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PubMed2001

IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness.

Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.

Animals↗
PubMed2003

Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways.

We have previously demonstrated that administration of the recently described cytokine IL-17 in rat airways in vivo recruits and activates neutrophils locally. In the current study, we examined whether endogenous IL-17 is involved in mediating neutrophil recruitment caused by endotoxin exposure in mouse airways. Our in vivo data show that local endotoxin exposure causes the release of free, soluble IL-17 protein 6 h later. Systemic pretreatment with a neutralizing anti-IL-17 Ab almost completely inhibits neutrophil recruitment 24 h, but not 6 h, after endotoxin exposure in the airways. Pretreatment with neutralizing anti-IL-6 and anti-macrophage inflammatory protein (MIP)-2 Abs inhibits neutrophil recruitment caused by local endotoxin exposure and IL-17, respectively. Our in vitro data show that endotoxin exposure stimulates the release of soluble IL-17 protein in T lymphocytes harvested from lung and spleen, respectively, and that this cytokine release requires coculture with airway macrophages. Intracellular IL-17 protein is detected in T lymphocytes from spleen but not in airway macrophages after coculture and stimulation of these two cell types. Finally, anti-IL-17 does not alter endotoxin-induced release of IL-6 and MIP-2 from T lymphocytes and airway macrophages in coculture. In conclusion, our results indicate that endotoxin exposure causes the release of IL-17 from T lymphocytes and that this cytokine release requires the presence of macrophages. Once released, endogenous IL-17 acts in part by inducing local release of neutrophil-mobilizing cytokines such as IL-6 and MIP-2, from nonlymphocyte, nonmacrophage cells, and this contributes to recruitment of neutrophils in the airways. These IL-17-related mechanisms constitute potential targets for pharmacotherapy against exaggerated neutrophil recruitment in airway disease.

Administration, Intranasal↗
PubMed2006

Induction of RelB participates in endotoxin tolerance.

Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of IkappaB in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-kappaB transcription factors. Despite this, endotoxin-inducible NF-kappaB-dependent innate immunity genes, like IL-1beta, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that RelB, another member of the NF-kappaB family, is induced during the establishment of tolerance. RelB expression correlated with IL-1beta repression, and sepsis patients showed increased RelB when compared with normal controls. Transient expression of RelB inhibited IL-1beta in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased RelB expression in tolerant cells and restored endotoxin induction of IL-1beta. When we examined tolerant cell extracts, we found transcriptionally inactive NF-kappaB p65/RelB heterodimers. Taken together, our findings demonstrate that RelB can repress proinflammatory gene expression, and suggest that RelB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.

Cell Line, Tumor↗
PubMedDate not supplied

Endotoxin regulates the maturation of sterol regulatory element binding protein-1 through the induction of cytokines.

Endotoxin (LPS), by raising the levels of cytokines, markedly influences lipid metabolism. To clarify the molecular mechanism of this effect, we examined the action of endotoxin in vitro and in vivo on the regulation of sterol regulatory element binding protein-1 (SREBP-1). In HepG2 cells stimulated with LPS, a dose-dependent increase in the level of the mature form of SREBP-1 was observed. For in vivo studies, endotoxin was administered intraperitoneally to CD1 mice fed with a standard or a cholesterol-enriched diet to increase the basal levels of circulating and liver cholesterol. Endotoxin raised cholesterol levels and stimulated the maturation of hepatic SREBP-1 in both normal and cholesterol-fed mice, indicating that the lipogenic effect of LPS was independent of endogenous sterol levels. To assess whether the lipogenic effect of endotoxin was linked to cytokine production, we administered LPS to C57Bl/6J endotoxin-sensitive and to C3H/HeJ endotoxin-resistant mice, which do not produce tumor necrosis factor in response to LPS. Significant induction of cholesterol levels and SREBP-1 activation was observed only in C57Bl/6J mice, indicating that cytokine production is crucial for the regulation of SREBP-1, and that the transcriptional activation of cholesterol biosynthesis may be part of the acute-phase response.

Animals↗
PubMed2002

Endotoxin tolerance: A review.

Endotoxin tolerance was initially described when it was observed that animals survived a lethal dose of bacterial endotoxin if they had been previously treated with a sublethal injection. In animal models, two phases of endotoxin tolerance are described, an early phase associated with altered cellular activation and a late phase associated with the development of specific antibodies against the polysaccharide side chain of Gram-negative organisms. Recently, there has been a tremendous resurgence of interest in the mechanisms responsible for altered responsiveness to bacterial endotoxin. Host immune cells, particularly macrophages and monocytes, that are exposed to endotoxin for 3 to 24 hrs are rendered "tolerant" and manifest a profoundly altered response when rechallenged with bacterial endotoxin or lipopolysaccharide. The "lipopolysaccharide-tolerant" phenotype is characterized by inhibition of lipopolysaccharide-stimulated tumor necrosis factor production, altered interleukin-1 and interleukin-6 release, enhanced cyclooxygenase-2 activation, inhibition of mitogen-activated protein kinase activation, and impaired nuclear factor-kappaB translocation. Human monocytes and macrophages can be induced to become tolerant, and there is increasing evidence that monocytic cells from patients with systemic inflammatory response syndrome and sepsis have many characteristics of endotoxin tolerance.

Journal Article↗
PubMed2002

[The study on the role of modeling peptides derived from bactericidal/permeability increasing protein on the endotoxin neutralization].

OBJECTIVE: To observe the role of four modeling peptides (10342, 10343, 10344, 10345) derived from bactericidal/permeability increasing protein (BPI) in neutralizing endotoxin (LPS) in vitro and in vivo. METHODS: Quantitative limulus amoebocyte lysate assay was employed to evaluate the capacity of BPI peptides in neutralizing endotoxin in vitro. The protective capacity of the peptides was observed in mice challenged with endotoxin by intravenous administration via the tail vein. The influence of the peptides on serum TNFalpha and IL-6 levels in rats with endotoxemia were also observed. RESULTS: All of the four peptides possessed endotoxin-neutralizing capacity which was strengthened along with the increase in their concentration. Among the peptides, 10342 is the strongest one. All of the peptides had strong power to protect mice from endotoxin with 90% protective rate. In the rats with endotoxemia, the four peptides could reduce the levels of serum TNFalpha and IL-6 significantly at different time-points. CONCLUSION: Four BPI modeling peptides possessed not only endotoxin-neutralizing capacity in vitro, but also potential protective capacity in animals challenged with endotoxin.

Animals↗
PubMed1991

Renal perfusion and metabolism in experimental endotoxin shock.

Central and renal hemodynamics, renal oxygenation, renal uptake of glucose, lactate, fats, renal carnitine metabolism, arterial atrial natriuretic factor (ANF) and catecholamine release were studied in sixteen adult beagle dogs during pentobarbital anesthesia. Renal cortical oxygen tension was recorded by means of a Silastic tonometer. Twelve animals underwent acute circulatory shock induced by intravenous Escherichia coli endotoxin 0.5 mg/kg. Four control dogs received normal saline. The endotoxin infusion resulted in decreased cardiac function, renal blood flow and renal cortical PO2. The renal venous PO2 increased during the experiment. Arterial and renal venous glucose concentrations increased transiently during endotoxemia. Circulating lactate concentrations increased significantly whereas the arteriovenous lactate difference remained almost unchanged. Renal uptake of lactate and glucose were not influenced during the moderate renal hypoperfusion caused by endotoxin. Arterial free fatty acid (FFA) concentrations increased significantly 2 hours after onset of the endotoxin infusion whereas renal venous FFA levels remained rather stationary. The renal uptake of FFA increased with increasing arterial FFA concentrations. Circulating free carnitine concentrations increased significantly in endotoxin shock. Blood acyl-carnitine concentrations remained essentially unchanged. Carnitine concentrations declined significantly in endotoxic renal tissue. The arterial concentrations of ANF, epinephrine, norepinephrine and the norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) increased in plasma during early endotoxemia. The levels of these hormones remained very low and constant in the controls. To summarize, endotoxin injection resulted in impaired renal perfusion and oxygenation, increased uptake of free fatty acids and unchanged uptake of glucose, lactate, glycerol and triglycerides. Decreased renal carnitine concentrations were observed. Arterial plasma concentrations of ANF and catecholamines increased in endotoxin shock.

Animals↗
PubMed1978

Dexamethasone antagonism of glucose dyshomeostasis in endotoxin shock.

Dexamethasone acetate (100 microgram IP) protected male Holtzman rats (300-330 gm) against endotoxin shock due to Salmonella enteritidis lipopoly-saccharide B IV. Endotoxin (5.0 mg/rat) produced hypoglycemia within 180 minutes, ie, plasma glucose fell from 87 to 24 mg/dl; dexamethasone prevented the hypoglycemia, ie, plasma glucose levels were 129 mg/dl at 180 minutes after endotoxin. Dexamethasone antagonized both endotoxin-induced depression of hepatic gluconeogenesis and enhanced glucose oxidation as evaluated in vivo. Epididymal fat pads from endotoxic rats (100-110 gm) had increased rates of glucose oxidation as evaluated by the in vitro conversion of 14C-D-glucose to 14CO2. Dexamethasone both in vivo and in vitro antagonized endotoxin glucose hypercatabolism by isolated epididymal fat pads following administrated of endotoxin. Glucocorticoid protection against endotoxin shock is related to antagonism of glucose dyshomeostasis.

Adipose Tissue↗
PubMed1989

[The effects of ONO 3708, a new thromboxane receptor antagonist, on cardiovascular response during the early phases of endotoxin shock in anesthetized dogs].

The effects of ONO 3708, a new thromboxane A2 receptor antagonist, on cardiovascular and airway responses, at an early phase during endotoxin shock were investigated in anesthetized dogs. The i.v. infusion (1mg.kg-1) of E.coli endotoxin caused an increase in mean pulmonary artery pressure (MPAP) from 9.9 +/- 1.0 to 19.1 +/- 2.3 mmHg at 5 min, and at 15 min after infusion, elevated MPAP returned toward the control level. Pretreatment with ONO 3708 abolished these effects of endotoxin on pulmonary artery pressure at an early phase. The change in airway pressure reached a maximum of 14.4 +/- 1.7 cmH2O from 10.0 +/- 1.9 at 5 min, followed by a gradual decline toward a baseline value at 30 min in the control group. ONO 3708 significantly attenuated increase in airway pressure induced by E. coli endotoxin. But pretreatment with ONO 3708 could not prevent decrease in systemic arterial pressure and cardiac output induced by endotoxin. These results suggest that role of thromboxane A2 on the cardiovascular response during endotoxin shock is played only on pulmonary vascular changes, and ONO 3708 has a beneficial effect at least during the early phase of endotoxin shock.

Animals↗
PubMed1986

Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells.

We have examined the effects of bacterial lipopolysaccharide (endotoxin) on the fibrinolytic activity of bovine pulmonary artery endothelial cells. Endotoxin suppressed the net fibrinolytic activity of cell extracts and conditioned media in a dose-dependent manner (threshold dose, 0.1 ng/ml; maximal dose, 10-100 ng/ml). The effects of endotoxin required at least 6 h for expression. Cell extracts and conditioned media contained a 44-kDa urokinase-like plasminogen activator. Media also contained multiple plasminogen activators with molecular masses of 65-75 and 80-100 kDa. Plasminogen activators in extracts and media were unchanged by treatment of cells with endotoxin. Diisopropyl fluorophosphate (DFP) abolished fibrinolytic activity of extracts and conditioned media. DFP-treated samples from endotoxin-treated but not untreated cells inhibited urokinase and tissue plasminogen activator, but not plasmin. Inhibitory activity was lost by incubation at pH 3 or heating to 56 degrees C for 10 min. These treatments did not affect inhibitory activity of fetal bovine serum. Incubation of 125I-urokinase with DFP-treated medium from endotoxin-treated cells produced an inactive complex with an apparent molecular mass of 80-85 kDa. The complex could be detected by chromatography on Sephadex G-100, but not by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These findings suggest that low doses of endotoxin suppress fibrinolytic activity in endothelial cells by stimulating the production or expression of a fast-acting, relatively labile inhibitor of plasminogen activator.

Animals↗
PubMed1987

Use of indium-111 oxine to study the effects of terbutaline on pulmonary and hepatic platelet sequestration in endotoxin shock.

This study describes the effects of the beta 2 receptor agonist terbutaline on platelet sequestration in sheep exposed to endotoxin shock. The in vivo behavior of Indium-111-labeled platelets was followed simultaneously in the lungs, liver, spleen, and kidneys. The effects on the respiratory function and the central hemodynamics were also followed. Twelve adult sheep were given endotoxin (10 micrograms/kg bw), and six of those received a continuous intravenous infusion of terbutaline (20 micrograms/kg/hr) during 4 hr, starting 30 min after injection of endotoxin. The other six acted as controls. It was found that a marked pulmonary and hepatic platelet sequestration occurred during and just after the endotoxin infusion and was followed by a marked platelet disaggregation within 30 min in both groups. Three hours after the endotoxin a second wave of platelet trapping occurred in the control animals in both the lungs and the liver, while no such increase was seen in the terbutaline-treated animals. In the spleen, however, there was a decrease in platelet sequestration after endotoxin in both groups, and in the kidneys only minor changes occurred. Furthermore, less marked hemodynamic and respiratory alterations occurred in the terbutaline group compared with the controls. It was concluded that terbutaline decreased sequestration of platelets in the lungs and in the liver of sheep in endotoxin shock, which may be of importance in the development of multiple organ failure.

Animals↗
PubMed1977

Effect of dopamine infusion on the hemodynamics of normal and sympathectomized rhesus monkeys in endotoxin shock.

Infusion of endotoxin in chemically sympathectomized monkeys caused a fall in the mean aortic pressure, but the cardiac output, stroke volume, and central venous pressure were well maintained. Endotoxin-induced tachycardia in monkeys with functional sympathetics was not seen in the sympathectomized animals. Infusion of dopamine improved the hemodynamic and cardiovascular status, probably by causing vasoconstriction of the splenic and hepatic artery where the pooling of blood is believed to occur in endotoxin shock. However, these beneficial effects were not apparent when dopamine was administered in the chemically sympathectomized animal infused with endotoxin. Since chemical sympathectomy did not affect the endotoxin-induced decline in the systolic and mean aortic pressure or the severity of the endotoxin shock, it is suggested that catecholamines may not be the primary initiator or trigger substances in endotoxin shock.

Animals↗
PubMed1984

Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor.

The arachidonic acid derivative thromboxane A2, a very potent platelet aggregator, is increased in endotoxin shock. Ibuprofen blocks the formation of thromboxane A2 and has antiplatelet and antileukocyte aggregability properties. The effects of ibuprofen on pulmonary platelet trapping, platelet and leukocyte counts, platelet aggregability, hematocrit, and blood pressure were evaluated in endotoxin-shocked dogs. The initial decrease in blood pressure and in leukocyte and platelet counts seen in endotoxin shock was not altered by ibuprofen treatment. At 2 h the ibuprofen-treated dogs had less hypotension compared to endotoxin control. Platelet counts were also higher in the ibuprofen-treated dogs at 2 h. Significant recovery of leukocytes was seen only when pretreatment was used. Pulmonary platelet trapping was significantly lower in the ibuprofen-treated dogs compared to endotoxin controls and not significantly different from the sham dogs when ibuprofen was given before endotoxin injection. This study demonstrates the efficacy of ibuprofen not only in reducing pulmonary platelet trapping but also in obviating the late hypotension in experimental endotoxin shock.

Animals↗
PubMed1984

Effect of cyproheptadine on endotoxin-induced pulmonary platelet trapping.

The adult respiratory distress syndrome (ARDS) seen in endotoxin shock is accompanied by the release of beta-endorphin. The hypotension that is seen in endotoxin shock can also be produced by injection of beta-endorphin and is effectively blocked by the use of antiserotonin drugs. Serotonin injection in dogs causes lung changes similar to those seen in endotoxin shock. Pulmonary platelet trapping (PPT) is one of the factors in the evolution of ARDS. The effects of cyproheptadine, an antiserotonin drug, were evaluated on PPT in dogs injected with endotoxin. Dogs treated with cyproheptadine both prior to and after induction of endotoxin shock were compared with the standard endotoxin shock model. Blood pressure, platelet aggregability, and wet/dry lung weight ratio were studied in all groups. Posttreatment with cyproheptadine obviated PPT indicating the applicability of cyproheptadine in the treatment of ARDS. Pretreated dogs had PPT not significantly different from endotoxin controls, suggesting that blocking of serotonin before shock activates other vasoactive substances, which may include prostaglandins or prostaglandin derivates.

Animals↗
PubMed1982

Endotoxin-induced fever and associated haematological and blood biochemical changes in the goat: the effect of repeated administration and the influence of flurbiprofen.

Flurbiprofen, a potent non-steroidal anti-inflammatory and antipyretic agent, was given as an intravenous infusion (2 mg/kg) followed by a bolus injection of 1 mg/kg six hours later. After drug administration body temperature and rumen contractions were slightly depressed, whereas urea values gradually increased; serum sorbitol dehydrogenase (SDH) activity, plasma iron concentration and the number of circulating lymphocytes were significantly lower. Intravenous injection of endotoxin from Escherichia coli O111B4 (0.1 microgram/kg) caused shivering, fever, inhibition of rumen contractions, changes in heart rate, lymphopenia, neutropenia followed by neutrophylic leucocytosis, changes in urea values, hypoferraemia, hypozincaemia and a decline in serum alkaline phosphatase (ALP) activity, whereas gamma-glutamyltranspeptidase, glutamic oxalacetic transaminase, lactic dehydrogenase and SDH values were not significantly altered. Pretreatment with flurbiprofen completely abolished the febrile reactions to endotoxin. The endotoxin-induced inhibition of rumen contractions was only delayed. The drug blocked the initial tachycardia to endotoxin but did not prevent the secondary biphasic increase in heart rate. Flurbiprofen failed to modify the endotoxin-induced decrease in both plasma zinc and serum ALP activity whereas the decline in plasma iron concentration was delayed. After drug pretreatment the changes in circulating white blood cells were more pronounced. These data demonstrate that most of the haematological, blood biochemical and clinical effects of endotoxin cannot be blocked by flurbiprofen, and that these effects are not due to the increase in body temperature alone. Tolerance induced by repetitive daily intravenous administration of endotoxin resulted in an almost complete abolition of all the effects. However, the plasma iron values from tolerant goats were significantly lower than those from non-tolerant animals, which demonstrates that the development of a refractory state can result in modification of this biochemical parameter.

Animals↗
PubMed1982

Insulin hypersecretion and potentiation of endotoxin shock in the rat.

Endotoxin has been shown to disrupt the metabolic regulation of blood glucose and insulin levels. This study determined the effect of arginine on plasma glucose and insulin regulation during endotoxicosis in order to assess its contribution to glucose dyshomeostasis in the pathogenesis of endotoxin shock. In addition, the ability of arginine to stimulate insulin secretion from the endotoxic pancreas was assessed directly by using the in vitro perfused rat pancreas model. Arginine significantly increased the lethal effects of endotoxin in rats and shortened the time course to death. Rats treated with both arginine and endotoxin demonstrated 1) a rapidly ensuing hypoglycemia, 2) an absence of the characteristic endotoxin-induced hyperglycemia, and 3) a rapidly progressive and profound hypoglycemia. In contrast alanine (which does not stimulate insulin secretion) did not profoundly exacerbate the glucose dyshomeostases of endotoxin shock. Lastly, arginine induced a hypersecretion of insulin as directly determined from the in vitro perfused pancreas of the endotoxic rat. These results demonstrated that arginine, through its direct insulinotropic effect on the hypersecretory endotoxic pancreas, contributed to the endotoxic hyperinsulinemia and thereby accelerated the development of glucose dyshomeostasis and lethal hypoglycemia in the endotoxic rat. This study has emphasized the important role for insulin in the pathogenesis of endotoxin-induced hypoglycemia. Furthermore, the potential role of insulin secretagogues other than glucose has been identified with regard to the insulin hypersecretory state of the endotoxic pancreas.

Alanine↗
PubMed1982

Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.

Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG) F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 +/- 0.82 to 0.147 +/- 0.032 ng/ml (P less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Beta-adrenergic-dependent and -independent actions of naloxone on perfusion during endotoxin shock.

Naloxone, an opioid antagonist, has been shown to improve cardiovascular status during endotoxin shock, including splanchnic perfusion. Enhancement of adrenergic action has been implicated as a physiological path by which naloxone effects changes in cardiac function during endotoxin shock, but the mechanism for changes in various splanchnic vascular beds has not been examined. In this study, we examined the role of beta-adrenergic actions in cardiovascular performance and the splanchnic perfusion changes caused by naloxone during endotoxin shock. Rats were instrumented with catheters in the tail artery, left cardiac ventricle, and jugular vein. Twenty-four hours later, rats received saline or endotoxin (2 mg/kg) challenge intravenously over 30 min, followed at 40 min by i.v. naloxone (or saline) treatment (4 mg/kg + 2 mg/kg.hr) in the presence or absence of propranolol (1 mg/kg + 1 mg/kg.hr). Radiolabelled microspheres were used to determine cardiac outputs and blood flows at 0, 30, 60, and 120 min after beginning endotoxin infusion. Blood pressure was not affected by endotoxin challenge, but cardiac output and most organ blood flows fell over time. beta-Adrenergic blockade did not alter this response. Naloxone improved cardiac output and blood flow to the stomach, small intestine, colon, and spleen but not to other splanchnic organs. Naloxone also increased renal and coronary blood flows. The improvements in cardiac output with naloxone were ablated in the presence of propranolol, as were the increases in gastric, colonic, splenic, coronary, and renal blood flows. However, the beneficial effect of naloxone on small bowel blood flow was not diminished by blockage of beta receptors. These results suggest that the effects of opioid antagonism are mediated, in part, by enhancing endogenous beta-adrenergic actions in vivo. Improvements in the splanchnic circulation are selectively altered by naloxone during endotoxin shock, some independent of beta-adrenergic actions. Understanding this phenomenon can lead to the appropriate use of opioid antagonism, should it prove clinically useful in the treatment of septic shock.

Animals↗