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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.
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PMID:Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep. 171 64

Experiments were designed to determine the role of the endothelium in response to hypoxia in the human internal mammary artery (IMA). Segments of IMA were harvested during coronary artery bypass surgery. Rings (4 mm in length) of IMA, with and without endothelium, were suspended to force transducers in organ baths containing a physiologic salt solution (37 degrees C, 95% O2/5% CO2, and pH = 7.4). The rings were contracted with norepinephrine (NE, 1 x 10(-7) M, initial tension), and then exposed to hypoxia (95% N2/5% CO2, PO2 = 35 +/- 5 mmHg). In IMA segments with endothelium, hypoxia caused an initial, transient relaxation (hypoxic inhibition) to 52 +/- 9% of the initial tension, followed by contraction of the blood vessel (hypoxic potentiation; 178 +/- 10% of initial tension). In vessels without endothelium, hypoxia only induced relaxation (to 10 +/- 2% of initial tension). In vessels with endothelium, reoxygenation induced transient rapid relaxation (to 31 +/- 12%; post-hypoxic inhibition) which then stabilized to 50 +/- 14% of the initial tension. However, segments without endothelium returned to their initial tension. Indomethacin (1 x 10(-5) M) reduced the endothelium-dependent hypoxic contraction and abolished the hypoxic and post-hypoxic inhibition. Free radical scavengers (superoxide dismutase plus catalase and deferoxamine) did not modify the responses to hypoxia and reoxygenation. These experiments indicate that hypoxia induces the release of an endothelium-derived constricting cyclooxygenase product from the human IMA endothelium, and that reoxygenation causes release of a cyclooxygenase-dependent endothelium-derived relaxing factor. The release of endothelium-derived constricting factor(s) could induce vasospasm and cause cardiovascular collapse if IMA grafts are exposed to hypoxia perioperatively.
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PMID:Vasoconstriction to hypoxia of the human internal mammary artery. 193 21

The fact that PAF-acether elicites acute circulatory collapse in anesthetized dogs supports the hypothesis that its endogenous double is involved in shock state events. The fact that cysteinyl containing leukotrienes has been shown to be released in various shock states, themselves producing noxious effects related to such circulatory disturbances, suggests a possible role of these arachidonic acid metabolites in shock syndrome. The present report summarizes the part played by these mediators in shock developments. More precisely, nanograms PAF-acether IV in anesthetized dogs produced biphasic effects on mesenteric blood flow and inhibited, in dogs and rats, histamine induced gastric acid secretion. These results confirm the distributive component of the PAF-acether circulatory collapse. On the other hand, as leukotrienes, nanograms PAF-acether elicited both plasma extravasation and vasoconstriction in guinea pig skin. Lastly, in conscious mice, lipoxygenase antagonists, but not cyclooxygenase antagonists, inhibited lethal effects of PAF-acether, suggesting a mutual and synergistic action of PAF-acether and leukotrienes in shock state.
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PMID:PAF-acether and leukotriene participation in acute circulatory shock. 377 41

Ketorolac is an analgesic drug known to induce its therapeutic effect by inhibiting prostaglandin synthesis. In this work we introduce the nonsteroidal antialgesic drug as a compound with ionophoretic properties for calcium ions, showing that ketorolac induces mitochondrial Ca++ release. This reaction did not depend on an uncoupler-like action, because the drug does not collapse the internal negative membrane potential nor does it affect oxidative phosphorylation. In addition, it is shown that ketorolac ferries calcium ions into energized liposomes and has a hydrophobic phase with an affinity constant of 4 x 10(-3). The therapeutic action of ketorolac is related to its ionophoretic properties in addition to its well known inhibitory effect on the cyclooxygenase enzyme.
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PMID:Ionophoretic-like properties of ketorolac for calcium. 750 27

The present study was designed to obtain a basic pharmacological profile of venom from the inland taipan (Oxyuranus microlepidotus). Venom (0.05-50 micrograms/ml) produced dose-dependent contractions in guinea-pig ileum, which could not be reproduced upon second administration. The cyclooxygenase inhibitor indomethacin (1 microM), a preceding anaphylactic response induced by egg albumin and inactivation of phospholipase A2 (PLA2) by incubation with 4-bromophenacyl bromide (1.8 mM) all significantly inhibited responses to venom (0.5 micrograms/ml). Venom (0.5 micrograms/ml) caused inhibition of stimulation-induced contractions in the prostatic segment of rat vas deferens which was not significantly affected by the alpha 2-adrenoceptor antagonist idazoxan (0.3 microM). Venom (10 micrograms/ml) caused time-dependent inhibition of the rat electrically stimulated phrenic nerve-diaphragm preparation, positive inotropic and chronotropic responses in rat isolated atria and relaxation in rat endothelium-denuded and -intact isolated aortae. In endothelium-intact aortae, the nitric oxide synthase inhibitor N-nitro-L-arginine (NOLA, 0.1 mM) significantly inhibited the response to venom (10 micrograms/ml). Venom (50 micrograms/kg, i.v.) caused an immediate drop in blood pressure followed by cardiovascular collapse in anaesthetised rats. Venom (10 micrograms/kg, i.v.) caused a gradual fall in blood pressure which was sometimes accompanied by a temporary cessation of respiration. A PLA2 assay detected the presence of PLA2 in the venom. These results suggest that the venom contains a component capable of causing the synthesis of arachidonic acid metabolites and a component capable of relaxing vascular smooth muscle. The inhibitory effect on the phrenic nerve-diaphragm is probably due to the previously identified neurotoxin (paradoxin).
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PMID:Some pharmacological studies of venom from the inland taipan (Oxyuranus microlepidotus). 960 83

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whether pretreatment with H1, H2, H3 receptor blockers, and cyclooxygenase and leukotriene pathway inhibitors was useful in preventing the depression in left ventricular (LV) contractility known to occur in this model. The dose of allergen was varied to produce similar degrees of shock between treatments. The animals were studied under pentobarbital anesthesia in which the treatment studies were approximately 3 wk apart. LV volumes were measured by sonomicrometric techniques. During challenge, mean arterial blood pressure (Pa), cardiac output (Q), and LV end-diastolic pressure (LVEDP) decreased approximately 50% compared with preshock values in all treatments. Histamine H3 receptor blockade was associated with higher heart rates (HR) and higher stroke work (SW) (p < 0.05) as compared with the other treatment studies. We conclude that histamine H3 activation by inhibiting adrenergic neural norepinephrine release contributes to cardiovascular collapse in AS.
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PMID:Histamine H3 receptor blockade improves cardiac function in canine anaphylaxis. 1050

We studied the hemodynamic responses of 29 anesthetized and mechanically ventilated piglets to acute hypoxia [reduction of Pao2 from 130 to 38 mm Hg induced by inhalation of 7% fraction of inspired oxygen (Fio2) for 7.5 min] before and during group B beta-hemolytic streptococci (GBS) sepsis. During hypoxia, nonseptic piglets maintained stable systemic blood pressure [105+/-9 (SD) to 97+/-14 mm Hg] and cardiac output (CO) (667+/-72 to 685+/-113 mL/min). However, during GBS/hypoxia, systemic blood pressure fell from 94+/-17 to 49+/-25 mm Hg, CO fell from 397+/-146 to 223+/-142 mL/min (both p < 0.001 versus pre-GBS), and cardiac arrest often ensued. We tested three hypotheses that might underlie GBS-induced intolerance to systemic hypoxia: 1) GBS-induced reduction of systemic CO/systemic oxygen delivery (QO2) below a critical QO2 beyond which the superimposition of hypoxia becomes intolerable; this mechanism is unlikely as nonseptic piglets with comparable reductions in CO/QO2 (induced by inflation of a left atrial balloon) tolerated hypoxia well; 2) GBS-induced inhibition of nitric oxide (NO) synthesis that is vital to tolerance of hypoxia; this mechanism is unlikely as infusion of the NO substrate L-arginine did not restore tolerance to hypoxia during GBS infusion (as it did after inhibition of NO synthesis during infusion of N-nitro-L-arginine in nonseptic piglets); and 3) GBS-induced production of pathologic prostaglandins that impaired the piglet's capacity to tolerate hypoxia; this mechanism finds support in the observation that inhibition of prostaglandins with the cyclooxygenase inhibitor indomethacin completely restored the ability of septic piglets to tolerate hypoxia. Further evaluation of GBS-induced intolerance to systemic hypoxia may provide insight into the incompletely understood mechanisms by which sepsis induces circulatory collapse in experimental animals and in humans.
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PMID:Hemodynamic homeostasis during acute hypoxia in septic and nonseptic piglets: differential role of prostaglandins and nitric oxide. 1075 60

Systemic complement activation has been noted in a variety of shock states, and there is growing evidence that, in addition to being proinflammatory effectors, products of complement activation contribute directly to generalized manifestations of shock, such as hypotension and acidosis. To study the effects of complement activation, we examined responses in rats to systemic activation of complement with cobra venom factor (CVF), including blood pressure, metabolic acidosis, changes in vascular permeability, and lung function. High doses of CVF produced circulatory collapse (mean arterial pressure = 110 +/- 16 and 35 +/- 9 mmHg in control and with CVF, respectively, P < 0.05), metabolic acidosis (HCO concentration = 27.8 +/- 1.7 and 9.6 +/- 3.4 meq/l in control and with CVF, respectively, P < 0.05), extravasation of albumin into the lung and gut, and modest arterial hypoxemia (PO2 = 486 +/- 51 and 201 +/- 36 Torr in control and during 100% O2 breathing, respectively, P < 0.05). Prior depletion of complement protected against these abnormalities. Other interventions, including neutrophil depletion and cyclooxygenase inhibition, prevented lung injury but had much less effect on systemic hemodynamics or gut permeability, suggesting that complement activation products induce injury by neutrophil- and cyclooxygenase-dependent pathways in the lung but not in the gut. These studies underscore the significant systemic abnormalities developing after systemic activation of complement.
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PMID:Systemic and lung physiological changes in rats after intravascular activation of complement. 1135 94

Vascular endothelial growth factor (VEGF) displays neurotrophic and neuroprotective activities, but the mechanisms underlying these effects have not been defined. Neuropilin-1 (NP-1) is a receptor for VEGF165 and placental growth factor-2 (PlGF-2), but the role of NP-1 in VEGF-dependent neurotrophic actions is unclear. Dorsal root ganglion (DRG) neurons expressed high levels of NP-1 mRNA and protein, much lower levels of KDR, and no detectable Flt-1. VEGF165 and PlGF-2 promoted DRG growth cone formation with an effect similar to that of nerve growth factor, whereas the Flt-1-specific ligand, PlGF-1, and the KDR/Flt-4 ligand, VEGF-D, had no effect. The chemorepellent NP-1 ligand, semaphorin 3A, antagonized the response to VEGF and PlGF-2. The specific KDR inhibitor, SU5614, did not affect the anti-chemorepellent effects of VEGF and PlGF-2, whereas a novel, specific antagonist of VEGF binding to NP-1, called EG3287, prevented inhibition of growth cone collapse. VEGF stimulated prostacyclin and prostaglandin E2 production in DRG cultures that was blocked by inhibitors of cyclooxygenases; the anti-chemorepellent activities of VEGF and PlGF-2 were abrogated by cyclooxygenase inhibitors, and a variety of prostacyclin analogues and prostaglandins strikingly inhibited growth cone collapse. These findings support a specific role for NP-1 in mediating neurotrophic actions of VEGF family members and also identify a novel role for prostanoids in the inhibition of neuronal chemorepulsion.
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PMID:Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. 1512 2

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown chemopreventive properties in colorectal cancer, involving both cyclooxygenase (COX)-dependent and -independent mechanisms. Apart from their selectivity for COX isoenzymes, NSAIDs differ in their acidic character which supports ability to uncouple oxidative phosphorylation. To assess the possible contribution of uncoupling to their antineoplastic properties, we compared the effect of sulindac sulfide (SS), an acidic NSAID and NS-398, a non-acidic tricyclic, on mitochondrial function and apoptosis in colorectal cancer cell lines (HT29, Caco-2, HCT15 and HCT116). Although cell lines displayed a different COX status, SS and NS-398 caused growth arrest in a dose-related manner. High dose (10(-4)M) of SS but not of NS-398, increased the percentage of subG1 cell population while reducing mitochondrial transmembrane potential (DeltaPsim). Cyclosporin A (CsA, 1 microM) prevented collapse of DeltaPsim induced by 10(-4)M SS but not by 7.5 microM FCCP used as a protonophoric control. SS and FCCP increased the cytosolic release of Smac/DIABLO which was differently affected by CsA pretreatment depending on the uncoupler. Finally, 7.5 microM FCCP failed to induce apoptosis whereas CsA prevented apoptosis induced by SS from 16% in HCT15 to 41% in HCT116. The present study shows that despite the ability of sulindac sulfide to behave as a protonophoric uncoupler, CsA-sensitive opening of mitochondrial permeability transition pore contributes little to its pro-apoptotic effect in colorectal cancer cells.
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PMID:Uncoupling of oxidative phosphorylation and Smac/DIABLO release are not sufficient to account for induction of apoptosis by sulindac sulfide in human colorectal cancer cells. 1575 4


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