Suprarenal aortic cross clamping (SRACC) and reperfusion may cause acute pulmonary hypertension and multiple organ failure.

The organic mononitrites of 1,2-propanediol (PDNO), an nitric oxide donor with a very short half-life, are a more efficient pulmonary vasodilator and attenuator of end-organ damage and inflammation without significant side effects compared with nitroglycerin and inorganic nitrite in a porcine SRACC model.

Anesthetized and instrumented domestic pigs were randomized to either of four IV infusions until the end of the experiment (n = 10 per group): saline (control), PDNO (45 nmol kg min), nitroglycerin (44 nmol kg min), or inorganic nitrite (a dose corresponding to PDNO). Thereafter, all animals were subjected to 90 min of SRACC and 10 h of reperfusion and protocolized resuscitation. Hemodynamic and respiratory variables as well as blood samples were collected and analysed.

During reperfusion, mean pulmonary arterial pressure and pulmonary vascular resistance were significantly lower, and stroke volume was significantly higher in the PDNO group compared with the control, nitroglycerin, and inorganic nitrite groups. In parallel, mean arterial pressure, arterial oxygenation, and fraction of methaemoglobin were similar in all groups. The serum concentration of creatinine and tumor necrosis factor alpha were lower in the PDNO group compared with the control group during reperfusion.

PDNO was an effective pulmonary vasodilator and appeared superior to nitroglycerin and inorganic nitrite, without causing significant systemic hypotension, impaired arterial oxygenation, or methaemoglobin formation in an animal model of SRACC and reperfusion. Also, PDNO may have kidney-protective effects and anti-inflammatory properties.

To examine the biochemical and histopathological effects of ischemia/reperfusion (I/R) injury in a ruptured abdominal aortic aneurysm (RAAA) model in rats, and to investigate the potential protective role of resveratrol.

Thirty-two male Sprague-Dawley rats were randomly assigned into four groups-control, I/R, sham (I/R + solvent/dimethyl sulfoxide), and I/R + resveratrol. The control group underwent midline laparotomy only. In the other groups, infrarenal vascular clamps were attached following 60-min shock to the abdominal aorta. Ischemia was applied for 60 min followed by reperfusion for 120 min. In the I/R + resveratrol group, intraperitoneal 10 mg/kg resveratrol was administered 15 min prior to ischemia and immediately before reperfusion. The I/R + dimethyl sulfoxide group received dimethyl sulfoxide, and the I/R group was given saline solution. All animals were sacrificed by exsanguination from the carotid artery at the end of the experiment. In addition to histopathological examination of the rat kidney tissues, malondialdehyde, glutathione, catalase, and nitric oxide levels were also investigated.

A decrease in glutathione, catalase and nitric oxide levels, together with increases in malondialdehyde levels, numbers of apoptotic renal tubular cells, caspase-3 levels, and tubular necrosis scores, were observed in the IR and I/R + dimethyl sulfoxide groups. In contrast, resveratrol increased glutathione, catalase and nitric oxide levels in renal tissues exposed to I/R, while reducing malondialdehyde levels, apoptotic renal tubular cell numbers, caspase-3 levels, and tubular necrosis scores.

Our findings suggest that resveratrol can be effective against I/R-related acute kidney damage developing during RAAA surgery by reducing oxidative stress and apoptosis.

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.

As the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved.

We used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol-stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis.

Pre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-α, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects.

Exogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite-induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase.

Acute kidney injury (AKI) can occur after aortic clamping due to microvascular dysfunction leading to renal hypoxia. In this rat study, we have tested the hypothesis that the administration of the precursor of the nitric oxide synthase essential cofactor tetrahydrobiopterin (BH4) could restore renal oxygenation after ischemia reperfusion (I/R) and prevent AKI. We randomly distributed rats into 4 groups: sham group; ischemia-reperfusion group; I/R + sepiapterin, the precursor of BH4; and I/R + sepiapterin + methotrexate, an inhibitor of the pathway generating BH4 from sepiapterin. Cortical and outer medullary microvascular oxygen pressure, renal oxygen delivery, renal oxygen consumption were measured using dual-wavelength oxygen-dependent quenching phosphorescence techniques during ischemia and throughout 3 hours of reperfusion. Kidney injury was assessed using myeloperoxidase staining for leukocyte infiltration and urine neutrophil gelatinase-associated lipocalin levels. Ischemia reperfusion induced a drop in microvascular PO2 (P < 0.01 vs. Sham, both), which was prevented by the infusion of sepiapterin. Sepiapterin partially prevented the rise in renal oxygen extraction (P < 0.001 vs. I/R). Finally, treatment with sepiapterin prevented renal infiltration by inflammatory cells and decreased urine neutrophil gelatinase-associated lipocalin levels indicating a decrease of renal injury. These effects were blunted when adding methotrexate, except for myeloperoxidase. In conclusion, the administration of sepiapterin can prevent renal hypoxia and AKI after suprarenal aortic clamping in rats.

Renal ischemia/reperfusion (I/R) is characterized by severe inflammatory damage. We assessed the effect of administrating recently developed nitrosothiol compounds acting as nitric oxide (NO) donors on the production of cytokines and other markers of acute inflammatory reaction in an experimental model of warm (I/R), and in a model of cold ischemia and transplant in rats. Warm ischemia was achieved by ligation of left renal pedicle for 60 min, followed by contralateral nephrectomy. NO-donors LA-803, LA-807, LA-810 were administered i.v. (1.8 micromol/kg) during 30 min before reperfusion. Cold ischemia was achieved by preservating the kidney for 24 h in Euro Collins and grafting it in consanguineous Fisher 344/Ico rats. LA-803 was administered in the preservation fluid and in the recipient rat. Reperfusion time was 4 h in warm ischemia and 3 h in cold ischemia + transplantation. Administration of LA-803, LA-807 and, in a lower proportion, LA-810 prevented from the enhanced production of tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), and interleukin-1beta (IL-1beta), the decrease in interleukin-6 (IL-6) and interleukin-10 (IL-10), the increase in tissue level of superoxide anion (SOA) and superoxide dismutase (SOD), and the increase in neutrophil infiltration induced by warm I/R. Treatment with LA-803 in animals with renal transplantation after cold ischemia was also associated with reduced plasma levels of TNF, IFN-gamma, and IL-1beta, increased plasma levels of IL-6 and IL-10, reduced renal levels of SOA and SOD, and reduced neutrophil infiltration. These data demonstrate that systemic administration of new NO-donors with nitrosothiol structure diminished inflammatory responses in a kidney subjected to warm I/R or cold ischemia and transplantation.

Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H(2)S) together make up a family of biologically active gases (the so-called 'gaseous triumvirate') with an increasingly well defined range of physiological effects plus roles to play in a number of disease states. Over the years, most researchers have concentrated their attention on understanding the part played by a single gas in one or more body systems. It is becoming more clear that all three gases are synthesised naturally in the body, often by the same cells within the same organs, and that all three gases exert essentially similar biological effects albeit via different mechanisms. Within the cardiovascular system, for example, all are vasodilators, promote angiogenesis and vascular remodelling and are protective towards tissue damage in for example, ischaemia-reperfusion injury in the heart. Similarly, all exhibit complex effects in inflammation with both pro- and anti-inflammatory effects recognised. It seems likely that cell function is controlled not by the activity of single gases working in isolation but by the concerted activity of all three of these gases working together.

The aim of this study was to design an aggressive nonlethal animal model that would simulate surgical treatment of the abdominal aorta with a view to studying the systemic inflammatory response. Fourteen pigs were subjected to two sequential experiments. Experiment A was performed to determine the response to two degrees of hemorrhage: (A1) 40% bleeding; and (A2) 60% bleeding over 15 minutes followed by midline laparotomy and aortic dissection. Experiment B included two methods of aortic repair: (B1) aortic resection and replacement with a prosthesis; and (B2) aortic bypass without aortic resection. In the latter two groups, suprarenal aortic cross-clamping was placed for 30 minutes after a 40% hemorrhage. We analyzed various inflammatory markers and mortality. The 40% bleeding (vs. 60%) elicited a smaller decrease in mean arterial pressure (110 +/- 6 vs. 89 +/- 9 mmHg) but did not cause irreversible shock or mortality. After the 40% hemorrhage, the B1 aortic repair caused two cases of paraplegia. We have developed a model to study the combined effect of bleeding and aortic cross-clamping.

Ischemia-reperfusion injury is a serious clinical situation which can cause serious morbidity and mortality. An experimental renal ischemia-reperfusion injury model was designed to evaluate the role of glyceryl trinitrate (GTN) on renal function and histology.

50 Wistar albino rats were used in our study. Five groups were formed: (1) sham-control group; (2) acute renal ischemia (ARI) group with placebo (0.9% NaCl) infusion; (3) GTN infusion with a 75 microg/kg/min dose prior to ARI was administered; (4) GTN infusion with a 150 microg/kg/min dose prior to ARI was given, and finally (5) 150 microg/kg/min GTN infusion after the ARI period was applied. Serum BUN and creatinine levels were measured for evaluation of renal function. T(max-sec), glomerular filtration rate (GFR), and T(max-min) results following a (99m)Tc-DTPA diuretic renal scintigraphy were used. Histological examination was performed on nephrectomy specimens.

Groups 2 and 5 showed higher BUN, creatinine, and lower GFR values than the other groups (p = 0.0001). There was no difference in BUN, creatinine, and GFR levels between groups 2 and 5 (p = 0.971, p = 0.739, p = 0.393). Also the T(max-sec) values were higher in groups 2 and 5 compared with the other groups (p = 0.0001). The presence of tubular necrosis was different between groups and was higher in groups 2 and 5 (p = 0.002).

The application of GTN, a nitric oxide donor, has caused significant improvement in renal function when applied prior to an experimentally designed renal ischemia-reperfusion model. But administration of GTN had no effect after occurrence of ischemia.

Several experimental studies have shown the beneficial effects of nitric oxide (NO) in the modulation of the systemic inflammatory response syndrome (SIRS). Nitric oxide is involved in and affects almost all stages in the development of inflammation. We have attempted to ascertain whether the nitric oxide donor molsidomine prevents aortic graft contamination through control of the SIRS and a decrease in bacterial translocation (BT).

Twenty-four mini-pigs were divided into 4 groups. The animals were subjected to suprarenal aortic/iliac cross-clamping (for 30 minutes) and by-pass with a Dacron-collagen prosthetic graft impregnated in rifampicin. Groups: 1) sham (aortic dissection alone); 2) cross-clamping and bypass; 3) hemorrhage of 40% of total blood volume before cross-clamping and by-pass; and 4) the same as in group 3 but also including the administration of the NO donor molsidomine (4 mg/kg) 5 minutes before cross-clamping.

1) bacteriology of mesenteric lymph nodes (MLN), kidney, blood, and prosthesis; 2) serum TNF-alpha (ELISA); and 3) iNOS expression in kidney and liver (Western blot).

Aortic cross-clamping with or without hemorrhage was associated with BT in 80% and 100% of the animals, respectively. About 86% of the bacteria isolated in the graft were also present in MLN. This contamination coincided with an increase in TNF-alpha and with a greater expression of iNOS. Molsidomine administration decreased TNF-alpha and iNOS, decreased BT (from 100% to 20% of the animals), and decreased graft contamination (from 83% to 20%).

The present model induces high levels of BT and SIRS, both acted as sources of contamination for the implanted Dacron graft. Molsidomine administration decreased the presence of bacteria in the graft by controlling BT and modulating SIRS.

To investigate the hemodynamic and metabolic effects of the peroxisome proliferator-activated receptor (PPAR)-gamma ligand and nuclear-factor (NF)-kappa B inhibitor 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2) during long-term, hyperdynamic porcine endotoxemia.

Prospective, randomized, controlled experimental study with repeated measures.

Investigational animal laboratory.

19 anesthetized, mechanically ventilated and instrumented pigs.

At 12 h of continuous intravenous endotoxin and hydroxyethylstarch to keep mean arterial pressure (MAP)>60 mmHg, swine randomly received vehicle (control group, n=10) or 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2 group, n=9; 1 microg kg(-1) min(-1) loading dose during 1 h; thereafter,0.25 microg kg(-1) min(-1) for 11 h).

Hemodynamic, metabolic and organ function parameters were assessed together with parameters of nitric oxide production and oxidative stress. 15d-PGJ2 prevented the endotoxin-induced progressive hypotension, due to a positive inotropic effect, which resulted in a significantly higher blood pressure during the treatment phase and prevented the rise in hepatic vein alanine-aminotransferase activity. It did not affect, however, any other parameter of organ function nor of nitric oxide production, proinflammatory cytokine release or lipid peroxidation (8-isoprostane).

15d-PGJ2 stabilized systemic hemodynamics, due to improved myocardial performance, and resulted in an only transient effect on alanine-aminotransferase activity, without further beneficial effect on endotoxin-induced metabolic and organ function derangements. Low tissue 15d-PGJ2 concentrations and/or the delayed drug administration may explain these findings.