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)

The effects of a clinically used purified micronized flavonoid fraction (S 5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin, and leukotriene B4 (LTB4) were investigated by intravital microscopy in the hamster cheek pouch preparation. The authors also investigated the effects of S 5682 on macromolecular permeability increase and leukocyte adhesion during ischemia-reperfusion by using the same preparation. S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally to male hamsters for ten days at 20 mg/kg/day (10 mg/kg twice a day). Fluorescein isothiocyanate (FITC)-labeled dextran (mol wt 150,000) was given intravenously, thirty minutes after completion of the cheek pouch preparation. The leukocytes were stained by continuous IV infusion of acridine orange (0.5 mg/kg/minute). Histamine (2 microM), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for five minutes, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) that occurred either at five minutes after the beginning of each topical application or ten minutes after the onset of reperfusion was quantified in ultraviolet light microscopy. The results from 60 animals divided into 10 groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing effect of histamine (343.5 +/- 22.3 versus 207.5 +/- 32.0 leaks/cm2; P < 0.01), bradykinin (345.2 +/- 19.0 versus 206.2 +/- 21.6 leaks/cm2; P < 0.01), and LTB4 (353.3 +/- 27.5 versus 242.7 +/- 33.6 leaks/cm2; P < 0.05). At reperfusion, after thirty minutes of ischemia, S 5682 significantly decreased the observed macromolecular permeability (103.6 +/- 15.4 versus 42.6 +/- 9.3 leaks/cm2; P < 0.01). Flavonoid-treated animals also displayed a statistically significant lower number of adhering leukocytes to the venular endothelium (83.5 +/- 9.5 versus 48.4 +/- 12.3 per 6 mm2; P < 0.05). These results demonstrate that oral administration of S 5682 for ten days at 20 mg/kg body weight/day had a protective effect against leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature. Since firm leukocyte attachment to the endothelial wall and subsequent emigration of leukocytes into the interstitium is a mechanism for tissue damage during inflammation, attenuation of this phenomenon during conditions of ischemia-reperfusion can in part explain previous observations that this purified micronized flavonoid fraction decreases edema formation. The present data illustrating the inhibitory effect of a clinically relevant dose of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.
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PMID:Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in the hamster cheek pouch. 915 83

In the brain intravascular and interstitial spaces are separated by a highly specialized endothelial lining, which is the morphological substrate of the blood-brain barrier (BBB). Under physiological conditions the BBB exerts rigid control of water soluble compounds moving from blood into brain and from brain into blood, respectively. Under pathological conditions such as trauma or ischemia, an increase in BBB permeability may occur that allows plasma constituents to escape into the brain tissue. This "opening" of the BBB may, at least in part, be due to a massive release of autacoids, which thus act as mediators of vasogenic brain edema. Five criteria have to be fulfilled by a given autacoid to be considered a mediator candidate: (i) a permeability-enhancing action under physiological conditions; (ii) a vasodilatory action; (iii) the ability of inducing vasogenic brain edema; (iv) an increase of concentration in tissue or interstitial fluid under pathological conditions; and (v) a decrease of brain edema by inhibiting the release or action of a given autacoid. Among the mediator candidates discussed, only bradykinin fulfills all these criteria. Histamine, arachidonic acid and free radicals, including nitric oxide, may also be considered mediator candidates of brain edema, but for each of these compounds evidence is less clear than for bradykinin. Although the concept of autacoids mediating brain edema is well established and supported by experimental data, it has not yet gained entrance into the clinics. Treatment of patients suffering from vasogenic brain edema is symptomatic and mainly concentrated on the control of intracranial pressure.
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PMID:Brain edema: pathogenesis and therapy. 918 9

Brief mesenteric ischemia (10 min) can stimulate both visceral A delta- and C-fiber afferents and evoke reflex excitation of the cardiovascular system. We have shown that exogenous histamine causes reflex cardiovascular responses and that intra-arterial injection of 5-hydroxytryptamine (5- HT) into a mesenteric artery stimulates visceral A delta- and C-fiber afferents. We therefore hypothesized that brief abdominal ischemia is associated with release of histamine and 5-HT into the interstitium, where these mediators could stimulate or sensitize ischemically sensitive visceral afferent nerve endings. Accordingly, we measured concentrations of histamine and 5-HT in portal venous blood plasma and intestinal lymph fluid in cats. Cannulas were placed in a portal vein and in an intestinal lymphatic duct distal to the lymph node. Lymph and plasma histamine and 5-HT concentrations were measured by high-performance liquid chromatography before, during, and immediately after 10-min occlusion of the descending thoracic aorta. Histamine concentration increased significantly (P < 0.01) in portal venous blood plasma from a preocclusion level of 2.2 +/- 0.6 to 4.6 +/- 1.0 and 6.4 +/- 1.3 nmol/ml and in lymph fluid from a preocclusion level of 3.4 +/- 1.0 to 6.3 +/- 1.3 and 6.4 +/- 1.3 nmol/ml (n = 18) during brief ischemia and reperfusion, respectively. Also, the 5-HT concentration was significantly (P < 0.01) elevated in portal venous blood plasma from a preocclusion concentration of 1.1 +/- 0.5 to 2.7 +/- 0.8 and 2.5 +/- 0.8 nmol/ml and in lymph from a preocclusion level of 1.8 +/- 0.7 to 4.0 +/- 1.4 and 4.6 +/- 1.3 nmol/ml (n = 13) during brief ischemia and reperfusion, respectively. Because visceral afferent nerve endings are located in the interstitium, elevation of the interstitial concentration of histamine and 5-HT may contribute to the stimulation or sensitization of these nerve terminals during the brief ischemia and reperfusion period.
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PMID:Increased histamine and 5-HT in portal vein plasma and mesenteric lymph during brief ischemia and reperfusion. 932 99

Resuscitation in pediatric emergency and some neurological interventions may result in ischemia reperfusion-induced cerebral injuries. Histamine is one of the well established mediators of cerebral swelling and H1- and H2-receptor antagonists could prevent the development of ischemic brain edema. In the present study, time-dependent changes in the blood-brain barrier (BBB) permeability were investigated in the cerebral cortex of male Wistar rats 1, 2, 4, 8, and 16 h after the beginning of post-ischemic reperfusion. Cerebral ischemia-reperfusion evoked by the 4-vessel occlusion model resulted in significant (p < 0.05) elevations in BBB permeability for albumin, but not for sodium fluorescein. Pre-treatment with a new intracellular histamine receptor antagonist could not prevent ischemic brain edema formation in that model. We conclude that experimental studies could help us to reveal the therapeutic role of histamine receptor antagonists during ischemic brain edema.
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PMID:Cerebral ischemia reperfusion-induced vasogenic brain edema formation in rats: effect of an intracellular histamine receptor antagonist. 978 44

Histamine plays a role in the regulation of the blood-brain barrier function. In this study, effects of N, N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE), an intracellular histamine binding site antagonist on the cerebrovascular permeability were investigated in control and post-ischemic male Wistar rats. Intravenous administration of DPPE, in a dose of 1 and 5 mg/kg, was not followed by any major clinical change, but 20 mg/kg proved to be toxic. A significantly (P<0.05) increased permeability for sodium fluorescein (MW=376) was seen in hippocampus, striatum, and cerebellum, but not in parietal cortex, of rats 2 h after the injection of 5 mg/kg DPPE, whereas no increase was measured later. There was a more intense (5- to 12-fold) and prolonged elevation in Evan's blue-labeled albumin (MW=67,000) extravasation 2, 4, and 8 h after 5 mg/kg DPPE administration in each brain region. In parietal cortex, a dose-dependent increase in albumin extravasation developed 4 h after intravenous injection of 1, 5, and 20 mg/kg DPPE, but doses applied resulted in no significant change in sodium fluorescein permeability. Cerebral ischemia-reperfusion evoked by four-vessel occlusion caused a significant (P<0.05) increase in the permeability for albumin in each region, but few changes in that of sodium fluorescein. DPPE treatment failed to prevent the ischemia-reperfusion-induced changes in the blood-brain barrier permeability. In conclusion, DPPE induced an increased permeability in the rat, which supports a role for histamine, as an intracellular messenger, in the regulation of the blood-brain barrier characteristics.
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PMID:Effects of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine on the blood-brain barrier permeability in the rat. 1063 62

The blood-brain barrier (BBB) which is located in the continuous endothelial lining of cerebral blood vessels rigidly controls exchange of water soluble compounds under physiological conditions. Under pathological conditions such as trauma or ischemia, BBB permeability may increase thus allowing plasma constituents to escape into brain tissue. This "opening" of the BBB may, at least in part, be mediated by massive release of autacoids resulting in vasogenic brain edema. Five criteria have to be fulfilled by an individual autacoid to be considered a mediator candidate of cerebral edema: i) a permeability-enhancing action under physiological conditions, ii) a vasodilatory action, iii) the ability to induce vasogenic brain edema, iv) an increase of concentration in the tissue or interstitial fluid under pathological conditions, and v) a decrease of brain edema by specific interference with the release or action of a given autacoid. Among the mediator candidates considered, bradykinin is the only one to meet all criteria. Histamine, arachidonic acid and free radicals including nitric oxide may also be considered mediators of brain edema, but for each of these compounds evidence is less clear than for bradykinin. Although the concept of mediators inducing brain edema is well established by experimental studies, only a bradykinin receptor antagonist has so far gained entrance into clinical evaluation.
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PMID:Mediators of cerebral edema. 1063 98

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

An extensive blood loss activates generalized inflammatory response. Abdominal organs and especially intestines are very sensitive to the ischemia-reperfusion insults due to hemorrhagic shock (HS) and blood volume restoration. Previously obtained results suggest that studies on peritoneal lavage fluid (PLF) can contribute to elucidation of inflammatory processes in abdominal organs in HS. Histamine (H) levels, total cell, and mast cell (MC) numbers, and MC ultrastructure in the fluid lavaged from peritoneal cavity were compared in the following groups of rats: control (gr. 1), sham operation (gr. 2), untreated hemorrhagic shock (gr. 3), shock treated with blood volume restoration with lactated Ringer's solution (LR) (gr. 4), shock treated with platelet activating factor (PAF)-receptor antagonist Ginkgolide B (BN52021), and LR (gr. 5). A shock-related significant increase in total cell numbers, MC numbers, MC degranulation, and histamine levels in PLF were observed. The restoration of blood volume caused further elevation of the above phenomena (gr. 4) while BN52021 seemed to inhibit peritoneal MC mobilization and degranulation as well as to attenuate increase in peritoneal H level (gr. 5). The peritoneal cavity is a place of rapid and strong reaction to hemorrhage. Evaluation of peritoneal histamine levels might be helpful in the monitoring of shock dependent intra-abdominal processes. Peritoneal MC mobilization and degranulation, and increase in histamine level is inhibited by BN52021.
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PMID:BN52021 inhibits activation of peritoneal mast cells caused by hemorrhage and blood volume restoration. 1072 Dec 66

Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.
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PMID:[Cerebral ischemia and histamine]. 1242 46

Rat stomach ECL cells release histamine in response to gastrin. Submucosal microinfusion of endothelin or adrenaline, known to cause vasoconstriction and gastric lesions, mobilized striking amounts of histamine. While the histamine response to gastrin is sustainable for hours, that to endothelin and adrenaline was characteristically short-lasting (1-2 h). The aims of this study were to identify the cellular source of histamine mobilized by endothelin and adrenaline, and examine the differences between the histamine-mobilizing effects of gastrin, and of endothelin and adrenaline. Endothelin, adrenaline or gastrin were administered by submucosal microinfusion. Gastric histamine mobilization was monitored by microdialysis. Local pretreatment with the H1-receptor antagonist mepyramine and the H2-receptor antagonist ranitidine did not prevent endothelin- or adrenaline-induced mucosal damage. Submucosal microinfusion of histamine did not cause damage. Acid blockade by ranitidine or omeprazole prevented the damage, suggesting that acid back diffusion contributes. Gastrin raised histidine decarboxylase (HDC) activity close to the probe, without affecting the histamine concentration. Endothelin and adrenaline lowered histamine by 50-70%, without activating HDC. Histamine mobilization declined upon repeated administration. Endothelin reduced the number of histamine-immunoreactive ECL cells locally, and reduced the number of secretory vesicles. Thus, unlike gastrin, endothelin (and adrenaline) is capable of exhausting ECL-cell histamine. Microinfusion of alpha-fluoromethylhistidine (known to deplete ECL cells but not mast cells of histamine) reduced the histamine-mobilizing effect of endothelin by 80%, while 1-week pretreatment with omeprazole enhanced it, supporting the involvement of ECL cells. Somatostatin or the prostanoid misoprostol inhibited gastrin-, but not endothelin-stimulated histamine release, suggesting that endothelin and gastrin mobilize histamine via different mechanisms. While gastrin effectively mobilized histamine from ECL cells in primary culture, endothelin had no effect, and adrenaline, a modest effect. Hence, the striking effects of endothelin and adrenaline on ECL cells in situ are probably indirect, possibly a consequence of ischemia.
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PMID:Submucosal microinfusion of endothelin and adrenaline mobilizes ECL-cell histamine in rat stomach, and causes mucosal damage: a microdialysis study. 1450 42


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