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 aim of the present study was to determine whether the ET(A) receptor antagonist LU135252 can protect the mesenterium against ischaemia/reperfusion (I/R) damage. Direct occlusion of the superior mesenteric artery was performed for 30 min in two groups of dogs. Declamping was followed by 90 min of reperfusion. Mesenteric release of ET-1 was studied in series 1 (n=6). In series 2, 5 min before cross-clamping, the treated group (n=7) received an intravenous bolus of LU135252 (5 mg/kg), whereas the control group (n=6) was given vehicle. Mean arterial blood pressure and mesenteric blood flow were recorded. Mesenteric venous and systemic arterial serum lactate and glucose, plasma creatine kinase and free radical concentrations were determined at 15 min intervals. Ischaemia for 30 min induced a significant increase (P<0.05) in mesenteric ET-1 release (1594+/-526 pg/min, compared with 343+/-258 pg/min at baseline), which had returned to baseline after 20 min of reperfusion. LU135252 administration significantly decreased mesenteric blood flow during ischaemia (204+/-23%) compared with controls (320+/-34%, P<0.05). In contrast, mesenteric blood flow was higher in the treated group (120+/-19% compared with 82+/-7%; P<0.05) after 90 min of reperfusion. Mesenteric lactate production was reduced by ET(A) antagonist administration under ischaemia (0.77+/-0.02 mmol/l) compared with controls (1.36+/-0.04 mmol/l; P<0.01). Lower levels of venous creatine kinase were present in the treated group during ischaemia as well as after reperfusion (120+/-7% compared with 150+/-16%; P<0.01). Administration of LU135252 also improved the total scavenger capacity of the mesenteric bed during ischaemia [(15.9+/-3.9)x10(6) compared with (6.4+/-3.6)x10(6) relative light units; P<0.05] and early reperfusion [(8.7+/-3.1)x10(6) compared with (1.1+/-2.9)x10(6) relative light units]. Thus ET-1 is involved in I/R-induced disturbances in the intestine. LU135252 seems to counteract these changes, in part by increasing the antioxidant capacity of the mesenterium.
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PMID:ET(A) receptor blockade protects the small intestine against ischaemia/reperfusion injury in dogs via an enhancement of antioxidant defences. 1219 55

We have demonstrated that ischemia and reperfusion promoted augmented contractile response to endothelin-1 (ET) in coronary arteries in the presence of polymorphonuclear leukocytes (PMN). It has been also reported that ischemia and reperfusion increase ET binding sites in cardiac membrane in isolated rat heart perfused by blood cell-free system. To determine the role of PMN and L-arginine to nitric oxide (NO) pathway in these phenomena, isolated perfused rabbit hearts were subjected to 30 min of global ischemia followed by 30 min of reflow in the absence or presence of PMN and 10(-5)M of L-nitro-arginine (LNA). PMN was prepared with Percoll density gradients from peritoneal exudate elicited by glycogen. PMN activated with 10(-6)M of phorbol myristate acetate or their supernatant were infused into the coronary perfusion circuit after 5 min of reflow. LNA was added to perfusate also after reflow. The effect of superoxide dismutase (SOD: 50 IU/ml) was also determined. After the end of protocols, membrane fraction was isolated from the hearts for (125)I-ET-1 binding assay. ET-1 binding (Bmax) showed a significant increase by ischemia and reperfusion (P<0.01 vs control). That was markedly augmented with addition of activated PMN or their supernatant (both P<0.01), but abolished either by LNA or SOD (P<0.01 and P<0.05, respectively). These results indicate that increase in ET-receptor by ischemia and reperfusion is mediated by free radicals generated via L-arginine to NO pathway.
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PMID:L-nitro-arginine inhibits increase in endothelin binding sites induced by ischemia and reperfusion. 1223 73

Heme oxygenase (HO)-1 is up-regulated after ischemia/reperfusion and contributes to maintenance of hepatic perfusion and integrity. Blockade of HO-1 leads to an increased portal pressor response in the stress-exposed liver. We tested whether the increase in portal pressure reflects unmasking of a concomitant up-regulation of the vasoconstrictor endothelin (ET)-1. Hemorrhagic shock induced messenger RNAs encoding HO-1 (16-fold) and ET-1 (9-fold) with a similar time course in the liver. At maximum induction of both mediators, rats received either vehicle or the endothelin ET(A/B) antagonist bosentan (10 mg/kg intravenously). Subsequently, the HO pathway was blocked in all animals by tin-protoporphyrin (SnPP)-IX (50 micromol/kg intravenously). Portal and sinusoidal hemodynamics were measured using microflow probes and intravital microscopy, respectively. Blockade of the HO pathway led to a significant increase in portal resistance (sham/SnPP-IX, 0.17 +/- 0.046 mm Hg. min. mL(-1); shock/vehicle/SnPP-IX, 0.57 +/- 0.148 mm Hg. min. mL(-1); P <.05) and a decrease in sinusoids conducting flow (shock/vehicle/SnPP-IX: baseline, 28.3 +/- 0.85 sinusoids/mm; 10 minutes after SnPP-IX, 23.1 +/- 1.09 sinusoids/mm; P <.05). Intravital microscopy showed narrowing of failing sinusoids colocalizing with stellate cells after blockade of the HO pathway. Blockade of ET(A/B) receptors attenuated the increase in portal resistance (shock/bosentan/SnPP-IX, 0.29 +/- 0.051 mm Hg. min. mL(-1)) and prevented sinusoidal perfusion failure (shock/bosentan/SnPP-IX: baseline, 28.2 +/- 0.97 sinusoids/mm; 10 minutes after SnPP-IX, 28.8 +/- 1.18 sinusoids/mm) as well as sinusoidal narrowing. In conclusion, a functional interaction of the up-regulated vasodilatory HO system and the vasoconstrictor ET-1 on the sinusoidal level exists under stress conditions. Both mediator systems affect sinusoidal diameter via direct action on hepatic stellate cells in vivo.
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PMID:Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver. 1244 72

Immediately after an acute myocardial infarction (AMI) or in models of ischemia-reperfusion injury, cardiac endothelin (ET) system is markedly activated, and plasma levels of ET are increased. In the heart, expression of the main components of the ET system (ET-1 peptide, both receptor subtypes ETA and ETB, though not endothelin converting enzyme) are increased both at the gene level and protein level, in the viable myocardium, and--even more substantially--in the necrotic area. Despite these conspicuous abnormalities, the role of ET in this setting remains unclear. In the absence of human data, most short-term studies in animals (in terms of hours to up to 8 days post-AMI) and in the reperfused ischemic heart, have found beneficial effects of ET receptor blockade on survival rate, incidence of arrhythmias, cardiac function, and morphology. In contrast, many studies in which a long-term ET inhibition was started immediately post-infarction and the late effects were examined in animals with ensuing chronic heart failure (14-100 days postinfarction), adverse effects were also observed, such as scar thinning, further ventricular dilation, or even a worse survival rate. It appears that the ET system plays a dual role during the early post-AMI period. At present, it is not clear whether the short-term beneficial effects or long-term adverse effects of ET receptor blockade would prevail. Acute use of short-acting ET receptor antagonists in patients with AMI complicated by an acute heart failure is an attractive possibility that also remains to be investigated.
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PMID:The endothelin system and its role in acute myocardial infarction. 1283 71

Circadian rhythms have long been recognized to occur in many biologic phenomena, including secretion of hormones as well as autonomic nervous system. There is increasing evidence that circadian rhythms have been also found in cardiovascular events, for example, myocardial infarction, sudden cardiac death as well as stroke have shown a circadian pattern of the distribution. Transient myocardial ischemia, detected by ambulatory ST segment monitoring, is also unevenly distributed during the day. The pathophysiology and the mechanism underlying these variations are the focus of much investigation, while it is not full understood up to date. Heart rate, blood pressure, neural and humoral vasoactive factors such as plasma norepinephrine levels and renin activity, and probably also contractility are increased in the morning hours, indicating that increase in myocardial oxygen demand contribute importantly to the increased prevalence of ischemia in the morning. Our recent study found that circadian rhythm of ischemic threshold detected by repetitive exercise treadmill tests in patients with chronic coronary artery disease is also apparently associated with levels of plasma ET-1. This information should enable better understanding as well as treatment on patients on circadian variation of cardiovascular events.
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PMID:Circadian variation in myocardial ischemia: the possible mechanisms involving in this phenomenon. 1288 12

The aim of the present study was to investigate the putative role of endothelin (ET) in mediating ischemia/hypoxia-induced ANP release utilizing exogenous ET-1 or ET receptor antagonists (BQ-123 or Bosentan). Isolated rat hearts with non-distended atria were perfused using a Langendorff apparatus and heart rate maintained constant via atrial pacing. Global ischemia was induced either by direct reduction in perfusion or by infusion of exogenous ET-1 (5 x 10(-10) M) for 30 minutes. Perfusion with the ET receptor antagonists, BQ-123 (10(-6) M) or Bosentan (10(-5) M) was initiated 10 minutes before onset of ischemia. Moderate or severe ischemia was induced by reduction (52-61% and 70-82%, respectively) in perfusate flow. Thirty minutes of ischemia/hypoxia (5% O2) was followed by 30 minutes of reperfusion/re-oxygenation. Both moderate and severe ischemia increased ANP release. BQ-123 and Bosentan did not affect basal or ischemia-induced ANP release. Exogenous ET-1 perfusion induced a late increase in ANP release (P < 0.01) that did not exceed the increase in ANP release associated with equivalent direct flow reduction. Hypoxia induced an 8-fold increase in ANP release rate. The ANP release rate returned toward basal levels after re-oxygenation. Bosentan, but not BQ-123, significantly attenuated (P < 0.01) hypoxia-induced ANP release. In conclusion, in this system, ANP release is stimulated by moderate (or severe) ischemia and severe hypoxia independent of change in atrial distension; endogenous ET does not mediate basal and ischemia-induced ANP release; and hypoxia-induced ANP release is partially modulated via interaction with endogenous ET.
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PMID:The role of endothelin in mediating ischemia/hypoxia-induced atrial natriuretic peptide release. 1471 10

Over contraction of vascular smooth muscle may result in ischemia to ocular neuronal cells and deteriorate the glaucoma. The purpose of this study was to investigate the inhibitory effects of various commercial antiglaucoma drugs including brimonidine, dipivefrin, betaxolol, timolol, levobunolol, carteolol, brinzolamide, dorzolamide, unoprostone, latanoprost, pilocarpine, and preservative benzalkonium chloride on endothelin-1(ET-1) and KCl-induced increase of intracellular free Ca2+ ([Ca2+]i) in cultured rat A7r5 vascular smooth muscle cells. These drugs were diluted from original concentrations to 1/100, 1/1000, and 1/10000. [Ca2+]i mobility was analyzed by spectrofluorometry after loading with fura-2-AM. Betaxolol, timolol, levobunolol, and carteolol were found to inhibit KCl-induced release of [Ca2+]i in a dose-dependent manner. High concentrations of betaxolol, timolol, levobunolol, carteolol, and unoprostone also inhibited ET-1-induced increase of [Ca2+]i in A7r5 cells. However, ET-1- and KCl-induced increase of [Ca2+]i was not diminished by other drugs including brimonidine, dipivefrin, brinzolamide, dorzolamide, latanoprost, pilocarpine, and benzalkonium chloride. These results indicate that high concentrations of unoprostone and beta-adrenergic blocking agents including betaxolol, timolol, levobunolol, and carteolol may inhibit ET-1-induced increase of [Ca2+]i. The mechanism may be mediated by inhibition of extracellular calcium influx via blocking of L-type voltage-dependent Ca2+ channel in A7r5 cells.
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PMID:Inhibition of endothelin-1 and KCL-induced increase of [CA2+]i by antiglaucoma drugs in cultured A7r5 vascular smooth-muscle cells. 1527 25

In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.
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PMID:The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. 1555 28

Endothelial dysfunction is an early marker for transplant atherosclerosis. Potential mechanisms for allograft endothelial dysfunction include stimulation of alloimmune-dependent pathways, ischemia/reperfusion injury, metabolic alterations, chronic infections, as well as direct endothelial cell activation by immunosuppressive drugs. Thus far, no study has directly compared different immunosuppressive drugs with respect to their potential to modulate endothelial function under normoxic and hypoxic conditions. We examined human microvascular endothelial cells (HMEC-1) in vitro after stimulation with therapeutic concentrations of methylprednisolone (MP), mycophenolic acid (MMF), cyclosporine A (CS), rapamycin (Rapa), and tacrolimus (Tac) to designate the corresponding induction of oxidative stress, apoptosis, metabolic activity, proliferation, endothelin (ET-1) release, and nitric oxide (NO) production. HMEC-1 stimulation with CS, MMF, and Rapa resulted in a stronger induction of oxidative stress compared with MP and Tac. Induction of oxidative stress by immunosuppressives correlated with metabolic activity and apoptosis. Low- and high-dose MMF significantly inhibited cell proliferation under hypoxic conditions, whereas low-dose CS and MP increased endothelial cell proliferation. ET-1 release was significantly elevated by Rapa, Tac, and MP. NO production was significantly enhanced by all immunosuppressive drugs except Tac. Quality and quantity of immunosuppression modify endothelial function and lead to a dose-dependent and oxygenation-state-related endothelial activation. MP and MMF induced minor changes in endothelial function compared with CS, Rapa, and Tac.
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PMID:The impact of immunosuppression on endothelial function. 1561 84

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.
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PMID:FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. 2824 Aug 25


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