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)

Using confocal microscopy, onset of the mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The MPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the MPT in these models and prevent cell killing, showing that the MPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the MPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the MPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the MPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the MPT. Similarly, salicylate induces a CsA-sensitive MPT and killing of cultured hepatocytes. These in vitro findings suggest that the MPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the MPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the MPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this MPT and prevents apoptosis. The MPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the MPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the MPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.
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PMID:The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. 971 96

Cyclosporin A (CyA) has been shown to prevent mitochondrial injury following ischemia-reperfusion injury. Therefore, the present study was designed to investigate the effect of CyA on ischemia-reperfusion injury in the isolated rat heart preparation. Hearts from Sprague-Dawley rats were perfused in the Langerdorffmode at constant pressure (80 cm H2O) and paced (270 beats/min). After equilibration, hearts were treated with CyA (10(-5) mol/l) (n = 8) or its vehicle, cremophor (Cr) (n = 8) for 10 minutes before exposure to 30 minutes of global ischemia and 60 minutes of reperfusion. Hemodynamic variable vascular reactivity, and oxygen consumption (MVO2) were tested at baseline and at selected points during reperfusion Hemodynamic variables were significantly improved in the CyA group. The maximal mean percentage of preservation for left ventricular developed pressure (PDVG) was -14.9 +/- 10.7% and +31.5 +/- 23.6% respectively for Cr and CyA group (p<0.05) The maximal mean percentage of preservation for dp/dt was -11.7 +/- 11.4% and +28.3 +/- 29.9% respectively for Cr and CyA group (p < 0.05): the compliance, -dP/dt was also preserved, maximal mean preservation was -25.9 +/- 9.2% and +53.1 + 30.1% respectively in Cr and CyA group (p < 0.01). Oxygen debt was decreased at 30 minutes of reperfusion in the CyA-treated hearts: 0.06 x 10(-2) +/- 0.23 x 10(-2) cc/min/g compared to Cr-treated hearts: 0.61 x 10(-2) +/- 0.37 x 10(-2) cc/min/g (p = 0.05). The coronary endothelial dependent and independent responses were similarly decreased in both groups during reperfusion. Thus, in the isolated rat heart preparation, CyA preserves myocardial function (hemodynamic variables) and oxygen consumption without affecting the coronary vascular function during ischemia-reperfusion injury.
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PMID:[Cyclosporine A prevents ischemia-reperfusion induced myocardial dysfunction in the isolated heart of the rat]. 973 3

Credit for the first pediatric heart transplant is given to Kantrowitz and colleagues who, in 1967, transplanted the heart of an anencephalic infant into a 3-week-old with tricuspid atresia (1). Although the infant only survived a few hours after surgery, this pioneering procedure emphasized the technical feasibility of heart transplantation in childhood. Over the next decade, enthusiasm for heart transplantation declined in both adults and children, as it became apparent that the therapeutic armamentarium for controlling acute allograft rejection was inadequate for achieving graft and patient survival. Towards the end of the 1970s, several advances led to renewed interest in human heart transplantation. These included topical cooling of the donor heart to protect the myocardium from ischemia (and enabling distant procurement), the technique and interpretation of endomyocardial biopsy for the diagnosis of allograft rejection (2) and, most importantly, the introduction of cyclosporine into human clinical trials (3). Cyclosporine was the first oral agent specifically to inhibit T lymphocytes, the principal mediators of allograft rejection. The favorable impact on survival of adult heart transplant recipients was immediately apparent (4) and led to renewed interest in pediatric heart transplantation. The pediatric heart transplant program at the University of Pittsburgh commenced in 1982, drawing on the experience of the adult program which had begun two years earlier. It rapidly became apparent that children present unique problems for the transplant physician and surgeon. This review draws on many of the lessons learned in our program over the last 15 years and reviews some of the prospects for the future of pediatric thoracic organ transplantation.
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PMID:15 years of pediatric heart transplantation at the University of Pittsburgh: lessons learned and future prospects. 1008 82

Hypertension is a significant and prevalent risk factor for the development of cardiovascular disease and target organ damage. The urgency of treatment of high blood pressure depends on the level of blood pressure elevation and the presence of coexistent risk factors for cardiovascular disease. Likewise, the level to which blood pressure is reduced is not restricted to the definition of high blood pressure but instead depends on the underlying disease. Diabetes and renal insufficiency, for example, require blood pressure goals below those that are traditionally defined. In the absence of contraindications, beta-blockers and diuretics are still recommended as first-line agents for treatment of uncomplicated hypertension. Calcium channel antagonists also may reduce mortality. In patients with diabetes, ACE inhibitors are effective first-line agents in type 1 and type 2 diabetic patients who are hypertensive or have microalbuminuria. ACE inhibitors may be beneficial in patients with nondiabetic renal insufficiency as well. Calcium channel antagonists may have some effect in retarding progression of diabetic nephropathy although a recent trial found a higher incidence of death as a secondary endpoint in hypertensive diabetic patients who were treated with calcium channel antagonists. Beta-blockers seem to be safe and well tolerated in patients with mild to moderate intermittent claudication, although patients with rest pain or limb ischemia have not been studied. Beta-blockers should not be used in patients with asthma. Dihydropyridine calcium channel antagonists are the preferred treatment of hypertension in patients with Raynaud's but should be avoided in patients with severe gastroesophageal reflux disease. NSAIDs, particularly piroxicam and indomethacin, raise mean blood pressure by approximately 5 mm Hg, enough to consider a change of either NSAID or antihypertensive to one that is not as affected by NSAIDs. Cyclosporine A can induce hypertension by its vasoconstrictive effects, particularly on the kidney. Calcium channel antagonists may antagonize this vasoconstriction while allowing the clinician to reduce the dose of cyclosporine A required to achieve its immunosuppressive effect.
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PMID:Evaluation and treatment of hypertension. 1046 27

Cyclosporin A (CsA) reduces ischemic brain damage when administered in such a way that its penetration across the blood-brain barrier is enhanced. Since only pretreatment has previously been used in focal ischemia, the objective of the present study was to establish whether posttreatment is efficacious and to assess the window of therapeutic opportunity for CsA. To that end, CsA was given 5 min to 6 h after the start of reperfusion following 2 h transient ischemia, and infarct volume was assessed after 48 h by triphenyltetrazolium chloride staining. Attempts were made to circumvent the BBB to CsA by an intracerebral needle lesion, by an increase in the intravenous CsA dose, or by osmotic opening with intracarotid mannitol. The results were compared to those obtained with FK506. Intravenous CsA in a dose of 10 mg/kg failed to reduce infarct volume, unless preceded by a needle lesion. That procedure, and an increase in CsA dose to 50 mg/kg, reduced infarct volume to about 50% of control, but the higher dose had toxic side effects. The coupled intracarotid infusion of mannitol and CsA (10 mg/kg) was more efficacious, without overt side effects. However, mannitol proved dispensable since CsA alone reduced infarct volume to 30% of control, with a therapeutic window of 3-6 h. When given after 5 min of reflow, CsA reduced infarct volume to 10% of control and was clearly more neuroprotective than FK506. Possibly, this is because CsA blocks the mitochondrial permeability transition pore which is opened under adverse conditions.
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PMID:Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia. 1051 51

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability transition (PT) pore in the mitochondrial inner membrane abruptly increases the permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition (MPT) and prevents necrotic cell death from oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischemia/reperfusion injury, and other models of cell injury. Confocal fluorescence microscopy directly visualizes onset of the MPT from the movement of green-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicating fluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca2+, and mitochondrial generation of reactive oxygen species precede and contribute to onset of the MPT. Confocal microscopy also shows directly that the MPT is a critical event in apoptosis of hepatocytes induced by tumor necrosis factor-alpha. Progression to necrotic and apoptotic cell killing depends, at least in part, on the effect the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are at least partially maintained, apoptosis follows the MPT. Cellular features of both apoptosis and necrosis frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis) depending on modifying factors such as ATP.
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PMID:Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. 1066 21

Pretransplant transfusions were repeatedly shown to be associated with improved graft survival in the "pre-cyclosporine era," and have recently been shown to be beneficial in patients on modern immuno-suppressive regimes. In an attempt to improve this transfusion effect and minimize the potential development of cytotoxic antibodies, we have given these transfusions, with concomitant cyclosporine cover, prior to transplantation. Ninety-two renal transplantations were performed in 91 children in the study group (group 1) and all received pretransplant transfusions with cyclosporine cover. Results were compared with a preceding group of 102 children (104 transplantations) who had received pretransplant transfusions without cyclosporine cover (group 2). There were 70 cadaver and 22 living-related donor (LRD) transplants in group 1, and 88 cadaver and 16 LRD transplants in group 2. Graft survival rates (1- and 5-year) for cadaver transplantation were 96% and 90% in group 1 compared with 78% and 64% in group 2 (P = 0.001). For LRD transplantation, these figures were 95% and 87% in group 1 and 81% and 69% in group 2. There was no difference between the two groups in terms of age at transplantation, sex, donor age, HLA-A, -B, -DR mismatches, or cold and warm ischemia times. All cadaver graft recipients received quadruple, sequential immunosuppression post transplant. However, 9 patients in group 1 were changed to tacrolimus for recurrent rejection episodes. No patient developed persistent lymphocytotoxic antibodies post transfusion or side effects of cyclosporine. Cyclosporine can be safely given with whole blood prior to transplantation with no adverse effect and no sensitization. Graft survival was significantly improved in this group of patients and graft loss due to rejection was exceptional. This effect should be further evaluated in prospective studies.
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PMID:Pretransplant blood transfusions with cyclosporine in pediatric renal transplantation. 1087 82

Cyclosporin A (CsA) has been shown to be efficacious in protecting against ischemic injury after short periods (5 to 10 min) of forebrain ischemia. The present experiments were undertaken to study if a long period of forebrain ischemia (30 min), induced at a brain temperature of 37 degrees C, is compatible with survival and if the brain damage incurred can be ameliorated by CsA. The results showed that animals subjected to 30 min of forebrain ischemia at a brain temperature of 37 degrees C failed to survive after the first 24 h of recovery and showed extensive neuronal necrosis in all selectively vulnerable regions after 1 day of survival. CsA, when injected in combination with an intracerebral lesion to open the blood-brain barrier, markedly prolonged the survival time. CsA-injected animals also showed amelioration of histological lesions, an effect that was sustained for at least 4 days. Experiments with mitochondria isolated from the neocortex and hippocampus showed that state 3 respiratory rates decreased during ischemia, recovered after 1 and 3 h of recirculation, and then showed a secondary decline at 6 h. Administration of CsA prevented this secondary decline. Measurements of neocortical cerebral blood flow showed that there was no secondary hypoperfusion prior to secondary mitochondrial dysfunction, implying that changes in blood flow may not be responsible for the rapidly developing, secondary brain damage. The results thus demonstrate that if brain temperature is upheld at 37 degrees C, a 30-min period of ischemia is not compatible with survival after the first day of recovery, and gross histopathological damage develops within that period. CsA was efficacious in prolonging animal survival, ameliorating brain damage, and preventing the secondary mitochondrial dysfunction. Since CsA blocks the mitochondrial permeability transition pore its action may, at least in part, be on mitochondrial integrity and function.
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PMID:Cyclosporin A enhances survival, ameliorates brain damage, and prevents secondary mitochondrial dysfunction after a 30-minute period of transient cerebral ischemia. 1096 94

The opening of the mitochondrial permeability transition pore (PTP) has been suggested to play a key role in various forms of cell death, but direct evidence in intact tissues is still lacking. We found that in the rat heart, 92% of NAD(+) glycohydrolase activity is associated with mitochondria. This activity was not modified by the addition of Triton X-100, although it was abolished by mild treatment with the protease Nagarse, a condition that did not affect the energy-linked properties of mitochondria. The addition of Ca(2+) to isolated rat heart mitochondria resulted in a profound decrease in their NAD(+) content, which followed mitochondrial swelling. Cyclosporin A(CsA), a PTP inhibitor, completely prevented NAD(+) depletion but had no effect on the glycohydrolase activity. Thus, in isolated mitochondria PTP opening makes NAD(+) available for its enzymatic hydrolysis. Perfused rat hearts subjected to global ischemia for 30 min displayed a 30% decrease in tissue NAD(+) content, which was not modified by extending the duration of ischemia. Reperfusion resulted in a more severe reduction of both total and mitochondrial contents of NAD(+), which could be measured in the coronary effluent together with lactate dehydrogenase. The addition of 0.2 microm CsA or of its analogue MeVal-4-Cs (which does not inhibit calcineurin) maintained higher NAD(+) contents, especially in mitochondria, and significantly protected the heart from reperfusion damage, as shown by the reduction in lactate dehydrogenase release. Thus, upon reperfusion after prolonged ischemia, PTP opening in the heart can be documented as a CsA-sensitive release of NAD(+), which is then partly degraded by glycohydrolase and partly released when sarcolemmal integrity is compromised. These results demonstrate that PTP opening is a causative event in reperfusion damage of the heart.
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PMID:Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. 1107 47

Na(+) influx has been implicated to play an important role in the mechanisms of neuronal cell damage under ischemia as well as in neurodegenerative disorders. Thus far, however, the effects of Na(+) influx on astrocytic damage have not been studied extensively. In the present study, we have examined the effects of Na(+) influx induced by veratridine (Na(+) channel opener), monensin (Na(+) ionophore), and glutamate (co-transportation with Na(+)) on rat cultured astroglial damage. Cells were incubated with bicarbonate buffer with 25 mM glucose containing either 100 microM veratridine, 10 microM monensin, or 1 mM glutamate with or without 1 mM ouabain for 20 h. Cellular damage was evaluated quantitatively by lactate dehydrogenase (LDH) release or 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reduction. Veratridine, monensin, or glutamate alone did not induce significant astroglial damage. Veratridine and monensin co-incubated with ouabain, which inhibits active extrusion of Na(+) by Na(+),K(+)-ATPase, thereby enhances intracellular Na(+) accumulation, caused significant cell death (P<0. 001, approximately 50% cell damage), whereas glutamate did not. Na(+)-free solution substituted by choline (impermeable cation) attenuated cell damage induced by veratridine and monensin markedly, while Li(+) substitution (permeable cation) rather exacerbated. Nifedipine (100 microM), a blocker of L-type Ca(2+) channel, reduced veratridine-induced glial damage by 50%. Neither bepridil nor benzamil, a blocker of Na(+)-Ca(2+) exchanger, had any protection. Cyclosporin A (1 or 10 microM), an inhibitor of mitochondrial permeability transition or 10 microM N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (zVAD-fmk), which inhibits a broad range of caspases, did not show protective effects.
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PMID:Astroglial cell death induced by excessive influx of sodium ions. 1108 May 18


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