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1 In this investigation the NO production rate is quanti®ed in the pig during normotensive endotoxininduced shock with increased cardiac output and during subsequent treatment with the NO synthase inhibitor N o -monomethy-L-arginine (L-NMMA). NO production rate was derived from the plasma isotope-enrichment of 15 N-labelled nitrate ( 15 NO 3 7 ). 2 Three groups of animals (control, n=5; endotoxin, n=6; endotoxin+L-NMMA, n=6) were anaesthetized and instrumented for the measurement of systemic and pulmonary haemodynamics. Each animal received a primed-continuous infusion of stable, non-radioactively labelled Na 15 NO 3 (bolus 30 mg, infusion rate 2.1 mg h 71 ). Arterial blood samples were taken 5, 10, 15, 30, 60 and 90 min later and every 90 minutes until the end of the experiment. 3 Continuous i.v. infusion of endotoxin was incrementally adjusted until mean pulmonary artery pressure (PAP) reached 50 mmHg and subsequently titrated to keep mean PAP &35 mmHg. Hydroxyethylstarch was administered as required to maintain mean arterial pressure (MAP)460 mmHg. Six hours after the start of the endotoxin continuous i.v. L-NMMA (1 mg kg 71 h 71 ) was administered to the endotoxin+L-NMMA group. Haemodynamic data were measured before as well as 9 h after the start of the endotoxin. 4 After conversion of NO 3 7 to nitro-trimethoxybenzene and gas chromatography-mass spectrometry analysis the total NO 3 7 pool, basal NO 3 7 production rate and the increase per unit time in NO 3 7 production rate were calculated from the time-course of the 15 NO 3 7 plasma isotope-enrichment. A two compartment model was assumed for the NO 3 7 kinetics, one being an active pool in which newly generated NO 3 7 appears and from which it is eliminated, the other being an inactive volume of distribution in which only passive exchange takes place with the active compartment. 5 Although MAP did not change during endotoxin infusion alone, cardiac output (CO) increased by 42+40% (P50.05 versus baseline) by the end of the experiment due to a signi®cant (P50.05 versus baseline) fall in systemic vascular resistance (SVR) to 65+25% of the baseline value. L-NMMA given with endotoxin did not change MAP, and both CO and SVR were maintained close to the pre-shock levels. 6 Baseline plasma NO 3 7 concentrations were 43+13 and 40+10 mmol l 71 in the control and endotoxin animals, respectively, and did not di er at the end of the experiment (39+8 and 44+15 mmol l 71 , respectively). The mean NO 3 7 pool and basal NO 3 7 production rate were 1155+294 mmol and 140+32 mmol h 71 , respectively, without any intergroup di erence. Endotoxin signi®cantly increased NO 3 7 production rate (23+10 mmol h 72 , P50.05 versus control (6+7 mmol h 72 ) and endotoxin+L-NMMA groups). L-NMMA given with endotoxin (71+2 mmol h 72 , P50.05 versus control and endotoxin groups) had no e ect. 7 Analysis of the time course of the 15 NO 3 7 plasma isotope enrichment during primed-continuous infusion of Na 15 NO 3 allowed us to quantify the endotoxin-induced increase in NO 3 7 production rate i...

The aim of this study was to investigate the effects of intrarenal administration of the cyclooxygenase-2 inhibitor parecoxib during suprarenal aortic cross-clamping. In a prospective, controlled, blinded, randomized manner, 16 anesthetized and mechanically ventilated pigs were instrumented to measure systemic and right kidney hemodynamics, oxygen exchange, and metabolism. During 45 min of suprarenal aortic cross-clamping, animals received 40 mg of parecoxib (n = 8) or vehicle (n = 8) infused continuously into the right renal artery. Hemodynamic and metabolic data, right kidney venous blood, as well as urine samples were obtained before clamping, as well as before and 75 and 195 min after declamping. Clamping transiently increased mean arterial pressure in both groups. Systemic and renal blood flow did not differ between the pre- and postclamping measurements or between groups. Parecoxib attenuated the otherwise significant fall in right kidney creatinine clearance (controls: from 45 [7;111] to 17 [9;22] mL/min; parecoxib: from 39 [3;59] to 27 [11;45] mL/min, P = 0.039 and P = 0.297, respectively versus before clamping, P = 0.021 versus controls at 195 min) and prevented the impairment of renal lactate balance observed in the control group (controls: from 0.5 [-0.8;3.5] to 0.2 [-0.2;0.6] mumol/kg/min; parecoxib: from 0.6 [-1.0;2.0] to 0.4 [-1.2;0.6] mumol/kg/min, P = 0.038 and P = 0.285, respectively, versus before clamping). In conclusion, intrarenal parecoxib infusion beneficially influenced kidney function in this clinically relevant model of suprarenal aortic cross-clamping.

Activation of the poly(ADP-ribose)polymerase (PARP), a highly energy-consuming DNA-repairing enzyme, plays a crucial role in the pathogenesis of multiorgan failure. Most results, however, were derived from experiments with hypodynamic shock states characterized by a markedly decreased cardiac output (CO) and/or using a pretreatment approach. Therefore, we investigated the effects of the novel potent and selective PARP-1 inhibitor PJ34 in a posttreatment model of long-term, volume-resuscitated porcine endotoxemia. Anesthetized, mechanically ventilated and instrumented pigs received continuous intravenous (i.v.) lipopolysaccharide (LPS) over 24 h. Hydroxyethyl starch was administered to maintain a mean arterial pressure > 65 mmHg. After 12 h of LPS infusion, the animals were randomized to receive either vehicle (Control, n = 9) or i.v. PJ34 (n = 6; 10 mg/kg over 1 h followed by 2 mg/kg/h until the end of the experiment). Measurements were performed before as well as at 12, 18, and 24 h of LPS infusion. In all animals CO increased because of reduced systemic vascular resistance (SVR) and fluid resuscitation. PJ34 further raised CO (P < 0.05 vs. control group) as the result of a higher stroke volume indicating its positive inotropic effect. In addition, it diminished the rise in the ileal mucosal-arterial PCO2 gap, which returned to baseline levels at 24 h of LPS, and improved the gut lactate balance (P = 0.093 PJ34 vs. control) together with significantly lower portal venous lactate/pyruvate ratios. By contrast, it failed to influence the LPS-induced derangements of liver metabolism. Incomplete PARP inhibition because of dilutional effects and/or an only partial efficacy when used in post-treatment approaches may account for this finding.

The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.

Heme oxygenase (HO) has both deleterious and protective effects in various shock models. Most of these data have been derived from experiments with hypodynamic shock states associated with depressed cardiac output. Therefore we studied the role of HO during long-term porcine hyperdynamic endotoxemia characterized by a sustained increase in cardiac output resulting from colloid resuscitation to maintain mean arterial pressure > 60 mmHg. Systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of the HO-inhibitor tin-mesoporphyrin (SnMP) were assessed in anesthetized and mechanically ventilated animals. After 12 h of continuous intravenous lipopolysaccharide (LPS), animals received either vehicle (n = 6) or SnMP (n = 8; 6 micromol kg(-1) i.v. over 30 min at 12 and 18 h of LPS). Measurements were performed before LPS, before SnMP infusion, and at 24 h of LPS. SnMP did not influence systemic hemodynamics but significantly increased mean pulmonary artery pressure. Although liver blood flow was not affected, SnMP markedly impaired liver lactate clearance. HO inhibition was associated with increased plasma nitrate levels likely the result of increased NO production. Our results suggest a protective role of HO activation during hyperdynamic porcine endotoxemia possibly as a result of an interaction with the LPS-induced increase in NO formation.

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