 25 or 45 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IV) caused a significant reduction in infarct size, from 60Ϯ3% (nϭ8) to 36Ϯ6% (nϭ7) and from 78Ϯ2% (nϭ11) to 58Ϯ4% (nϭ9), respectively. The reduction in infarct size caused by ONO-AE-248 in rats subjected to 25 minutes of ischemia and reperfusion was abolished by a selective inhibitor of ATP-sensitive potassium (K ATP ) channels, 5-hydroxydecanoate (nϭ6), and the protein kinase C inhibitors staurosporine (nϭ6) and chelerythrine (nϭ6). In anesthetized rabbits subjected to coronary artery occlusion for 45 or 60 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IV) caused a significant reduction in infarct size, from 61Ϯ2% (nϭ10) to 36Ϯ4% (nϭ8) and from 63Ϯ4% (nϭ7) to 42Ϯ4% (nϭ7), respectively. The reduction in infarct size caused by ONO-AE-248 in the rabbit was also abolished by 5-hydroxydecanoate. The cardioprotective effect of ONO-AE-248 in rats or rabbits was not associated with any hemodynamic effects. Selective activation of the prostanoid EP 3 receptor reduces myocardial infarct size in rodents by a mechanism(s) that may involve the activation of protein kinase C and the opening of K ATP channels.

1 Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclooxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts bene®cial e ects in animal models of shock. 2 Here we compare the e ects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg 71 , i.p., n=7) and SC-58635 (3 mg kg 71 , i.p., n=9) with those of dexamethasone (3 mg kg 71 , i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg 71 , i.v., n=11) in the rat. 3 Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF 1a (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4 Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5 Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.

1 This study investigates the eects of two agonists of the prostanoid EP 3 -receptor (M&B 28767 and GR 63799X) on the infarct size caused by regional myocardial ischaemia and reperfusion in the anaesthetized rat. 2 One hundred and sixty-seven, male Wistar rats were anaesthetized (thiopentone, 120 mg kg 71 , i.p.), ventilated (8 ± 10 ml kg 71 , 70 strokes min 71, inspiratory oxygen concentration: 30%; PEEP: 1 ± 2 mmHg) and subjected to occlusion of the left anterior descending coronary artery (LAD, for 7.5, 15, 25, 35, 45 or 60 min) followed by reperfusion (2 h). Infarct size was determined by staining of viable myocardium with a tetrazolium stain (NBT), histological evaluation by light and electron microscopy and determination of the plasma levels of cardiac troponin T. 3 M&B 28767 (0.5 mg kg 71 min 71 , i.v., n=7) or GR 63799X (3 mg kg 71 min 71 , i.v., n=7) caused signi®cant reductions in infarct size from 60+3% (25 min ischaemia and 2 h reperfusion; salinecontrol, n=8) to 39+6 and 38+4% of the area at risk, without causing a signi®cant fall in blood pressure. Pretreatment of rats with 5-hydroxydecanoate (5-HD), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective eects of both EP 3 -receptor agonists. The reduction in infarct size aorded by M&B 28767 was also abolished by glibenclamide and the protein kinase C (PKC) inhibitors staurosporine and chelerythrine. 4 Thus, M&B 28767 and GR 63799X reduce myocardial infarct size in the rat by a mechanism(s) which involves the activation of PKC and the opening of ATP-sensitive potassium channels.

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