Effects of intrarenal administration of the cox-2 inhibitor parecoxib during porcine suprarenal aortic cross-clamping.

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.

HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism.

OBJECTIVE: To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled study with repeated measures. SETTING. Animal laboratory. SUBJECTS: Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h(-1), n=8). INTERVENTIONS: Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h. RESULTS: HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O(2) delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state. CONCLUSION: The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.

Systemic, pulmonary, and hepatosplanchnic effects of N-acetylcysteine during long-term porcine endotoxemia.

OBJECTIVE: Controversial data have been reported on the effects of N-acetylcysteine in patients with septic shock. We therefore investigated the systemic, pulmonary, and hepatosplanchnic hemodynamic, gas exchange, and metabolic effects of N-acetylcysteine during long-term, volume-resuscitated, hyperdynamic porcine endotoxemia, which mimics the features of hyperdynamic human sepsis. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Investigational animal laboratory. SUBJECTS: Eighteen pigs were randomized to receive endotoxin alone (controls, n = 9) or endotoxin plus N-acetylcysteine (n = 9). INTERVENTIONS: Anesthetized, mechanically ventilated, and instrumented animals received continuous intravenous endotoxin and were resuscitated with hydroxyethylstarch to keep mean arterial pressure >60 mm Hg. After 12 hrs of endotoxemia, they were randomized to receive either placebo or N-acetylcysteine (150 mg/kg loading dose over 1 hr followed by 20 mg.kg-1.hr-1 for 11 hrs). MEASUREMENTS AND MAIN RESULTS: Before as well as 12, 18, and 24 hrs after starting the endotoxin infusion, systemic, pulmonary, and hepatosplanchnic hemodynamics, oxygen exchange, and metabolism as well as nitric oxide, glutathione, and 8-isoprostane concentrations were assessed. N-acetylcysteine failed to improve any of the variables of the systemic, pulmonary, or hepatosplanchnic hemodynamics, gas exchange, and metabolism. Although N-acetylcysteine significantly elevated glutathione concentration, it did not influence the 8-isoprostane concentrations and even further reduced hepatic venous pH. CONCLUSIONS: Despite the increased glutathione concentration, N-acetylcysteine did not improve systemic, pulmonary, and hepatosplanchnic hemodynamics, oxygen exchange, and metabolism. When compared with previous reports in the literature, a different timing of N-acetylcysteine administration and/or an ongoing or even N-acetylcysteine-induced aggravation of oxidative stress may account for this result.

Tin-mesoporphyrin for inhibition of heme oxygenase during long-term hyperdynamic porcine endotoxemia.

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.

Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia.

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.