RÉSUMÉ
BACKGROUND: Prolonged postoperative decrease in lung function is common after major upper abdominal surgery. Evidence suggests that ventilation with low tidal volumes may limit the damage during mechanical ventilation. We compared postoperative lung function of patients undergoing upper abdominal surgery, mechanically ventilated with high or low tidal volumes. METHODS: This was a double-blind, prospective, randomized controlled clinical trial. One hundred and one patients (age ≥ 50 yr, ASA ≥ II, duration of surgery ≥ 3 h) were ventilated with: (i) high [12 ml kg(-1) predicted body weight (PBW)] or (ii) low (6 ml kg(-1) PBW) tidal volumes intraoperatively. The positive end-expiratory pressure was 5 cm H(2)O in both groups and breathing frequency adjusted to normocapnia. Time-weighted averages (TWAs) of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) until 120 h after operation were compared (P<0.025 considered statistically significant). Secondary outcomes were oxygenation, respiratory and non-respiratory complications, length of stay and mortality. RESULTS: The mean (sd) values of TWAs of FVC and FEV(1) were similar in both groups: FVC: 6 ml group 1.8 (0.7) litre vs 12 ml group 1.6 (0.5) litre (P=0.12); FEV(1): 6 ml group 1.4 (0.5) litre vs 12 ml group 1.2 (0.4) litre (P=0.15). FVC and FEV(1) at any single time point and secondary outcomes did not differ significantly between groups. CONCLUSIONS: Prolonged impaired lung function after major abdominal surgery is not ameliorated by low tidal volume ventilation.
Sujet(s)
Abdomen/chirurgie , Ventilation artificielle/méthodes , Volume courant/physiologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Méthode en double aveugle , Femelle , Volume expiratoire maximal par seconde/physiologie , Humains , Soins peropératoires/méthodes , Période peropératoire , Maladies pulmonaires/étiologie , Mâle , Adulte d'âge moyen , Oxygène/sang , Pression partielle , Complications postopératoires , Études prospectives , Spirométrie/méthodes , Capacité vitale/physiologieRÉSUMÉ
With recent advances in surgical and anaesthetic management, clinical medicine has responded to societal expectations and the number of operations in patients with a high-risk of perioperative liver failure has increased over the last decades. This review will outline important pathophysiological alterations common in patients with pre-existing liver impairment and thus highlight the anaesthetic challenge to minimise perioperative liver insults. It will focus on the intraoperative balancing act to reduce blood loss while maintaining adequate liver perfusion, the various anaesthetic agents used and their specific effects on hepatic function, perfusion and toxicity. Furthermore, it will discuss advances in pharmacological and ischaemic preconditioning and summarise the results of recent clinical trials.
Sujet(s)
Anesthésie de conduction , Anesthésiques par inhalation , Agents cardiovasculaires/pharmacologie , Soins peropératoires/méthodes , Maladies du foie/physiopathologie , Soins périopératoires/méthodes , Anesthésiques par inhalation/administration et posologie , Anesthésiques par inhalation/effets indésirables , Anesthésiques par inhalation/métabolisme , Agents cardiovasculaires/usage thérapeutique , Hémodynamique/effets des médicaments et des substances chimiques , Humains , Foie/vascularisation , Maladies du foie/complicationsRÉSUMÉ
For a long time the significance of perioperative accidental hypothermia was overlooked. The possible undesirable effects of a relatively small reduction in the body core temperature of 1.5-2.0 degrees C were generally unknown and the treatment options were limited. The unfavourable climatic conditions in the operation room favour heat loss and simultaneously, there is considerable disturbance of temperature regulation through general as well as spinal anaesthesia. In many studies it has now been shown that the resulting decrease in body temperature can have a negative effect on immune function, coagulation, the cardiovascular system and recovery behaviour. Heat loss in the perioperative phase should, therefore, be minimised by effective insulation. Nevertheless, a negative heat balance can often only be avoided by an additional heat treatment of the body surface which ideally should be initiated in the preoperative phase. If large volumes must be infused, an important additional measure is to prewarm these solutions. This is the only way in which the objective, to avoid a fall in body temperature to below 36 degrees C in the perioperative phase and the possible subsequent negative effects on the course of events, can be reached. The incidence of perioperative hypothermia is often underestimated so that in this phase a reduction in body core temperature of more than 2 degrees C will occur in more than 50% of patients if no special measures are undertaken. In addition, the undesirable effects of such a reduction in core temperature were barely known and even only a few years ago there were hardly any possibilities for reliable prevention or effective treatment. Therefore, in this article the causes of perioperative hypothermia will initially be described. In the second section the possible negative consequences of a reduction in body core temperature will be presented and in the last section the resulting consequences for the practice will be discussed.
Sujet(s)
Anesthésie , Hypothermie/physiopathologie , Anesthésie de conduction , Anesthésie générale , Température du corps/physiologie , Humains , Hypothermie/immunologie , Complications peropératoires/physiopathologie , RéchauffementRÉSUMÉ
Traumatic brain injury (TBI) occurs frequently and is associated with a poor prognosis. Severe TBI results in substantial disability or death in more than 40% of cases. The major aim of treatment of these patients is to minimize secondary brain injury and in this respect, the prevention of intracranial hypertension plays a key role. In addition to surgical approaches, various conservative treatment options exist, such as the use of osmodiuretics, barbiturates, or corticosteroids, hyperventilation as well as induced therapeutic hypothermia. This review analyzes these treatment options and the therapeutic goals of lowering intracranial pressure (ICP) in patients after TBI using evidence-based criteria, and provides recommendations for clinical practice.
Sujet(s)
Lésions encéphaliques/complications , Lésions encéphaliques/thérapie , Hypertension intracrânienne/étiologie , Hypertension intracrânienne/thérapie , Hormones corticosurrénaliennes/usage thérapeutique , Barbituriques/usage thérapeutique , Diurétiques/usage thérapeutique , Médecine factuelle , Humains , Hyperventilation , Hypothermie provoquée , Hypertension intracrânienne/complications , Mannitol/usage thérapeutiqueRÉSUMÉ
Accidental hypothermia is a frequent event during the perioperative period. Recent studies revealed a drop in core temperature of over 2 degrees C in more than 50% of all patients undergoing an operation. This drop in core temperature seems to be primarily due to the following factors. Anaesthesia prevents behavioural adaptations to changes in ambient temperature. Simultaneously, autonomic mechanisms of temperature control are suppressed by general as well as by neuraxial anaesthesia. The interthreshold range between core temperatures that trigger responses to warmth and to cold increases up to 20-fold. This is primarily due to a decrease in the cold response threshold. As a result, body core temperature of anaesthetized patients is primarily determined by the much lower temperature of the environment. On one hand, decreases in body temperatures may exert organ protective effects under certain conditions, e.g., by increasing ischemic tolerance. On the other hand, there is accumulating evidence that accidental perioperative hypothermia may also adversely affect organ function and outcome. For example, unfavourable effects of perioperative hypothermia on the immune defence, on the function of the coagulation system, on cardiovascular performance, as well as on postoperative recovery have been reported. Consequently, measures should be taken to actively control the perioperative heat balance of patients.
Sujet(s)
Hypothermie/étiologie , Complications peropératoires/étiologie , Complications postopératoires/étiologie , Système nerveux autonome/physiopathologie , Régulation de la température corporelle/physiologie , Humains , Hypothermie/complications , Hypothermie/physiopathologie , Complications peropératoires/physiopathologie , Complications postopératoires/physiopathologie , Facteurs de risqueRÉSUMÉ
OBJECTIVE: To investigate the role of redox-sensitive transcription factors nuclear factor kappa-B (NF-kappaB) or activator protein-1 (AP-1) for hepatic gene expression of heme oxygenase (HO)-1 and inducible nitric oxide synthase (iNOS) in models of hemorrhagic or endotoxic shock. DESIGN: Prospective controlled laboratory study. SETTING: Animal research laboratory at a university hospital. SUBJECTS: Male Sprague-Dawley rats (250-350 g). INTERVENTIONS: After anesthesia, animals were assigned to hemorrhagic shock (mean arterial pressure 35-40 mm Hg for 60 mins), sham operation, or endotoxemia (1 mg/kg intraperitoneally). To assess the role of reactive oxygen species for activation of NF-kappaB or AP-1, animals were treated with the antioxidant trolox (6 mg/kg body weight). In additional experiments, animals were pretreated with dexamethasone (10 mg/kg body weight), an inhibitor of the transactivating function of DNA-bound AP-1 or with actinomycin-D (2 mg/kg body weight), an inhibitor of DNA-directed RNA synthesis. Activation of NF-kappaB or AP-1 was assessed by electrophoretic mobility shift assay. HO-1 and iNOS gene expression were assessed by Northern and Western blot. MEASUREMENTS AND MAIN RESULTS: Hemorrhage and resuscitation induced hepatic HO-1 transcripts 12-fold. Induction was abolished by actinomycin-D and was attenuated by dexamethasone and the antioxidant trolox. Activation of AP-1 was observed after hemorrhagic but not after endotoxic shock. AP-1 activation was inhibitable by trolox and correlated with accumulation of HO-1 transcripts. In contrast, a weak activation of NF-kappaB was observed after hemorrhage that was not affected by trolox. A profound activation of NF-kappaB after endotoxic shock correlated with induction of iNOS but failed to induce HO-1 transcripts. CONCLUSIONS: These data suggest that AP-1 but not NF-kappaB activation is dependent on reactive oxygen intermediates in vivo and contributes to HO-1 gene expression. Thus, AP-1-dependent HO-1 induction under oxidative stress conditions may subserve a similar function as a stress-inducible vasodilator system as does NF-kappaB-dependent iNOS expression in liver inflammation.
Sujet(s)
Heme oxygenase (decyclizing)/métabolisme , Nitric oxide synthase/métabolisme , ARN/analyse , Espèces réactives de l'oxygène/métabolisme , Choc hémorragique/métabolisme , Choc septique/métabolisme , Animaux , Technique de Northern , Technique de Western , Modèles animaux de maladie humaine , Régulation de l'expression des gènes , Heme oxygenase (decyclizing)/génétique , Mâle , Nitric oxide synthase/génétique , Probabilité , Rats , Rat Sprague-Dawley , Valeurs de référence , Sensibilité et spécificité , Choc hémorragique/sang , Choc septique/sangRÉSUMÉ
To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ET(A) receptor agonist ET-1 and of the selective ET(B) receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 x 10(-9) M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 x 10(-9) M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ET(B) receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.
Sujet(s)
Endothéline-1/pharmacologie , Foie/effets des médicaments et des substances chimiques , Système porte/effets des médicaments et des substances chimiques , Choc hémorragique/physiopathologie , Vasoconstriction/effets des médicaments et des substances chimiques , Animaux , Modèles animaux de maladie humaine , Hémodynamique/effets des médicaments et des substances chimiques , Foie/vascularisation , Foie/physiopathologie , Mâle , Microcirculation/effets des médicaments et des substances chimiques , Consommation d'oxygène/effets des médicaments et des substances chimiques , Système porte/physiopathologie , Rats , Rat Sprague-Dawley , Récepteur de l'endothéline de type B , Récepteur endothéline/agonistes , Réanimation , Résistance vasculaire/effets des médicaments et des substances chimiques , Venins de vipère/pharmacologieRÉSUMÉ
Heme oxygenase (HO) plays a pivotal role for the maintenance of liver blood flow and hepatocellular integrity after hemorrhagic shock. We investigated the role of Kupffer cells and neutrophils as paracrine modulators of hepatocellular HO-1 gene expression in a rat model of hemorrhage and resuscitation. Male Sprague-Dawley rats (n = 6-10/group) were anesthetized (pentobarbital, 50 mg/kg intraperitonal) and subjected to hemorrhagic shock (mean arterial blood pressure: 35 mmHg for 60 min) or a sham protocol. Based on the time course of HO-1 gene expression, the effect of various antioxidants, Kupffer cell blockade [gadolinium chloride (GdCl3); 10 mg/kg; 24 h prior to hemorrhage or dichloromethylene diphosphonate (Cl2MDP); 1 mg/kg; 2 days prior to hemorrhage], or neutrophil depletion (vinblastine, 0.5 mg/kg, 5 days prior to hemorrhage) on induction of the HO-1 gene was assessed at 5 h of resuscitation, i.e., the time point of maximal induction. Kupffer cell blockade and antioxidants abolished HO-1 mRNA and protein induction after hemorrhage, while neutrophil depletion failed to affect hepatocellular HO-1 gene expression. In addition, Kupffer cell blockade aggravated hepatocellular injury. N-formyl-methionine-leucyl-phenylalanin (fMLP) induced a substantial influx of neutrophils into the liver but failed to induce hepatocellular HO-1 mRNA expression. These data suggest that Kupffer cells but not neutrophils induce an adaptive hepatocellular stress response after hemorrhage and resuscitation. Oxygen-free radicals released by Kupffer cells may serve as paracrine regulators of a hepatocellular stress gene which is necessary to maintain liver blood flow and integrity under stress conditions.
Sujet(s)
Régulation de l'expression des gènes codant pour des enzymes , Heme oxygenase (decyclizing)/génétique , Hépatocytes/enzymologie , Cellules de Küpffer/physiologie , Granulocytes neutrophiles/physiologie , Choc hémorragique/génétique , Choc hémorragique/physiopathologie , Acétylcystéine/pharmacologie , Animaux , Antioxydants/pharmacologie , Pression sanguine , Cellules cultivées , Chromanes/pharmacologie , Acide clodronique/pharmacologie , Déferoxamine/pharmacologie , Modèles animaux de maladie humaine , Gadolinium/pharmacologie , Régulation de l'expression des gènes codant pour des enzymes/effets des médicaments et des substances chimiques , Heme oxygenase-1 , Cellules de Küpffer/effets des médicaments et des substances chimiques , Mâle , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Rats , Rat Sprague-Dawley , Réanimation , Choc hémorragique/enzymologie , Facteurs temps , Vinblastine/pharmacologieRÉSUMÉ
Recent evidence suggests that the hepatic expression of heme oxygenase-1 (HO-1) may preserve hepatocellular integrity after hemorrhagic shock and resuscitation (HR). Because nitric oxide (NO) has been shown to modulate HO-1 expression in cultured cells in vitro, we determined its potential role in the regulation of HO-1 expression after HR in the rat liver in vivo. HO-1 mRNA and protein were highly induced and HO enzyme activity was higher after HR when compared with time-matched sham controls. Administration of the NO donor, molsidomine (MOL) (3 mg. kg(-1)), during resuscitation attenuated the accumulation of HO-1 mRNA and protein and the rise in HO activity. In addition, MOL prevented the shock-induced increase in DNA binding activity of the transcription factor, activator protein-1 (AP-1), but did not alter the activity of nuclear factor-erythroid 2 related factor (Nrf-2), nuclear transcription factor-kappaB (NF-kappaB), and hypoxia-inducible factor-1 (HIF-1). The suppressing action of MOL was not confined to HO-1, because the hepatic expression of the 70-kd major heat shock protein (HSP) in response to HR was also diminished. Moreover, MOL prevented the HR-induced increase in the serum activity of alanine transaminase (ALT) and alpha-glutathione-S-transferase (alpha-GST) that could otherwise be observed after HR. In contrast, the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg.kg(-1)), had either no or only minor effects on the primary experimental endpoints. These findings would be consistent with a reduction of shock-induced liver damage by exogenous NO, which in turn prevents the subsequent activation of injury-sensitive transcription factors, thus attenuating the expression of stress-inducible proteins such as HO-1.
Sujet(s)
Heme oxygenase (decyclizing)/métabolisme , Foie/métabolisme , Monoxyde d'azote/pharmacologie , Choc hémorragique/métabolisme , Animaux , Pression sanguine/effets des médicaments et des substances chimiques , Antienzymes/pharmacologie , Expression des gènes , Protéines du choc thermique HSP70/métabolisme , Heme oxygenase (decyclizing)/génétique , Heme oxygenase-1 , Hémodynamique , Foie/anatomopathologie , Mâle , Molsidomine/pharmacologie , L-NAME/pharmacologie , Donneur d'oxyde nitrique/pharmacologie , Rats , Rat Sprague-Dawley , Réanimation , Choc hémorragique/anatomopathologie , Choc hémorragique/physiopathologie , Facteurs de transcription/métabolismeRÉSUMÉ
OBJECTIVE: To investigate the role of the vasodilator systems heme oxygenase-1/heat shock protein 32 (HO-1/HSP32) and nitric oxide synthase-II (NOS-II), generating carbon monoxide and nitric oxide respectively, as modulators of liver injury in an experimental model of reversible hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-350 g. INTERVENTIONS: Animals were anesthetized and assigned to a hemorrhagic shock (mean arterial pressure, 35-40 mmHg for 60 mins) or a sham protocol. On the basis of the time course of gene expression, HO-1/HSP32 or NOS-II was blocked 5 hrs after onset of resuscitation. To assess the role of the antioxidative properties of the heme oxygenase (HO) pathway in additional experiments, Trolox, a potent antioxidant, was administered at the time of blockade of HO. Liver injury was assessed morphometrically and by plasma alpha-glutathione-S-transferase (alpha-GST) release 11 hours after onset of resuscitation. MEASUREMENTS AND MAIN RESULTS: Hemorrhage and resuscitation increased HO-1/HSP32 messenger RNA and protein primarily in parenchymal cells, and a faint induction of NOS-II, restricted to nonparenchymal cells, was observed. Inhibition of the HO pathway with tin protoporphyrin-IX (SnPP-IX) increased the incidence of pericentral necrosis (intact acini: shock/vehicle 68.8%; shock/SnPP-IX 42.6%) and alpha-GST levels (sham 94+/-24 microg/L; shock/vehicle 377+/-139 microg/L; shock/SnPP-IX 1708+/-833 microg/L), whereas blockade of NOS-II with S-methylisothiourea did not affect liver injury. Coadministration of Trolox failed to attenuate the aggravation of necrosis associated with blockade of HO, whereas alpha-GST levels were reduced (intact acini: shock/vehicle/Trolox 82.1%, shock/SnPP-IX/Trolox 42.7%; alpha-GST: shock/vehicle/Trolox 202+/-55 microg/L; shock/SnPP-IX/Trolox 236+/-61 microg/L). CONCLUSIONS: These data suggest that HO-1/HSP32, but not the alternative cyclic guanosine monophosphate-generating enzyme NOS-II, is induced after hemorrhage and resuscitation and protects against hepatocellular injury. Both metabolites generated by the heme oxygenase pathway, e.g., carbon monoxide (a vasodilator) and biliverdin (an antioxidant) seem to contribute to the salutary effects of induction of HO-1/HSP32.
Sujet(s)
Protéines du choc thermique/métabolisme , Heme oxygenase (decyclizing)/métabolisme , Foie/enzymologie , Nitric oxide synthase/métabolisme , Choc hémorragique/métabolisme , Analyse de variance , Animaux , Monoxyde de carbone/métabolisme , Régulation de l'expression des gènes codant pour des enzymes , Glutathione transferase/sang , Heme oxygenase (decyclizing)/génétique , Hémodynamique/effets des médicaments et des substances chimiques , Foie/anatomopathologie , Mâle , Monoxyde d'azote/biosynthèse , Nitric oxide synthase/génétique , Rats , Rat Sprague-Dawley , Réanimation , Choc hémorragique/thérapieRÉSUMÉ
Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 microM), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/beta-hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 microM) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions.
Sujet(s)
Monoxyde de carbone/pharmacologie , Ischémie/prévention et contrôle , Foie/vascularisation , Microcirculation/effets des médicaments et des substances chimiques , Choc hémorragique/complications , Animaux , Bile/métabolisme , Heme oxygenase (decyclizing)/antagonistes et inhibiteurs , Hémodynamique/effets des médicaments et des substances chimiques , Techniques in vitro , Ischémie/étiologie , Isothiouronium/analogues et dérivés , Isothiouronium/pharmacologie , Foie/effets des médicaments et des substances chimiques , Mâle , Métalloporphyrines/pharmacologie , Mitochondries/effets des médicaments et des substances chimiques , Monoxyde d'azote/métabolisme , Nitric oxide synthase/antagonistes et inhibiteurs , Nitric oxide synthase type II , Oxydoréduction , Perfusion , Protoporphyrines/pharmacologie , Rats , Rat Sprague-DawleyRÉSUMÉ
Nitric oxide (NO), a gaseous mediator that accounts for the biological activity of endothelium-derived relaxing factor, has been shown to play an important role in the reduction of basal vascular tone in multiple vascular beds, including the hepatic circulation. On the other hand, recent studies have provided first evidence that endogenously generated carbon monoxide (CO) may exert vasodilatory effects in the hepatic portal vein and within sinusoids. Thus, we defined the differential role of NO and CO in the regulation of vascular resistance in the two inflows to the liver in the normal rat in vivo. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium and surgically instrumented in order to study the change in hepatic arterial (Rha) and portal venous vascular resistance (Rpv) in response to intravenous bolus administration of either the NO-synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg/kg; n = 7 animals) or of tin protoporphyrin-IX (SnPP-IX) (50 micromol/kg), a specific inhibitor of the CO-generating enzyme heme oxygenase (n = 8 animals). While L-NAME caused a substantial increase in Rha, Rpv increased only slightly under these conditions. In sharp contrast, SnPP-IX did not affect Rha, but caused a profound increase in Rpv. In conclusion, Rha and Rpv are differentially regulated by NO and CO in the normal rat liver in vivo, i.e., NO serves as a potent vasodilator in the hepatic arterial circulation, but exerts only a minor vasodilatory effect in the portal venous vascular bed. In contrast, while there is no intrinsic CO-mediated vasodilation in the hepatic artery, CO acts to maintain portal venous vascular tone in a relaxed state.
Sujet(s)
Monoxyde de carbone/métabolisme , Artère hépatique/métabolisme , Monoxyde d'azote/physiologie , Veine porte/métabolisme , Résistance vasculaire/physiologie , Animaux , Antienzymes/pharmacologie , Heme oxygenase (decyclizing)/antagonistes et inhibiteurs , Hémodynamique/physiologie , Artère hépatique/effets des médicaments et des substances chimiques , Mâle , Métalloporphyrines/pharmacologie , Muscles lisses vasculaires/effets des médicaments et des substances chimiques , L-NAME/pharmacologie , Nitric oxide synthase/antagonistes et inhibiteurs , Veine porte/effets des médicaments et des substances chimiques , Protoporphyrines/pharmacologie , Rats , Rat Sprague-Dawley , Résistance vasculaire/effets des médicaments et des substances chimiques , Vasodilatation/effets des médicaments et des substances chimiquesRÉSUMÉ
We determined the functional role of nitric oxide (NO) and endothelins (ET), two potent vasoactive mediator systems in the liver, for the pathogenesis of sinusoidal perfusion failure and lethal hepatocyte injury after low-flow ischemia/reperfusion in the isolated perfused rat liver. NO synthase blockade with Nomega-nitro-L-arginine methyl ester (L-NAME) (10[-3] mol/L) before reperfusion prevented increased N02-/NO3- the final products of NO oxidation, which could be observed in the vehicle group. Epifluorescence microscopy revealed that the decrease in functional sinusoid density during reperfusion was much more profound compared with vehicle. This was associated with a lower surface PO2, a substantially higher number of nonviable hepatocytes, as assessed by in situ propidium iodide staining, and enhanced enzyme release into the perfusate compared with vehicle. In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle. This indicates that hepatic generation of NO attenuates sinusoidal perfusion failure and improves liver tissue oxygenation, thus limiting hepatocyte injury during early reperfusion after hepatic low-flow ischemia. In contrast, endothelins counteract the microcirculatory effects of NO, i.e., mediate the no-reflow in hepatic sinusoids; however, the restoration of functional sinusoid density with bosentan resulted only in a small reduction in tissue damage, suggesting that additional components, which are independent of microcirculatory failure, contribute to hepatic reperfusion injury under these conditions.
Sujet(s)
Endothélines/physiologie , Foie/vascularisation , Monoxyde d'azote/physiologie , Lésion d'ischémie-reperfusion/étiologie , Animaux , Bosentan , Corps cétoniques/métabolisme , Mâle , L-NAME/pharmacologie , Rats , Rat Sprague-Dawley , Sulfonamides/pharmacologieRÉSUMÉ
Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P < .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells.
Sujet(s)
Heme oxygenase (decyclizing)/métabolisme , Isoenzymes/métabolisme , Foie/enzymologie , Animaux , Cobalt/pharmacologie , Régulation de l'expression des gènes codant pour des enzymes , Heme oxygenase (decyclizing)/génétique , Isoenzymes/génétique , Lipopolysaccharides/pharmacologie , Foie/effets des médicaments et des substances chimiques , Mâle , ARN messager/analyse , Rats , Rat Sprague-DawleyRÉSUMÉ
Although there is substantial evidence suggesting that the integrity of the microcirculation is an important determinant of tissue viability during reperfusion after ischemia in the liver, as well as other tissues, the mechanisms responsible for microvascular failure are not fully understood. It is now recognized that the microvascular response to reperfusion, similar to the whole organism response to shock, can consist of either a rapid exacerbation of injury after a severe ischemic episode or, alternatively, a more slowly developing alteration in responsiveness that occurs after a less severe insult. In the more slowly developing response, the alterations in vascular status are the result of up-regulation of stress-induced vascular mediators such as endothelin, nitric oxide synthase (NOS), and heme oxygenase, as well as changes in the reactivity of the effector cells to the mediators. The mechanisms for change in reactivity of vascular cells range from changes in receptor expression to overt phenotypic transformation, as can occur in the hepatic stellate cells in response to repeated injury. When maintained in balance, these counteracting constrictor and dilator influences can be protective; however, local imbalance can result in focal ischemia, thus propagating the injury. Thus, the remodeling of the hepatic microvascular responsiveness during reperfusion after ischemia may serve as a useful paradigm for consideration of the overall response of the organism to shock.
Sujet(s)
Foie/vascularisation , Microcirculation , Lésion d'ischémie-reperfusion/physiopathologie , Animaux , HumainsRÉSUMÉ
We determined the role of nitric oxide (NO) and endothelins (ETs) in the regulation of hepatic blood flow during resuscitation from hemorrhagic shock (HS) in anesthetized rats. Volume resuscitation restored systemic hemodynamics and increased hepatic arterial and portal venous flow above baseline in the vehicle group. Presence of N omega-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) during resuscitation increased systemic vascular resistance (SVR) above baseline, prevented the restoration of hepatic arterial flow, and abolished portal hyperemia. Although the ETA+B-receptor antagonist bosentan (10 mg/kg) did not alter the systemic hemodynamic response, it abolished the hepatic arterial and portal hyperemia. The ETA-receptor antagonist BQ-610 (150 micrograms/kg) reduced SVR below baseline, allowed hepatic arterial hyperemia to occur, and further enhanced the portal venous hyperemia. This indicates that 1) NO reduces SVR and acts to preserve hepatic blood flow during resuscitation from HS; 2) ETA-receptor-mediated vasoconstriction counteracts the systemic and portal hemodynamic effects of NO; and 3) simultaneous ETB-receptor stimulation enhances blood flow to the liver and may serve to modulate the ETA-receptor-mediated vasoconstrictive effects of ETs.
Sujet(s)
Endothélines/physiologie , Circulation hépatique , Monoxyde d'azote/physiologie , Réanimation , Choc hémorragique/physiopathologie , Animaux , Bosentan , Endothélines/sang , Hémodynamique , Mâle , Nitrates/sang , Nitrites/sang , Oligopeptides/pharmacologie , Rats , Rat Sprague-Dawley , Sulfonamides/pharmacologieRÉSUMÉ
Heme oxygenase (HO)-derived carbon monoxide (CO) may contribute to vascular control through elevation of guanosine 3',5'-cyclic monophosphate. In the present study, we investigated the functional significance of expression of the isoenzyme HO-1 (heat-shock protein 32) in liver after hemorrhage/resuscitation (H/R) in rats anesthetized with pentobarbital sodium. An increase of mRNA levels for HO-1 was observed at 3 h after resuscitation, followed by induction of the protein at 6 h in pericentral hepatocytes and sinusoidal lining cells. Concomitantly, lower portal resistance was observed in H/R (0.33 +/- 0.060 mmHg.ml-1.min) compared with control rats (0.47 +/- 0.035 mmHg.ml-1.min). Blockade of the HO-CO pathway by tin protoporphyrin-IX (SnPP-IX) led to a transient increase in portal pressure with no effect on portal low in controls, whereas an increase in pressure and a decrease in flow contributed to the sustained increase in portal resistance after H/R. These results indicate that HO contributes to maintenance of hepatic perfusion in vivo under stressful conditions, suggesting a functional link between stress response and vascular control in portal circulation.
Sujet(s)
Heme oxygenase (decyclizing)/biosynthèse , Foie/enzymologie , Système porte , Choc hémorragique/physiopathologie , Transcription génétique , Animaux , Pression sanguine , Induction enzymatique , Isoenzymes/biosynthèse , Cinétique , Foie/physiopathologie , Mâle , Système porte/effets des médicaments et des substances chimiques , ARN messager/biosynthèse , Rats , Rat Sprague-Dawley , Valeurs de référence , Réanimation , Choc hémorragique/enzymologie , Facteurs temps , Résistance vasculaireRÉSUMÉ
To test whether endothelins are involved in the regulation of portal resistance after endotoxin pretreatment and whether their effects are modulated by nitric oxide (NO), rats received intraperitoneal injections of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt) or saline. Six and twenty-four hours later, livers were isolated and perfused. Analyses of portal pressure-flow (P-Q) relationships and epifluorescence microscopy were performed before and after administration of 1) the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-3) M), followed by L-arginine (2 x 10(-3) M), or 2) the endothelin ETA/ETB-receptor antagonist bosentan (2 x 10(-4) M), followed by L-NAME (10(-3) M). LPS pretreatment increased all measures of resistance, which included total portal resistance, zero flow, incremental resistance (slopes of P-Q relationship), and sinusoid resistance. L-NAME had no effect in sham controls but increased all measures of resistance at 6 h after LPS and increased total and incremental resistance 24 h after LPS. L-Arginine reversed these changes. Bosentan reduced total and sinusoid resistance slightly in control livers and caused substantial reductions in all measures of resistance at 6 and 24 h after LPS; these were partially reversed after L-NAME at 6 but not at 24 h. Our data support the hypothesis that a critical balance between endothelin-mediated vasoconstrictor influences and NO-mediated vasodilator influences controls portal resistance after endotoxin pretreatment.
Sujet(s)
Endothélines/physiologie , Endotoxines/pharmacologie , Monoxyde d'azote/physiologie , Système porte/effets des médicaments et des substances chimiques , Système porte/physiologie , Résistance vasculaire/physiologie , Animaux , Arginine/pharmacologie , Pression sanguine/effets des médicaments et des substances chimiques , Bosentan , Antienzymes/pharmacologie , Hémodynamique/effets des médicaments et des substances chimiques , Lipopolysaccharides/pharmacologie , Mâle , L-NAME/pharmacologie , Veine porte/effets des médicaments et des substances chimiques , Veine porte/physiologie , Rats , Rat Sprague-Dawley , Débit sanguin régional/effets des médicaments et des substances chimiques , Sulfonamides/pharmacologie , Facteurs tempsRÉSUMÉ
OBJECTIVE: Study on simultaneous O2 supply/uptake relationships in liver and gut during endotoxaemia, to determine whether signs of dysoxia develop uniformly in the splanchnic region. DESIGN: Animal study to assess the early effects of endotoxaemia on oxygenation of both liver and small intestine. INTERVENTIONS: Eight anaesthetized pigs received a continuous portal venous infusion of lipopolysaccharide (0.5 microgram.kg-1.h-1) for 6 h. Systemic, pulmonary and splanchnic haemodynamics as well as systemic and splanchnic O2 supply/uptake relationships were determined. RESULTS: There was a multiphasic haemodynamic response pattern characterized by an early (within the 1st h) and a subsequent more prolonged phase (between the 2nd and 6th h) of decreases and recovery of hepatic arterial, portal venous and superior mesenteric arterial blood flows (electromagnetic flow probes) and splanchnic O2 deliveries. Unrelated to perfusion pressure and O2 delivery, there were early and sustained decreases in ileal mucosal surface partial pressure of oxygen (PO2) (multiwire PO2 electrode) and pH (tonometry). This was not reflected by ileal serosal surface PO2, O2 uptake and arteriomesenteric venous pH and partial pressure of carbon dioxide (PCO2) gradients. There was little evidence of concomitant hepatic dysoxia as evaluated by surface PO2. CONCLUSIONS: The study demonstrates early and sustained regional (mucosa) intestinal hypoxia with little evidence of simultaneous hepatic dysoxia during initial endotoxaemia.