Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various beneficial effects of calcium channel blockers on cell and organ function following endotoxic shock, organ ischemia, and reperfusion have been reported; however, it is not known whether these agents have any salutary or deleterious effects on immune responses after low-flow conditions. Therefore, the aim of this study was to determine (a) the effect of hemorrhage on lymphocyte IL-2, IL-3, IL-6, and IFN-gamma synthesis, and (b) whether diltiazem has any salutary or adverse effects on these parameters when administered following hemorrhage and resuscitation. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that level for 60 min, and resuscitated with shed blood plus twice that volume of Ringer's lactate. Immediately following resuscitation mice received either diltiazem (2400, 800, or 400 micrograms/kg body wt), or an equivalent volume of saline. The mice were sacrificed 24 hr later, splenic lymphocytes were obtained, and their capacity to produce lymphokines was assessed. The results indicated that in the vehicle-treated animals, hemorrhage significantly decreased (P less than 0.05) IL-2, IL-3, IL-6, and IFN-gamma synthesis by 82 +/- 19%, 64 +/- 28%, 71 +/- 11%, and 86 +/- 14%, respectively. However, diltiazem (400 but not 2400 micrograms/kg) treatment after hemorrhage restored lymphocyte capacity to produce IL-2, IL-3, IL-6, and IFN-gamma (P less than 0.05). Additional groups of animals were subjected to sepsis by cecal ligation and puncture 3 days following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diltiazem restores IL-2, IL-3, IL-6, and IFN-gamma synthesis and decreases host susceptibility to sepsis following hemorrhage. 190 99

Among the mediators for development of endotoxic shock, plasma kallikrein and prostanoids have been suggested to play an important role. The role of kallikrein and PGF2 alfa in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring inactive and active kallikreins and PGF2 alpha in superior mesenteric vein, right ventricle and aorta during shock induced by occlusion of the superior mesenteric artery. After removal of the clamp in dogs subjected to occlusion for 1 hour, the mean arterial blood pressure fell rapidly within 5 min and gradually increased over the next 60 min, with return to the control values. The plasma concentrations of PGF2 alfa in superior mesenteric vein, right ventricle and aorta increased three- to fivefold within 5 min of reperfusion. Thereafter the PGF2 alfa levels fell, so that at 60 min after declamping they did not significantly differ from the control values. No significant changes were observed in the levels of inactive and active kallikreins. The results suggest that PGF2 alfa released by intestinal tissues may contribute to the development of shock caused by intestinal ischemia.
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PMID:Changes in plasma kallikrein and PGF2 alfa concentrations during circulatory shock. Studies with superior mesenteric artery occlusion in anesthetized dogs. 292 98

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 +/- 4 (x +/- SEM) to 77 +/- 6 mm Hg and CBF from 159 +/- 12 to 116 +/- 14 ml/100 g/min (p less than 0.002). In contrast, CMRO2 increased from 9.7 +/- 0.9 to 11.7 +/- 1.1 ml/100 g/min after 15 min (p less than 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.
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PMID:Cerebrovascular and cerebrometabolic effects of intracarotid infused platelet-activating factor in rats. 339 15

Endotoxemia is a frequent complication of many health disorders. It is characterized by systemic release of a variety of endogenous inflammatory mediators which effect cardiovascular depression, reductions in organ blood flow, tissue ischemia and derangements in cellular metabolism leading to death. During a continuous intravenous infusion of Escherichia coli lipopolysaccharide, the chronology of alterations in hepatosplanchnic blood flow, hepatic carbohydrate metabolism and pancreatic insulin secretion has been studied in awake Yucatan miniature pigs (Sus scrofa). Endotoxic shock in this model is characterized by reductions in portal venous and hepatic arterial blood flow, early transient increases in pancreatic insulin secretion, increases in the 3H-glucose-derived rates of glucose appearance and disappearance, profound hypoglycemia, hyperlactatemia and metabolic acidosis. Reductions in hepatic oxygen delivery are compensated for by enhanced oxygen extraction efficiency, but hepatic gluconeogenesis continues at an inadequate rate to compensate for increased glucose utilization. Experimental therapies including lidocaine, naloxone, captopril, dichloroacetate and glucagon each effect specific improvements in cardiovascular or metabolic function, but none significantly alter the composite derangements responsible for lethality in this model.
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PMID:Endotoxemia in Yucatan miniature pigs: metabolic derangements and experimental therapies. 353 41

Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. 753 18

The free radical nitric oxide (NO.) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO. synthase (NOS). In the earlier phases of shock, activation of the endothelial, constitutive NOS (ecNOS) occurs, which, in the case of endotoxic shock, is triggered by endotoxin-induced, acute release of platelet-activating factor (PAF) and also other potential mediators. This early overproduction of NO. results in reduced contractile responsiveness to norepinephrine and contributes to the acute decrease in blood pressure afforded by endotoxin. In the delayed phase of endotoxic shock, a distinct isoform of NOS (iNOS) is induced in various organs and in the vessel wall. The induction of iNOS is mediated by the release of endogenous tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and PAF by endotoxin. These mediators, in turn, act in parallel, or in synergy to induce iNOS. Induction of iNOS contributes to delayed vascular hyporeactivity in vivo and ex vivo, and to the delayed decrease in blood pressure in rats with endotoxic shock. As endotoxic shock, hemorrhagic shock also leads to an early activation of ecNOS, which is responsible for the early vascular hyporeactivity, and a delayed induction of iNOS that contributes to delayed circulatory failure (vascular decompensation and hyporeactivity). The induction of iNOS in hemorrhagic shock is unlikely to be mediated by endogenous release of endotoxin, e.g., due to intestinal ischemia. Endogenous circulating glucocorticoids exert a tonic suppression of the induction of iNOS, as well as the cardiovascular failure in response to endotoxin. Endotoxin tolerance is associated with increased plasma levels of glucocorticoids, which may account for the blunted cardiovascular response and reduced induction of iNOS in these animals. A wide variety of drugs that exert protective effects in various models of circulatory shock also inhibit the induction of iNOS, and this effect is likely to contribute to their protective actions. These drugs include glucocorticoids, TNF-alpha antibodies, IL-1 receptor blockers/antibodies, PAF antagonists, dihydropyridine calcium-channel antagonists, tyrosine kinase inhibitors, and the experimental drug cloricromene. Various forms of shock can also lead to an inhibition of NO. production by the calcium-dependent ecNOS.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in nitric oxide production in various forms of circulatory shock. 753 48

Nitric oxide (NO.) plays a central role in the physiology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 758 76

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

Leukemia inhibitory factor (LIF) and tumor necrosis factor (TNF) have been shown to protect animals from radiation, hyperoxia, and endotoxic shock. TNF is also known to induce the expression of manganese superoxide dismutase (MnSOD) in vitro and in vivo. We therefore examined the effects of these cytokines on reperfusion injury in the isolated rabbit heart model. Rabbits were injected intravenously with 10 micrograms of either human TNF-alpha or lymphotoxin (TNF-beta), or murine TNF-alpha or murine LIF dissolved in saline. Control animals were injected with an equal volume of saline. After 24 h, hearts were isolated and perfused. Following an equilibration period, the hearts were subjected to 1 h ischemia and 1 h of reperfusion. All treated groups showed significant increases in percent recovery of developed tension (% preischemic) when compared to saline-treated control hearts. In addition there were significant decreases in lactate dehydrogenase release (LDH), accumulation of thiobarbituric acid reactive substances (TBARS), and accumulation of carbonyl proteins. These results correlate with increases in myocardial MnSOD activity. Thus, the protection from myocardial reperfusion injury seen in the pretreated group may be due to a mechanism that involves the induction of MnSOD.
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PMID:Leukemia inhibitory factor and tumor necrosis factor induce manganese superoxide dismutase and protect rabbit hearts from reperfusion injury. 776 Mar 46

Secretory phospholipase A2 type II is known to be involved in various inflammatory processes. This paper describes the changes in secretory phospholipase A2 (PLA2) gene expression induced by ischemia and endotoxic shock. Type I PLA2 (pancreatic type) is not expressed in ischemic and endotoxic-shock brains but both ischemia and endotoxin injection induce type II PLA2 expression. The first phase of PLA2 II gene expression following the ischemic insult occurs 1-6 h after ischemia. During that period, PLA2 II gene expression is slightly enhanced and it returns to control levels after 1 day. A second phase corresponding to higher levels of induction of mRNA for PLA2 appears at a later period after ischemia between 7 and 18 days. In situ hybridization shows that PLA2 gene expression in the ischemic brain is localized in regions known to be vulnerable to ischemia (hippocampus and neocortex). Endotoxic shock which leads to a major inflammatory state induces an abundant expression of the PLA2 II mRNA in the brain and this high level of expression appears in a large number of brain structures. The results suggest that the early phase of ischemia-induced PLA2 gene expression could be an additional element in mechanisms leading to neuronal death. The later phase of increased PLA2 mRNA levels is more probably related to the inflammatory response associated to neuronal degeneration.
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PMID:Expression of group II phospholipase A2 in rat brain after severe forebrain ischemia and in endotoxic shock. 792 87


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