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PubMed1984

Role of angiotensin I and glucagon in canine endotoxin shock: effect of converting enzyme inhibitor and prior immunization.

he intermediate and latter stages of canine endotoxin shock are characterized by a progressive decrease in cardiac output, increase in total peripheral resistance, and hypoglycemia. We have hypothesized that the renin-angiotensin system and glucagon may mediate the loss of cardiovascular and glucose homeostasis. E. Coli endotoxin shock (1 mg/kg; 055:B5) was induced in three groups of dogs and systemic hemodynamics, angiotensin I activity, and glucagon were monitored for 5 hr; endotoxin shock (n = 13); endotoxin shock + prior immunization with J5 mutant of E coli 0111 (n = 5); Endotoxin + captopril (20 micrograms/kg/hr; n = 9); and sham-operated time-matched controls (n = 8). Thirty minutes postshock, angiotensin I and glucagon began to increase. Angiotensin I activity reached a peak at 60 min postendotoxin (90 +/- 25 vs 5 +/- ng/ml/hr; p less than 0.001) and plateaued. Increased glucagon levels plateaued at 3.5 hr postshock (1500 +/- 200 vs 155 +/- 77 pg/ml; p less than 0.001). Cardiac output began to progressively decrease, total peripheral resistance began to increase, and persistent hypoglycemia developed at 3 hr postshock. Captopril inhibited the increase in total peripheral resistance and had no effect on the decrease in cardiac output or the hypoglycemia. The initial glucagon response was attenuated but there was no difference at 5 hr (950 +/- 150 vs 1200 +/- 200 pg/ml). Prior immunization significantly preserved cardiac output, total peripheral resistance, plasma glucose levels, glucagon levels, and angiotensin I activity. It is concluded that 1) the renin-angiotensin system is a physiologic and not a pathophysiologic compensatory mechanism during the course of endotoxin shock and that inhibition of this system is deleterious; 2) glucagon may serve as an important mediator of both the myocardial dysfunction and glucose dyshomeostasis of endotoxin shock; and 3) immunological inhibition of the initial phase of endotoxin shock significantly preserves cardiovascular and glucose homeostasis and adds support to the concept that the initial vascular phase of endotoxin shock plays a primary role in determining the severity of the endotoxin/septic shock syndrome.

Angiotensin I↗

PubMed1983

The effects of naloxone on the peripheral sympathetics in cat endotoxin shock.

The effects of naloxone on sympathetic nerve activity during E coli endotoxin hypotension were studied in alpha-chloralose anesthetized cats. Blood pressure and left preganglionic splanchnic nerve (PSN) activity were measured. Naloxone (2 mg/kg) was injected intravenously 30 min after endotoxin. In control group, 30 min after endotoxin, both mean blood pressure (MBP) and PSN activity decreased by 68 +/- 7% and 47 +/- 10%, respectively, and were followed by a gradual decline, so that after 60 min MBP and PSN activity were 54 +/- 8% and 48 +/- 7% of the pre-endotoxin level. The reduced blood pressure recovered to 81 +/- 4% of the pre-endotoxin level 5 min after naloxone. However, the naloxone-induced recovery of blood pressure was transient and there was a decline to the pre-naloxone level within 30 min after the injection. At the end of the experiment (60 min after endotoxin), the level of MBP was significantly higher than in the control group. Similarly, there was a modest recovery in PSN activity (61 +/- 7% of the pre-endotoxin level 5 min after naloxone) that was maintained for 20 min only to decline again. Three of five cats treated with an intermittent bolus injection (2 mg/kg, 30 min and 6 h after endotoxin) of naloxone survived, compared to only one of five nontreated cats. These observations suggest that at least part of the beneficial cardiovascular actions of naloxone in endotoxin shock involves activation of the efferent sympathetic system. To improve longterm survival it may be necessary to continuously administer naloxone.

Animals↗

PubMed1982

Centrally mediated hypotensive effect of E coli endotoxin in the anesthetized cat.

E coli endotoxin, 1 mg/kg, injected intravenously in cats anesthetized with alpha chloralose caused an initial transient rise followed by a prolonged decrease in systemic blood pressure. The renal blood flow decreased gradually while the nictitating membrane contracted. Calculated renal vascular resistance significantly decreased 10 min after intravenous injection of the endotoxin. E coli endotoxin injected into the cisterna magna (50 micrograms/kg), and the nucleus tractus solitarius (2.5 micrograms/kg) produced an abrupt and persistent fall in the systemic blood pressure, the heart rate, the renal blood flow, and the calculated values for the renal vascular resistance. The pressor response to carotid sinus hypotension (carotid occlusion) was reduced after intracisternal and intravenous injection of E coli endotoxin. The prolonged hypotensive effects caused by the intravenous and intracisternal administration of E coli endotoxin and the reduction of the pressor response to carotid occlusion were abolished by pretreatment with phentolamine (500 micrograms/kg) intracisternally, whereas the initial increase of the blood pressure and transient contraction of the nictitating membrane remained. In conclusion, the hypotensive effect of E coli endotoxin may be mediated by a central autonomic blood pressure regulatory circuit. The endotoxin activates central alpha-adrenergic receptors that are components of a brain stem inhibitory pathway which participate in the baroreflex pressor response. This central mechanism together with the peripheral actions of endotoxin would yield the complex pathophysiological responses seen in endotoxin shock.

Anesthetics↗

PubMedDate not supplied

[Decrease of the hypertensive responses to phenylephrine in the rat submitted to a sublethal dose of E. coli endotoxin. Restoration by indomethacin (author's transl)].

E. Coli endotoxin was injected by i.v. route to rats at a dose immediately lower than the minimal lethal dose. Assays were performed on anesthetized rats (urethane 1 g/kg i.p.). The carotid arterial pressure was recorded 1, 2, 4, 16 and 24 hours after endotoxin administration, and hypertensive responses to three successive doses of phenylephrine (2; 5 or 10 micrograms/kg i.v.) was measured until return to initial values. Compared to control rats the hypertensive responses in the endotoxin-treated rats were depressed. This depression was evident at the first hour following endotoxin administration and was maintained at least for four hours. This lower response was improved by a treatment of the rats with indomethacin (10 mg/kg i.v.) when this drug was administered half an hour before, or concomitantly with endotoxin. When indomethacin (10 mg/kg) was given two hours after endotoxin the improvement was less marked. So did indomethacin at 5 mg/kg dose level. Indomethacin alone did not potentiate the pressive responses to phenylephrine. These results show that the endotoxin-induced decrease in the hypertensive responses to phenylephrine does not appear to depend on its hypotensive or lethal effects. It can be brought together with the low cardiovascular responses to different drugs found in animals under endotoxin shock. These results show moreover that an early increase in prostaglandin synthesis under the influence of endotoxin may be involved in this depressant effect.

Animals↗

PubMed1982

Changes in phase transition temperature of phospholipids induced by endotoxin.

The effects of endotoxin (lipopolysaccharide from Salmonella minnesota Re 595) on the phase transition temperature (Tm) of various phospholipids were studied. Endotoxin had no effect on the Tm and the width of the phase transition of dipalmitoyl-sn-3-phosphatidylcholine. Endotoxin at 100 micrograms/ml increased the Tm of dipalmitoyl-sn-3-phosphatidylethanolamine by 1.1 degrees C (P less than 0.01) and narrowed the range of transition from 4.5 to 2.6 degrees C; the endotoxin-induced changes in the Tm and the transition range were abolished by the presence of 0.25 mM CaCl2. Endotoxin increased the Tm of dipalmitoyl-sn-3-phosphatidic acid by 1.1 (P less than 0.01), 1.2 (P less than 0.01), and 3.1 (P less than 0.01) degrees C at 25, 50 and 100 micrograms/ml, respectively. Furthermore, the width of phase transition of phosphatidic acid was narrowed from 6.5 to 4.0 degrees C by endotoxin at 100 micrograms/ml. The endotoxin-induced changes in the Tm and the transition range of phosphatidic acid were not affected by the presence of EDTA (1 mM) or CaCl2 (0.05-0.1 mM). These results suggest that endotoxin decreases the fluidity of negatively charged phospholipids such as phosphatidic acid and phosphatidylethanolamine. A change in the physical properties of membrane lipid bilayers induced by endotoxin may have an adverse effect on the function of biological membranes.

Endotoxins↗

PubMed1993

Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.

When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-alpha, and IL-6. However, this initial injection induces tolerance; a second injection of endotoxin results in lower levels of circulating cytokines. In our study, five healthy male volunteers between the ages of 18 and 30 were injected with Escherichia coli endotoxin. Four subjects received only saline. Immediately before the injection and 3, 6, and 24 h afterward, PBMC were isolated and stimulated in vitro with endotoxin, IL-1, or toxic shock syndrome toxin-1. Inasmuch as CD14+ monocytes are the primary source of the cytokines induced by these stimuli, results are expressed as cytokine production per 10(6) CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1 beta (p < 0.01), 47% less TNF-alpha (p < 0.001), 56% less IL-6 (p < 0.01), and 49% less IL-8 (p < 0.01) than cells obtained before the injection. This suppression was not specific for endotoxin; IL-1 beta-induced IL-1 alpha and TNF-alpha were reduced by 84% (p = 0.01) and 68% (p < 0.001), respectively. A decrease in cytokine synthesis was also observed using toxic shock syndrome toxin-1 as a stimulus: 57% for IL-1 beta (p = 0.06), 70% for TNF-alpha (p < 0.01), 56% for IL-6 (p < 0.05), and 71% for IL-8 (p = 0.001). When data were expressed as cytokine production per 10(6) PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-alpha, IL-6, and IL-8 than did PBMC from saline-injected controls. We conclude that endotoxin tolerance is due, in part, to changes in the stimulus-induced cytokine response of circulating CD14+ cells.

Antigens, CD↗

PubMed1994

Endotoxin binding to platelets in blood from patients with a sepsis syndrome.

Endotoxin, the lipopolysaccharide cell wall constituent of Gram-negative bacteria, produces symptoms of the Gram-negative sepsis syndrome. By measuring endotoxin in blood from septic patients it may be possible to select a subpopulation of patients in which mortality can be prevented by treatment with anti-endotoxin antibodies. We evaluated the performance of an endotoxin-free blood-collection tube. Within-run and between-run CVs of our endotoxin assay were 4-18% and 8-20%, respectively. In endotoxin-positive samples (LPS > or = 6 ng/L), the concentration of endotoxin in platelet-rich plasma was significantly higher (P < 0.001) than in platelet-poor plasma. Apparent binding of endotoxin to platelets ranged from 0% to 92%. The correlation between the apparent percentage binding of LPS to platelets and the platelet count in platelet-rich plasma is linear and positive, but LPS is not bound solely to platelets. We conclude that endotoxin must be measured in platelet-rich plasma.

Bacteremia↗

PubMed1994

[Changes in blood endotoxin levels after scald in rats].

We quantified the portal blood endotoxin level as well as the systemic blood endotoxin level after scald in rats. The results show that the portal blood endotoxin level is significantly higher than the systemic blood endotoxin level (P < 0.001) in control group. In scald group the portal blood endotoxin level shows double peaks (increase significantly at second hour, decrease to normal at sixth hour and increase significantly again at twelfth hour), but the systemic blood endotoxin level remained low (P > 0.05). The results indicate that there is some endotoxin in the portal blood in normal condition, but large amount of endotoxin escape into portal blood in normal condition, but large amount of endotoxin escape into portal blood from the intestine in early stage after scald, resulting in enterogenous endotoxemia. The origin of systemic endotoxemia is discussed in the present article.

Animals↗

PubMed1994

[Application of a bacterial endotoxin test for parenteral drugs].

The Limulus test, which has been adopted as the Test for Bacterial Endotoxins in the JP XII, can detect or quantitate endotoxins of Gram-negative bacterial origin using blood corpuscle extracts (Limulus amebocyte lysate, LAL) of horseshoe crabs (Limulus polyphemus, Tachypleus tridentatus, etc.). It may be conducted by the gel-clot or spectrophotometric (turbidimetric and colorimetric) techniques, the former being based on gel formation due to the activation of LAL by endotoxins. The turbidimetric technique is based on the LAL turbidity change during the gel formation and the colorimetric technique on activation of peptide hydrolytic enzymes in LAL. The Limulus test has been unofficially utilized as a simple and highly sensitive method for the determination of endotoxins in parenteral drugs in lieu of the in vivo Pyrogen Test using rabbits. For the Bacterial Endotoxins Test of the JP XII, the gel-clot technique alone was adopted, the technique being only allowed for Injection. Although most parenteral drugs show inhibition or enhancement in practice, this test can be most easily conducted by eliminating interfering effects through dilution of specimens by a factor not exceeding the maximum valid dilution (MVD) with water. Since MVD is dependent on the sensitivity of applied methodology, the turbidimetric and colorimetric techniques, which are more sensitive than the gel-clot technique, have a distinct advantage. The JP, as the leading Pharmacopoeia for the international harmonization of Bacterial Endotoxins Testing, has presented a "Draft towards International Harmonization of Bacterial Endotoxins Test", whose main purpose is the introduction of supplementary turbidimetric and colorimetric techniques. Under these circumstances the following subjects are discussed: (1) the proposal that, with a view towards international harmonization of the technical requirements of Pharmacopoeias, both the turbidimetric and colorimetic techniques should be included together with the gel-clot technique, (2) the differences in the testing principles and/or conditions prescribed in the current Bacterial Endotoxins Test of JP, USP and EP, and (3) the worldwide situation for Endotoxin Reference Standards.

Animals↗

PubMed1996

Endothelial "stunning" following a brief exposure to endotoxin: a mechanism to link infection and infarction?

BACKGROUND: There is an association between infection, inflammation and acute cardiovascular events. In an attempt to explore the mechanism of this association we have developed a model to examine the effects on endothelial function of a brief exposure to endotoxin. METHODS AND RESULTS: Endotoxin was instilled into isolated superficial hand veins of healthy volunteers. The vein was isolated by means of two wedges and endotoxin instilled into the isolated segment. After 1 h the contents of the vein were aspirated and the wedges removed. Dose-response curves to bradykinin (a stimulator of nitric oxide synthesis), arachidonic acid (the precursor of prostanoid production) and GTN (a nitric oxide donor) were constructed before and 1 h after endotoxin. Endotoxin caused a glucocorticoid-inhibitable attenuation in the dose-response curves to bradykinin and arachidonic acid (P < 0.05). This effect persisted for 48 h and took 7 days to recover. Exposure of saphenous vein to endotoxin in vitro also caused selective impairment of endothelium-dependent relaxation (P < 0.05) yet microscopy of the vessels exposed to endotoxin showed no endothelial denudation or structural damage. CONCLUSION: The results demonstrate that a brief local exposure to endotoxin caused endothelial dysfunction that persists for 48 h and takes up to 7 days to recover. The endothelial dysfunction is not due to expression of the inducible isoform of nitric oxide synthase and persists for far longer than the effects of endotoxin on vascular smooth muscle function. We have coined the term endothelial "stunning" to describe the transient endothelial dysfunction and suggest it might provide a mechanism underpinning the association between infection or inflammation and increased cardiovascular risk. Endothelial stunning appears to provide a novel, transient, variable and modifiable potential cardiovascular risk factor.

Adult↗

PubMed1997

Role of endotoxins and bile acids in the pathogenesis of septic circulatory shock.

It has long been known that the toxic effects of endotoxins under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring enteroendotoxemic diseases (e. g. septic and intestinal ischemic shocks) the endotoxins--which are produced by gram negative members of intestinal flora-, absorb from the intestinal tract to the blood circulation and can elicit pathological processes. It is an important distinction between natural and experimental endotoxin shock. If the common bile duct of rats were chronically cannulated a significant amount of perorally administered endotoxin was absorbed into the blood. This endotoxin shock can be prevented by bile acids. The physiological surfactants, the bile acids, are important facts in the defense of macroorganisms against endotoxins (physico-chemical defense). The production and passage of bile acids depend from the function of liver and the cholecystokinine (CCK) synthesis of small intestine wall. If the bile (bile acid) content of the intestinal canal decreases the endotoxin can translocate to the body and elicits toxic symptoms. So most important parts of defense against endotoxins in natural conditions are the CCK and bile acids. The consequence of damage of liver (place of bile acid synthesis) or small intestine (place of CCK synthesis) is the absorption of endotoxins.

Absorption↗

PubMed1997

[Use of the LAL test for quantitative determination of Bacteroids fragilis endotoxin].

The aim of this study was the evaluation of LAL test with chromogenic substrate usefulness for the quantitative detection of B. fragilis endotoxin and the determination of the amount of endotoxin in culture filtrates of the strains of this species. Also, the trial was undertaken to determine the influence of clindamycin on endotoxin release from B. fragilis rods to the culture medium. Four B. fragilis strains were examined: one nonenterotoxigenic (NTBF) and three enterotoxigenic (ETBF). The growth of cultures was determined and endotoxin liberated to the culture medium during growth of strains was detected. BHI broth and BHI broth with addition of sub inhibitory doses (sub-MIC) of clindamycin were applied. Bacterial cultures were incubated for 48 hours at 37 degrees C. Samples of bacterial cultures were collected after 4, 8, 16, 24 and 48 hours of cultivation, and the optical density was measured. Then the samples were centrifuged, supernatants were filtered through 0.45 micron filters and concentrated three times with 5000 D ultrafilters. Prepared samples were kept frozen at -70 degrees C until used. The amount of endotoxin in samples was determined using quantitative LAL test with chromogenic substrate S-2423. The results of the experiments indicate that LAL test is the useful method for determination of B. fragilis endotoxin concentration. This endotoxin activates the enzymatic system present in Limulus polyphemus amebocyte lysate. Endotoxin is shed spontaneously by B. fragilis rods to the culture medium during growth. Clindamycin at subinhibitory concentrations (sub-MIC) inhibits the growth of cultures of examined strains. The antibiotic caused increase in endotoxin amount in culture medium.

Bacteroides fragilis↗

PubMed1976

Effects of endotoxin in cortisone-treated rabbits with a hereditary deficiency of the sixth component of complement (C6 deficiency).

Endotoxin was infused into normal rabbits and C6 deficient rabbits prepared with cortisone for the generalized Shwartzman reaction. Endotoxin produced profound granulocytopenia and moderate thrombocytopenia in both normal and C6 deficient rabbits. In normal rabbits endotoxin consistently produced extensive intravascular clotting. In C6 deficient animals endotoxin resulted in intravascular clotting of variable extent. In one group of eight C6 deficient rabbits mean fibrinogen levels fell 0.67 g per 1 over 6 hrs after endotoxin and four of eight animals developed a generalized Shwartzman reaction. In a second group of seven C6 deficient rabbits mean fibrinogen level fell only 0.17 g per 1 over 6 hrs and one animal developed a generalized Shwartzman reaction. Values for mean fibrinogen consumption, calculated from plasma fibrinogen levels and rate of disappearance of 25I-fibrinogen, were as follows: normal animals infused with saline, 10 mg per kg; C6 deficient animals infused with endotoxin, 58 mg per kg. Fibrinogen consumption after endotoxin was found to be related to granulocyte levels prior to endotoxin, which determined the number of granulocytes disappearing from the blood after endotoxin. The data indicate that C6 deficiency in the rabbit does not prevent intravascular clotting and the generalized Shwartzman reaction.

Agranulocytosis↗

PubMed1998

Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance.

Endotoxin tolerance, the down-regulation of a subset of endotoxin-driven responses after an initial exposure to endotoxin, may provide protection from the uncontrolled immunological activation of acute endotoxic shock. Recent data suggest, however, that the inhibition of monocyte/macrophage function associated with endotoxin tolerance can lead to an inability to respond appropriately to secondary infections in survivors of endotoxic shock. IL-12 production by antigen-presenting cells is central to the orchestration of both innate and acquired cell-mediated immune responses to many pathogens. IL-12 has also been shown to play an important role in pathological responses to endotoxin. We therefore examined the regulation of IL-12 during endotoxin tolerance. Priming doses of lipopolysaccharide ablate the IL-12 productive capacity of primary human monocytes. This suppression of IL-12 production is primarily transcriptional. Unlike the down-regulation of TNF-alpha under such conditions, the mechanism of IL-12 suppression during endotoxin tolerance is not dependent upon IL-10 or transforming growth factor-beta, nor is IL-12 production rescued by IFN-gamma or granulocyte-macrophage colony-stimulating factor. Of note, human dendritic cells also undergo endotoxin tolerance, with potent down-regulation of IL-12 production. Endotoxin tolerance-related suppression of IL-12 production provides a likely mechanism for the anergy seen during the immunological paralysis which follows septic shock.

Cells, Cultured↗

PubMed1991

A selective thromboxane synthetase inhibitor, OKY-046, fails to improve blood rheology in endotoxin-shocked rabbits.

Effects of a selective thromboxane synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046), were studied hemorheologically in endotoxin shocked-rabbits. The animals were intravenously administrated with 0.1 mg of endotoxin 3 times at intervals of 3 days. At 7 days after the last endotoxin injection, endotoxin (0.2 mg.kg(-1)) was intravenously administrated to induce a shock. OKY-046 (30 mg.kg(-1)) was administrated after hypotension was developed by the endotoxin treatment and, then, it was continuously injected at 0.03 mg.kg(-1).min(-1). Blood pressure remained unchanged and hypotensive was maintained during the treatment with OKY-046. Blood was sampled from the femoral artery 15 (before the administration of OKY-046), 45, and 120 minutes after the final administration of endotoxin. Pa(O)(2) increased, and Pa(CO)(2), arterial pH, and base excess (BE) decreased during the endotoxin shock. The decrease of pH and BE was prevented by the administration of OKY-046. In the endotoxin-shocked animals, hematocrit, whole blood viscosity, erythrocyte deformability, plasma fluidity, and the ratio of hematocrit to whole blood viscosity showed no significant differences between the OKY-046 treated animals and non-treated ones. These data show that a selective thromboxane synthetase inhibitor (OKY-046) does not improve the blood rheology during endotoxin shock, although it seems to prevent the acidosis in some extent.

Journal Article↗

PubMed1990

Absorption of Escherichia coli endotoxin (lipopolysaccharide) from the uteri of postpartum dairy cows.

An experiment was conducted to test the hypothesis that Escherichia coli (E. coli ) endotoxin is readily absorbed from uteri of early postpartum cows and that the absorbed endotoxin provokes systemic relcase of prostaglandins. Eleven postpartum Holstein dairy cows (aged 3 to 7 yr) with normal puerperium were selected and divided into a treatment group (n=7), which received intrauterine infusions of E. coli endotoxin, and a control group (n=4), which received intrauterine infusions of 10 ml of saline on Days 5 and 20 post partum. Blood samples were collected once every 30 min for 6 h starting from the time of infusion. Harvested sera samples were analyzed for concentrations of stable metabolites of prostacyclin (PCM), prostaglandin F(2alpha) (PGFM), and thromboxane A(2) (TXB(2)). Plasma samples were qualitatively tested for the presence of endotoxin. Endotoxin was detected in the plasma samples of cows that received endotoxin on Day 5 post partum 4 h after the infusion. Endotoxin was not detected in any of the samples from control cows on Days 5 and 20 post partum or from treatment group cows on Day 20 post partum. Cows treated on Day 5 post partum showed increases in serum PGFM concentrations from 710 +/-64pg/ml to peak concentrations of 1223 +/- 47 pg/ml within 2 h, followed by a decline to baseline concentrations within 4 h. The amount of PGFM released in treated cows on Day 5 post partum was higher (P < 0.05) than in control cows on Day 5 or in treated and control cows on Day 20 post partum. Serum PCM concentrations increased from 156+/-24 pg/ml to peak concentrations of 1348+/-127 pg/ml within 1 h. The amount of PCM released in treated cows on Day 5 postpartum was higher (P< 0.05) than in control cows on Day 5 or in treated and control cows on Day 20 post partum. The TXB(2) concentrations increased from 315+/-38 pg/ml to peak concentrations of 5043 +/- 242 pg/ml within 1 h and fell to baseline concentrations within 5 h. The amount of TXB(2) concentrations released in treated cows on Day 5 post partum was significant (P < 0.05) compared with those of cows in the other groups. The results support the hypothesis that uteri of early postpartum cows are capable of absorbing endotoxin, and the absorbed endotoxin provokes changes in the serum concentrations of prostanoids.

Journal Article↗

PubMed1984

Skeletal muscle metabolism and insulin resistance during endotoxin shock in the dog.

The effect of locally infused endotoxin on gracilis muscle glucose uptake was determined in anesthetized mongrel dogs. The effects of infusion of small amounts of Escherichia coli endotoxin into the arteries of isolated, innervated, constant flow perfused gracilis muscles on glucose uptake and other metabolic variables were determined. Locally infused endotoxin consistently caused a significant and substantial increase in skeletal muscle glucose uptake with no alterations in muscle arteriovenous difference of insulin, oxygen, carbon dioxode, or pH, or in venous blood hematocrit or temperature. These data demonstrate that endotoxin can act locally to increase glucose uptake by skeletal muscle, independent of the action of insulin or other metabolic factors. During natural (free flow) conditions, glucose uptake by the muscle increased markedly during six hours of shock. Increased glucose uptake occurred concomitantly with muscle ischemia and hypoxia. However, when muscle blood flow was held constant, thereby preventing local muscle ischemia and hypoxia, glucose uptake by the gracilis muscle did not change during shock. These results implicate local muscle ischemia and/or hypoxia as the mediator(s) of the increased muscle glucose uptake during shock. Further studies demonstrated that local muscle hypoxia was the stimulus for increased glucose uptake by skeletal muscle during endotoxin shock, and muscle ischemia per se did not alter muscle glucose uptake. Since approximately 50% of body mass is composed of skeletal muscle, the contribution of this organ system to the hypoglycemia of endotoxin shock in the dog may be substantial. The ability of insulin to promote glucose diffusion into skeletal muscle before and during gram-negative endotoxin shock was studied in mongrel dogs anesthetized with sodium pentobarbital. The in vivo, isolated, innervated, constant flow perfused gracilis muscle preparation was used. Prior to shock induction, close intra-arterial insulin infusion resulted in a 320% increase in muscle glucose uptake. However, at one, two, and three hours of endotoxin shock, gracilis muscle glucose uptake was unaltered by insulin infusion. This loss of responsiveness to insulin occurred with no alteration in gracilis muscle oxygen uptake, muscle venous P02, or muscle blood flow. During control experiments, however, the muscle response to intra-arterial infusion of insulin (increased glucose uptake) was unaltered during the three-hour control period. These data demonstrate that skeletal muscle insulin resistance develops early and is maintained during three hours of endotoxin shock in the dog.

Animals↗

PubMed2002

Effects of ibuprofen on plasma endothelin levels and some vital parameters during endotoxin shock in rabbits.

BACKGROUND: There is evidence that septic shock results from breakdown in the balance between vasodilators such as prostacyclin, prostaglandin E(2), and nitric oxide, and the vasoconstrictors thromboxane A(2), serotonin, and endothelin. Increased plasma endothelin (ET) concentrations during septic shock were found. Inducing phospholipase A(2), ET causes release of arachidonic acid and production of prostaglandins. Ibuprofen is nonsteroidal anti-inflammatory drug inhibiting prostaglandin synthesis. There are no any information about the effects of ibuprofen on ET production in endotoxemia. In the present study we aimed to determine the effects of ibuprofen on plasma ET concentrations in an animal model of endotoxin shock. METHODS: A total of 28 rabbits were randomly allocated into four groups. The first group only received saline and served as controls. The rest of the animals (groups 2, 3, and 4) were injected intravenously with endotoxin at a dose of 2 mg/kg. To the third group, ibuprofen at 30 mg/kg dosage was given, 30 min following endotoxin administration, whereas in the fourth group animals, ibuprofen was administered 30 min before endotoxin administration. Animals were monitored through the canulation of femoral arteries and venules under the complete anaesthesia. At 0, 30, 60, 90, 120, 180, and 240 min, arterial blood pressure, heart rate, and ET determinations were carried out. RESULTS: Ibuprofen before the endotoxin administration was more effective in controlling the increase in heart rate. Ibuprofen was also effective in inhibiting the sudden reductions in blood pressure if administered before endotoxin. However, if administered after endotoxin injection, ibuprofen precipitated the reduction in blood pressure further. Ibuprofen reduced the ET production which was induced by the endotoxin administration. CONCLUSIONS: Ibuprofen administration during endotoxin shock seems to decrease the elevated ET concentrations, and increase the blood pressure.

Animals↗