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Biomedical subjects

W C Wise

Publications and source records attributed to W C Wise.

At least 37 records · Page 2Linked to original sources
PubMed1989

Alterations in plasma levels and complexing of Gc (vitamin D-binding protein) in rats with endotoxic shock.

Septic shock is known to involve increased metabolism of arachidonic acid and generation of certain eicosanoids. Recently, a new extracellular pool of unsaturated fatty acids including arachidonate has been found in relation to group-specific component (Gc), a vitamin D-binding plasma protein that sequesters monomeric G-actin. Since complexing with G-actin displaces fatty acids, possible alterations in plasma levels of Gc and extent of complexing were sought in serial samples obtained from rats with shock induced by Salmonella enteritidis endotoxin (12.5-15 mg kg-1). Gc levels in animals receiving endotoxin exhibited bimodal alterations, with a significant reduction (P less than 0.001) at 1 hour, followed by a progressive elevation to 160% of starting concentrations at 6 days in animals that survived, whereas in sham-injected animals the change observed was a continuous rise to 147% at 6 days. A statistically significant increase in the percentage of Gc complexed was observed in all endotoxemic rats from 2 hours onward (P less than 0.01), in contrast to sham-injected animals, in which the percentage of Gc complexed remained at less than 5%. Levels in survivors peaked at 30 +/- 5.2% at 8 hours and then decreased to normal (2 +/- 0.9%) by 6 days (n = 7), whereas in nonsurvivors complexed Gc continued to rise until time of death (66-80%) at 6-12 hours (n = 4). Correlation of these results with glucose, transaminases, and immunoreactive TXB2 and 6-keto-PGF1 alpha indicated that decreased absolute levels of Gc represent a consistent early change in endotoxic shock and that the percentage of Gc complexed is an accurate prognostic indicator of severity.

Actins↗
PubMed1988

Catalase pretreatment attenuates oleic acid-induced edema in isolated rabbit lung.

Because reactive O2 metabolites have been demonstrated to be potent mediators of vascular dysfunction and are synthesized by lung tissue, their involvement as mediators of oleic acid (OA)-induced pulmonary edema in the isolated Krebs-perfused rabbit lung was assessed. Injection of OA (0.1 ml) into the pulmonary artery after vehicle pretreatment induced marked increases in lung weight [50.4 +/- 13.9 vs. 4.2 +/- 2.0 (SE) g 45 min after OA or vehicle, respectively, P less than 0.05], an index of pulmonary edema, and airway pressure. OA also caused a significant though minimal increase in pulmonary arterial pressure. Pretreatment with catalase (1,000 U/ml), a scavenger of H2O2, significantly (P less than 0.05, Friedman's) attenuated the increases in lung weight (50.4 +/- 13.9 vs. 15.1 +/- 4.9 g), airway pressure, and pulmonary arterial pressure. In contrast to catalase, pretreatment with Cu-tryptophan (40 microM), a lipid-soluble scavenger of superoxide, provided no protective effect by itself, nor was there any potentiation of protection when combined with catalase. Further evidence implicating O2 metabolites in OA-induced edema was obtained by electron paramagnetic resonance (EPR) spectroscopy of perfusate samples to which the spin trap, sodium 3,5-dibromo-4-nitrosobenzenesulfonate (10 mM), was added. Analysis of these samples revealed the presence of free radicals after OA. Pretreatment with catalase (1,000 U/ml) and superoxide dismutase (250 U/ml) attenuated the EPR signal, indicating that proximal formation of O2 free radicals was in part responsible for the signal. These results suggest that reactive O2 metabolites are mediators of OA-induced pulmonary edema in the isolated perfused rabbit lung.

Animals↗
PubMed1988

Beneficial effects of a 5-lipoxygenase inhibitor in endotoxic shock in the rat.

The effects of a highly selective 5-lipoxygenase inhibitor, CGS8515 [methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl) amino]benzoate], on endotoxic shock sequelae and eicosanoid synthesis by peritoneal macrophages were evaluated in the rat. Pretreatment of peritoneal macrophages in vitro with CGS8515 significantly inhibited the synthesis (P less than .01) of immunoreactive leukotriene C4/leukotriene D4 stimulated by the calcium ionophore (A23187). Inhibition of 5-lipoxygenase produced significant shunting to immunoreactive thromboxane B2 formation (P less than .05). In rats sedated with ketamine.HCl (82.5 mg/kg) and xylazine. HCl (27.5 mg/kg), i.v. injection of Salmonella enteritidis endotoxin (25 mg/kg i.v.) produced significant decreases at 30 min in mean arterial pressure (from 89 +/- 4 to 44 +/- 8 mm Hg, N = 5, P less than .001); in white blood cell count (from 10.8 +/- 0.6 to 6.5 +/- 0.8 x 10(3)/mm3, N = 5, P less than .01); in platelet count (from 687 +/- 66 to 392 +/- 65 x 10(3)/mm3, N = 5, P less than .01); and produced an increase of hematocrit (from 46 +/- 1.2 to 57.4 +/- 1.8%, N = 5, P less than .03). CGS8515 (5 mg/kg i.v. 30 min before endotoxin injection, N = 6) blunted the endotoxin-induced hypotension by 35% (P less than .001), the leukopenia by 24% (P less than .03), the thrombocytopenia by 45% (P less than .006) and the hemoconcentration by 16% (P less than .03), compared to the shocked control rats 30 min after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Macrophage eicosanoid formation is stimulated by platelet arachidonic acid and prostaglandin endoperoxide transfer.

The present study was designed to determine whether platelets transfer arachidonic acid or prostaglandin endoperoxide intermediates to macrophages which may be further metabolized into cyclooxygenase products. Adherent peritoneal macrophages were prepared from rats fed either a control diet or an essential fatty acid-deficient diet, and incubated with a suspension of washed rat platelets. Macrophage cyclooxygenase metabolism was inhibited by aspirin. In the presence of a thromboxane synthetase inhibitor, 7-(1-imidazolyl)heptanoic acid, immunoreactive 6-ketoprostaglandin F1 alpha formation was significantly increased 3-fold. Since this increase was greater (P less than 0.01) than that seen with either 7-(1-imidazolyl)heptanoic acid-treated platelets or aspirin-treated macrophages alone, these results indicate that shunting of endoperoxide from platelets to macrophages may have occurred. In further experiments, macrophages from essential fatty acid-deficient rats were substituted for normal macrophages. Essential fatty acid-deficient macrophages, depleted of arachidonic acid, produced only 2% of the amount of eicosanoids compared to macrophages from control rats. When platelets were exposed to aspirin, stimulated with thrombin, and added to essential fatty acid-deficient macrophages, significantly more immunoreactive 6-ketoprostaglandin F1 alpha was formed than in the absence of platelets. This increased macrophage immunoreactive 6-ketoprostaglandin F1 alpha synthesis, therefore, must have occurred from platelet-derived arachidonic acid. These data indicate that in vitro, in the presence of an inhibition of thromboxane synthetase, prostaglandin endoperoxides, as well as arachidonic acid, may be transferred between these two cell types.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Beneficial effects of a leukotriene antagonist on endotoxin-induced acute hemodynamic alterations.

The role of lipoxygenase metabolites of arachidonic acid as inflammatory mediators of endotoxin shock remains uncertain. In this study the effect of LY171883, a selective leukotriene D4/E4 antagonist, on the hemodynamic alterations of endotoxin shock was assessed. Adult male rats were given an intraperitoneal injection of LY171883 (30 mg/kg) or vehicle 10 minutes prior to intravenous injection of endotoxin (15 mg/kg) or vehicle. Cardiac output, mean arterial pressure, and multiple organ blood flows were determined at 30 minutes after endotoxin or vehicle administration with 85Sr-radiolabeled microspheres. Cardiac output decreased from 32.1 +/- 2.7 ml/min/100 g in the control group to 16.3 +/- 2.7 ml/min/100 g in endotoxin-treated animals (P less than .05). Pretreatment with LY171883 blunted significantly (P less than .05) this fall in cardiac output (26.3 +/- 2.6 ml/min/100 g). Endotoxin reduced mean arterial pressure from 95 +/- 8 mm Hg in controls to 57 +/- 8 (P less than .05), which was not, however, different from control values in rats receiving the LTD4/E4 antagonist. There was also significant (P less than .05) blunting of the endotoxin-induced fall in blood flow to the heart, gastrointestinal tract, and kidneys in animals pretreated with LY171883. Our data demonstrate that this selective leukotriene D4/E4 antagonist has significant salutary actions in endotoxin shock and suggest that LTD4 and/or E4 mediate, in part, the acute hemodynamic sequelae of endotoxin shock.

Acetophenones↗
PubMed1987

Oleic acid induces pulmonary injury independent of eicosanoids in the isolated, perfused rabbit lung.

Intravenous injection of oleic acid (OA) induces acute, edematous lung injury resembling some of the features of adult respiratory distress syndrome. One class of inflammatory agents speculated to be mediators of acute lung injury are eicosanoids. We tested the hypothesis that 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acid mediate the pulmonary injury induced by OA. OA (0.1 ml), injected as a bolus into the pulmonary artery (PA) of isolated, Krebs-perfused rabbit lungs, resulted in significant (P less than .05) increases in lung weight (an index of pulmonary edema), maximum airway pressure, perfusate immunoreactive (i) 6-keto PGF1a, and a significant, though minimal, increase in perfusate i-thromboxane B2. No measurable increases were recorded in PA pressure or perfusate i-leukotriene (LT) C4/D4. Neither pretreatment with the LTD4/E4 antagonist, LY171883 (10 microM), nor the 5-lipoxygenase/cyclooxygenase inhibitor, BW755C (100 microM), attenuated the pulmonary edema. However, BW755C abrogated the increase in i6-keto PGF1a. Additionally, administration of exogenous LTD4 (100 nM) into the perfusate produced only a minimal increase in lung weight in the isolated rabbit lungs (n = 4). These results demonstrate that 5-lipoxygenase and cyclooxygenase metabolites do not appear to mediate OA-induced injury in the isolated, Krebs-perfused rabbit lung.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Role of thromboxane, prostaglandins and leukotrienes in endotoxic and septic shock.

Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB2 and 6-keto-PGF1 alpha in a large number of species. A smaller, delayed and more prolonged increase in TxB2 and 6-keto-PGF1 alpha are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA2 exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB2 and 6-keo-PGF1 alpha concentrations in patients with septic shock, and elevated LTD4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance.

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C4/D4 and prostaglandin (PG)E2 production by tolerant cells was greater than that by non-tolerant controls (p less than 0.001). However, A23187-stimulated i-6-keto-PGF1 alpha levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B2 synthesis by endotoxin or glucan was significantly less in tolerant macrophages compared to controls (p less than 0.05). iLTC4/D4 production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis of iLTB4 by control macrophages was stimulated by endotoxin (p less than 0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

The effects of alpha adrenergic blockade on arachidonic acid metabolism and shock sequelae in endotoxemia.

Previous studies have suggested that increased alpha adrenergic activity stimulated prostaglandin synthesis and may be involved in the modulation of eicosanoid metabolism. These observations prompted investigation of the effect of the alpha adrenergic receptor antagonist phenoxybenzamine and the cyclo-oxygenase inhibitor indomethacin on endotoxin-induced shock severity, and on plasma immunoreactive iTxB2 and i6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively. Pretreatment with indomethacin alone blunted the endotoxin- (8 mg/kg) induced hypoglycemia. Phenoxybenzamine pretreatment also blunted endotoxin-induced mortality (LD80), hypoglycemia, hemoconcentration, and decreased plasma beta-glucuronidase (BG). The combination of phenoxybenzamine and indomethacin resulted in the improvement of all indices of shock severity. Rats pretreated with phenoxybenzamine and indomethacin alone or conjointly also exhibited significantly (P less than 0.05) enhanced survival compared to that of shocked control rats. Percent survival at 48 hr was 24, 64, 80, and 92 in untreated, indomethacin, phenoxybenzamine, and indomethacin + phenoxybenzamine treated, respectively. Mean plasma iTxB2 values at 30 min postendotoxin (15 mg/kg i.v.) were 1,532 +/- 319 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10) (P less than 0.05). Plasma i6-keto-PGF1 alpha was increased 4 hr after endotoxin in shocked controls to 4,161 +/- 885 pg/ml (N = 5) and attenuated by phenoxybenzamine to a value of 1,184 +/- 363 pg/ml (N = 4) (P less than 0.05). The results suggest that increased alpha adrenergic activity may be an important stimulus for arachidonic acid metabolism during endotoxemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Elevated plasma 6-keto-prostaglandin F1 alpha in patients in septic shock.

Central venous plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha), the stable hydrolysis product of prostacyclin (PGI2, a vasodilator and antiaggregatory metabolite of arachidonic acid), were determined in patients with septic shock. In eight nonsurvivors, the median plasma 6-keto-PGF1 alpha level was 229 pg/ml (range 31 to 21,998), compared to 30 pg/ml (range 22 to 194) in six survivors. In three control patients who were not septic or in shock, the levels were less than 4 pg/ml. This study demonstrates that human septic shock is associated with elevated plasma levels of 6-keto-PGF1 alpha, and raises the possibility that increased PGI2 formation may play a role in human septic shock.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Experimental endotoxemia in the rat: efficacy of prostacyclin or the prostacyclin analog iloprost.

The purpose of this study was to examine the effects of PGI2 and iloprost, a prostacyclin analog, on the sequelae of experimental endotoxic shock. Endotoxemia was produced in rats by IV injection of 20 mg/kg Salmonella enteritidis (LPS). Mean arterial blood pressure fell from 117 +/- 5 mmHg (N = 22) to 92 +/- 5 mmHg and 71 +/- 10 mmHg at 30 and 180 min post-LPS, respectively. In LPS vehicle-treated rats, blood glucose levels fell from 100 +/- 10 mg/dl to 36 +/- 8 mg/dl at 180 min. Plasma glutamate-oxaloacetate transaminase and lactate dehydrogenase (liver fraction) activities were significantly elevated above concentrations in nonshocked animals, increasing to 426 +/- 86 IU/ml and 1,019 +/- 339 IU/ml, respectively. Infusion of PGI2 or iloprost (0.5 micrograms/kg/min) did not alter the blood pressure response to LPS compared to vehicle controls. PGI2 significantly prevented the LPS-induced hypoglycemia while neither treatment significantly reduced the elevations in plasma enzymes nor prevented the lethality of LPS. Thus, the hemodynamic and biochemical indices of shock severity were not significantly improved by either prostacyclin or iloprost. It is suggested that the beneficial effects of PGI2 or prostacyclin analogs observed in other species during endotoxemia does not extend to the rat.

Animals↗
PubMed1985

Protective effect of a selective leukotriene antagonist in endotoxemia in the rat.

The role of lipoxygenase metabolites as inflammatory mediators in endotoxic shock remains uncertain. In the present study, the effects of a selective leukotriene (LT) D4/LTE4 antagonist, LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-YL)-butoxy]-phenyl ethanone], on endotoxin-induced sequelae in the rat were assessed. LY171883 was given as a bolus (30 mg/kg i.v.) 10 min before Salmonella enteritidis endotoxin (40 mg/kg) in ketamine-anesthetized (200 mg/kg i.m.) rats, followed by an infusion (10 mg/kg/hr) starting at 30 min postendotoxin. Carotid artery blood pressures were determined at 10 min before and at intervals up to 240 minutes postendotoxin administration. Compared to shocked vehicle controls LY171883 attenuated (analysis of variance, P less than .02) the initial (0-30 min), but not the later, endotoxin-induced hypotension. LY171883 prevented completely (analysis of variance, P less than .001) the neutropenia (0-180 min), but not the thrombocytopenia induced by endotoxin. Hemoconcentration resulting from endotoxemia was reduced by LY171883 compared to the vehicle control group (P less than .02). These data demonstrate that this LTD4/LTE4 antagonist has significant salutary actions in endotoxemia and suggest that LTs may contribute to some endotoxin-induced sequelae.

Acetophenones↗
PubMed1985

A more appropriate statistical method for analyzing mortality data in shock research.

Much of biological research deals with analysis of survival times such as time until death of an organism, length of survival of a skin graft, time of remission of an illness, or time until relief of a particular symptom. When analyzing data that consists of time until occurrence of an event, the commonly used parametric t-tests for comparing mean survival times of treatment groups is inappropriate when 1) the survival times do not follow the bell-shaped Gaussian (normal) distribution and/or 2) when some of the organisms are still "alive" (censored) at termination of the study period. As an alternative to the t-test, a relatively simple-to-use statistical procedure for comparing survival times of two groups is described. This procedure was developed to deal specifically with data consisting of survival times and to take into account the presence of censored observations.

Animals↗
PubMed1985

Ibuprofen, methylprednisolone, and gentamicin as conjoint therapy in septic shock.

Septic shock is associated with increased metabolism of arachidonic acid to thromboxane A2 (TxA2) and prostacyclin (PGI2). The effects of ibuprofen, methylprednisolone-sodium succinate, and gentamicin alone, or in combination on survival time and, TxA2 and PGI2 production in rats in a LD100 fecal peritonitis shock model were assessed. Plasma levels of TxA2 and PGI2 were measured by radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha, respectively. Drugs were given 30 min before induction of fecal peritonitis. Survival times in hours were as follows: fecal peritonitis = 10.5 +/- 0.4 (n = 50); ibuprofen (15 mg/kg) = 16.1 +/- 0.8 (n = 8); methylprednisolone-sodium succinate (40 mg/kg) = 17.1 +/- 0.7 (n = 22); methylprednisolone-sodium succinate (80 mg/kg) = 46.1 +/- 10.4 (n = 25) with 8% long-term survivors (survival greater than 7 days); gentamicin (4 mg/kg) = 23.8 +/- 4.4 (n = 16); methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 20.3 +/- 1.8 (n = 6); gentamicin + methylprednisolone-sodium succinate = 31.0 +/- 1.6 (n = 11); gentamicin + ibuprofen = 28.5 + 2.3 (n = 12); gentamicin + methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 46.9 +/- 5.4 (n = 8). Treatment with the combination of gentamicin + ibuprofen + methylprednisolone-sodium succinate (80 mg/kg) resulted in a mean survival time of 116 +/- 13.9 h with 26% long-term survivors. Methylprednisolone-sodium succinate (40 mg/kg) reduced (P less than 0.05) plasma iTxB2 from 995 +/- 78 (n = 16) to 714 +/- 48 (n = 18) pg/ml and i6-keto-PGF1 alpha from 4,090 +/- 334 (n = 12) to 2,009 +/- 119 (n = 17) pg/ml, 4 h post-FP. Methylprednisolone-sodium succinate (80 mg/kg) produced no further decrease in either iTxB2 or i6-keto-PGF1 alpha. Ibuprofen reduced the fecal peritonitis-induced iTxB2 and i6-keto-PGF1 alpha synthesis to nondetectable levels (less than 200 pg/ml). The latter results demonstrate that methylprednisolone-sodium succinate is less effective than ibuprofen in inhibiting arachidonic acid metabolism and suggest other salutary actions. These composite observations provide evidence that conjoint therapy with steroidal and nonsteroidal anti-inflammatory agents, and antibiotics in septic shock may be beneficial.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Exchange transfusions in rats with a perfluorated blood substitute: effect on thromboxane B2 levels during endotoxemia.

The effect of exchange transfusion with the perfluorated blood substitute (Fluosol-43) on endotoxin-induced synthesis of immunoreactive (i) thromboxane (Tx)B2, the stable metabolite of TxA2, was investigated in rats. Fluosol-43 was infused via the femoral vein with matched, incremental blood withdrawal from the carotid artery. Blood was replaced with Fluosol-43 to a final hematocrit of less than 3% in anesthetized rats maintained on 95% O2 and 5% CO2. Circulating platelet counts were reduced from 875 +/- 47 X 10(3)/mm3 in sham controls (N = 21) to 75 +/- 10 X 10(3)/mm3 in Fluosol-43 exchange transfused rats (N2 = 19, P less than 0.001). Circulating leukocytes were decreased from 105 +/- 6.3 X 10(2)/mm2 in sham controls (N = 21) to 17 +/- 1.4 X 10(2)/mm3 in the exchange transfused group (N = 19, P less than 0.001). Immunoreactive (i)TxB2 was measured in plasma or Fluosol-43 obtained from rats prior to and after injection of Salmonella enteritidis endotoxin (20 mg/kg). The iTxB2 levels at 30 minutes after endotoxin increased from 438 +/- 83 pg/ml (N = 4) to 2,895 +/- 663 pg/ml (N = 7) (P less than 0.01) in sham controls. iTxB2 also increased from 242 +/- 23 pg/ml (N = 7) to 2,213 +/- 589 pg/ml (N = 7) in the Fluosol-43 group (P less than 0.002) following endotoxin. The iTxB2 levels also remained significantly elevated (P less than 0.01) in both the sham and the Fluosol-43 groups 2 hours after endotoxin treatment. Endotoxin-stimulated iTxB2 levels at both 30 minutes and 2 hours in sham and Fluosol-43 exchange transfused rats did not vary significantly from each other. Indomethacin pretreatment (2 mg/kg) inhibited the increase in iTxB2 levels by greater than 85% in both groups (P less than 0.004). Blood and Fluosol-43 were taken from sham and exchange transfused rats and incubated ex vivo with the calcium ionophore, A23187 (10 microM). These studies demonstrated that ionophore-stimulated iTxB2 synthesis in the ex vivo Fluosol-43 samples was only 2.6% that of whole blood. Collectively these observations suggest that tissues other than blood components are potential sources of iTxB2 synthesis in endotoxin shock.

Animals↗
PubMed1984

The potential role of thromboxane and prostacyclin in endotoxic and septic shock.

The potential role of thromboxane (TxA2), a platelet aggregator and vasoconstrictor, and prostacyclin (PGI2) a platelet anti-aggregator and vasodilator, in endotoxic and septic shock was investigated. Early endotoxic shock in the rat is associated with marked elevations of plasma TxB2 (the stable metabolite of TxA2) and lesser increases in plasma 6-keto-PGF1 alpha (the stable metabolite of PGI2). Selective inhibition of TxA2 synthesis by several different chemical classes of Tx synthetase inhibitors was beneficial in endotoxic shock. In contrast, shock induced by acute intra-abdominal sepsis in the rat was characterized by high levels of plasma 6-keto-PGF1 alpha, which exceeded plasma TxA2 six- to eight fold at most time intervals studied. Tx synthetase inhibitors were not protective in this model of acute sepsis, but treatment with fatty acid cyclo-oxygenase inhibitors, an antibiotic (gentamicin), or reduction in arachidonic acid metabolism by essential fatty acid (EFA) deficiency significantly prolonged survival time. An important aspect of the latter study is that decreased arachidonic acid metabolism was an effective adjunct to antibiotic therapy. Conjoint administration of gentamicin in EFA-deficient rats or with indomethacin synergistically improved long-term survival, a result that was not evident with single treatment interventions. In addition to experimental studies, plasma TxB2 levels were measured during clinical sepsis. These studies demonstrated that plasma TxB2 levels were elevated tenfold in patients dying of septic shock compared with septic survivors or nonseptic controls. These composite experimental and clinical observations suggest that arachidonic acid metabolites play a role in the pathogenesis of endotoxic and septic shock.

Animals↗
PubMed1984

Kinin effects on chloride secretion do not require eicosanoid synthesis.

The actions of bradykinin on colonic epithelia from essential fatty acid-deficient (EFAD) rats has been examined. Electrogenic chloride secretion as short circuit current (SCC) and release of immunoreactive prostaglandin E2 (iPGE2) and i 6-keto PGF1 alpha have been measured. Resting release of prostanoids was significantly less in EFAD than in control tissues. Bradykinin, in a maximally effective concentration, produced no increase in prostanoid release in EFAD tissues in contrast to controls, while the SCC response was 55% of that in controls. In EFAD tissues the SCC response to bradykinin was the same whether or not the cyclooxygenase inhibitor piroxicam was present. EFAD tissues were not more sensitive to prostaglandins than control tissues. We conclude that while prostaglandin release contributes to the totality of the response to bradykinin, the latter's effect on electrogenic chloride secretion does not require the obligatory production of arachidonic acid metabolites.

6-Ketoprostaglandin F1 alpha↗