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)

Carvedilol's potent antioxidant activity could explain its protective action in brain ischemia, but may not apply to glutamate-induced excitotoxicity in cultured cerebellar granule cells, since glutamate neurotoxicity was not associated with the formation of lipid peroxidative products. Rather, carvedilol diminished the N-methyl-D-aspartate (NMDA)/glycine-induced increase in intracellular calcium ([Ca2+]i), lowering [Ca2+]i by a maximum of 66 +/- 5% (n = 8) with a 50% inhibitory concentration of 0.8 microM. Prior addition of 5 microM dihydropyridines did not shift the dose-response of carvedilol, but did significantly lower the NMDA/glycine-stimulated response to 64% of untreated (n = 8, P = 0.014). Inclusion of 5 microM carvedilol before the additions of NMDA/glycine prevented 85% of the increase in [Ca2+]i. Furthermore, carvedilol displaced 3[H]MK-801 binding to rat brain cortical membranes with a Kd of 29.4 +/- 2.2 microM (n = 6) and no selectively for the glutamate or glycine binding sites. These data therefore suggest that, in addition to its antihypertensive and anti-lipid peroxidative functions, carvedilol has neuroprotective activity as a calcium channel blocker and as a non-competitive inhibitor at the NMDA receptor.
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PMID:Neuroprotective effects of carvedilol, a new antihypertensive, at the N-methyl-D-aspartate receptor. 130 May

The influence of the azacrown ether derivative benzylaza-15-crown-5 on myocardial tolerance to ischemia and on the functional state of the zone of myocardial ischemia during coronary artery occlusion was investigated in experiments on anaesthetized open-chest cats. The compound tested produced a dose-dependent antiischemic effect and prevented the development of myocardial ischemia. In experiments on isolated guinea-pig papillary muscle benzylaza-15-crown-5 inhibited the first and second components of the isoproterenol-induced muscle contraction. The compound decreased the maximal contraction force and had no effect on the cardiac cycle duration and on the time necessary for reaching maximal tension. It is suggested that the protective effect of benzylaza-15-crown-5 during myocardial ischemia is mediated through the inhibition of calcium release from the sarcoplasmic reticulum.
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PMID:Investigation of antiischemic properties and mechanism of action of azacrown ether derivative. 130 17

The intracellular accumulation of PAF following cell stimulation suggests an intracellular signal transduction pathway. High affinity binding sites for PAF in microsomal membranes and displacement of PAF from these sites by structurally distinct PAF antagonists suggests the existence of an intracellular receptor. Suppression of primary genomic responses by a PAF antagonist selective for the intracellular Ca2+ and arachidonic acid metabolites, is linking the intracellular generation of PAF to immediate-early transcription. Several of the metabolites that transiently accumulate after injury may elicit beneficial effects on regenerative processes. The membrane metabolite PAF, which accumulates after seizure and ischemia, may initiate reparative processes by promoting transcriptional activation of immediate-early transcription factors. The long-term effects of these immediate-early gene transcription factors may provide a synthetic mechanism to replenish and rebuild cells following traumatic events.
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PMID:Second messengers derived from excitable membranes are involved in ischemic and seizure-related brain damage. 130 97

In culture the protracted and abusive stimulation of glutamate (GLU) receptors results in neuronal death through a mechanism involving the persistent translocation of PKC and the destabilization of (Ca2+)i homeostasis [(Ca2+)i HD]. In contrast, intermittent GLU receptor use elicits a coordinated expression of immediate early genes (IEG) acting as nuclear third messenger. Brain ischemia also is known to result in the paroxysmal abusive stimulation of glutamate receptors. The glutamate receptive elements in turn degenerate largely as a function of their inability to control homeostatic Ca2+ due to the irreversible translocation of PKC. In the present study we employed an in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal. With this model we sought to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LIGA 20 which in vitro have been demonstrated to block PKC translocation. Moreover, we sought to establish whether the persistent stimulation of ionotropic glutamate receptors would led to a change in ionotropic glutamate expression in the focal and perifocal area. Importantly, the perifocal area (i. e., the region surrounding the area of primary insult) is a region in which profound cellular reorganization occurs including neuronal death and glial proliferation and is a key region to target various neuroprotective drugs aimed at ameliorating the neurodegeneration following stroke. Receptor abuse dependent antagonists (RADA) drugs such as gangliosides selectively curtail the amplification steps that specifically differentiate signal transduction following physiological receptor use from that following pathological receptor abuse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sequelae of biochemical events following photochemical injury of rat sensory-motor cortex: mechanism of ganglioside protection. 130 98

The effects of gradually restoring calcium concentration in initiating reperfusion on cardiac function, coronary blood flow and myocardial calcium content during reperfusion following global ischemia have been observed in isolated working rat hearts. The results showed that gradually restoring calcium reperfusion facilitated the recovery of the contracting relaxing and pump functions as well as coronary blood flow, and decreased the occurrence of arrhythmias during reperfusion and myocardial calcium content after reperfusion. The mechanism of the protective effect of gradual calcium restoration on the hearts was probably due to the inhibition of calcium overload in cardiac cells. However high calcium reperfusion deteriorated cardiac function.
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PMID:[Protective effects of gradual restoring of calcium on working rat hearts with ischemia-reperfusion injury]. 130 99

1. For all outcome measures associated with delayed onset of urine output and the need for posttransplant dialysis, the prognosis is poor. Low 1-year graft survival of 49% and patient mortality of 13% associated with delayed function make it exceedingly important to identify measures that induce immediate posttransplant kidney function. 2. Intraoperative blood volume expansion with albumin improves short- and long-term posttransplant function at every level of analysis, including earlier urine onset, larger urine volumes, improved kidney function, decreased incidence of delayed and no function, and greater graft and patient survival. 3. Aggressive intraoperative blood volume expansion during cadaver renal transplantation enables the safe use of intraoperative verapamil without inducing hypotensive complications. 4. Intraoperative verapamil improves the decreased renal blood flow associated with poor function as seen after organ procurement and cold ischemia. 5. Clinical studies confirm previous animal research demonstrating that verapamil and other calcium antagonists prevent CsA-induced deterioration of renal blood flow. 6. Several studies have demonstrated elevated CsA blood concentrations during concomitant treatment with verapamil and diltiazem but not with the dihydropyridine class of calcium antagonists. 7. Despite the higher CsA blood levels, kidney function, as determined by serum creatinine and glomerular filtration rate, improves with verapamil. 8. Verapamil given intraoperatively into the renal artery after revascularization improves renal function and reduces the need for posttransplant hemodialysis. 9. The combination of intraoperative verapamil and blood volume expansion acts synergistically, resulting in larger urine volumes, improved renal function, and decreased incidence of delayed function. 10. Most importantly, perioperative administration of albumin and verapamil independent of each other, significantly improves graft survival. 11. The beneficial effects of albumin are probably due to improved hemodynamics from increased blood and plasma volumes leading to better renal perfusion and prompt oxygenation. Secondly, blood volume expansion provides a safeguard against the intraoperative use of verapamil. The beneficial effects of verapamil on posttransplant outcome may be related to cellular protection from ischemia, selected vasodilation of the afferent arteriole, inherent immunosuppressive properties, and elevated CsA blood levels.
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PMID:Perioperative fluid and drug therapy during cadaver kidney transplantation. 130 5

In order to clarify the effect of trauma and treatment as stresses on myocardia, we examined histological changes of myocardia in victims who received various kinds of traumata and treatments. We also undertook a histochemical study for calmodulin, which we found useful in the diagnosis of early ischemia. Those who died shortly after stab wounds, traffic accident or head injuries, showed mild cardiac lesions such as contraction bands or fragmentation and mild diffusion of calmodulin, a marker for necrosis. A case with hemorrhagic shock after a traffic accident, involving intense resuscitation for 2 h, showed severe cardiac lesions such as contraction bands, hydropic change and subendocardial hemorrhage along with severe diffusion of calmodulin. In most of the instant death cases after falls, severe contraction band necrosis and severe calmodulin diffusion were observed. Myocardia of victims, who died several days after head injuries or traffic accidents, generally demonstrated distinct diffusion of calmodulin as compared to the mild and non-specific lesions detected by hematoxylin-eosin (H&E) staining. In cases of long-term survival in a state of brain death, calmodulin staining was very low, which was not always associated with the severity of the lesions on H&E staining. In cases with intensive or extended treatment, it appeared to be difficult to determine the cause-effect relationship between trauma and cardiac lesions or to distinguish the lesions due to extrinsic factors from those of disease. In some cases, calmodulin intensely stained the areas with hydropic appearance or hypereosinophilia, which may be related to calcium overload.
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PMID:Myocardial lesions induced after trauma and treatment. 850 31

White matter of the mammalian CNS suffers irreversible injury when subjected to anoxia/ischemia. However, the mechanisms of anoxic injury in central myelinated tracts are not well understood. Although white matter injury depends on the presence of extracellular Ca2+, the mode of entry of Ca2+ into cells has not been fully characterized. We studied the mechanisms of anoxic injury using the in vitro rat optic nerve, a representative central white matter tract. Functional integrity of the nerves was monitored electrophysiologically by quantitatively measuring the area under the compound action potential, which recovered to 33.5 +/- 9.3% of control after a standard 60 min anoxic insult. Reducing Na+ influx through voltage-gated Na+ channels during anoxia by applying Na+ channel blockers (TTX, saxitoxin) substantially improved recovery; TTX was protective even at concentrations that had little effect on the control compound action potential. Conversely, increasing Na+ channel permeability during anoxia with veratridine resulted in greater injury. Manipulating the transmembrane Na+ gradient at various times before or during anoxia greatly affected the degree of resulting injury; applying zero-Na+ solution (choline or Li+ substituted) before anoxia significantly improved recovery; paradoxically, the same solution applied after the start of anoxia resulted in more injury than control. Thus, ionic conditions that favored reversal of the normal transmembrane Na+ gradient during anoxia promoted injury, suggesting that Ca2+ loading might occur via reverse operation of the Na+)-Ca2+ exchanger. Na(+)-Ca2+ exchanger blockers (bepridil, benzamil, dichlorobenzamil) significantly protected the optic nerve from anoxic injury. Together, these results suggest the following sequence of events leading to anoxic injury in the rat optic nerve: anoxia causes rapid depletion of ATP and membrane depolarization leading to Na+ influx through incompletely inactivated Na+ channels. The resulting rise in the intracellular [Na+], coupled with membrane depolarization, causes damaging levels of Ca2+ to be admitted into the intracellular compartment through reverse operation of the Na(+)-Ca2+ exchanger. These observations emphasize that differences in the pathophysiology of gray and white matter anoxic injury are likely to necessitate multiple strategies for optimal CNS protection.
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PMID:Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. 131 Oct 30

Insulin and insulin-like growth factors I and II (IGF-I and IGF-II) have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action in the brain are unknown. Since central neurons are particularly vulnerable to hypoglycemia that results from ischemia or other insults, we tested the hypothesis that growth factors can protect central neurons against hypoglycemic damage in vitro. IGF-I and IGF-II (3-100 ng/ml) each prevented glucose deprivation-induced neuronal damage in a dose-dependent manner in rat hippocampal and septal cell cultures. High concentrations of insulin (greater than 1 microgram/ml) also protected neurons against hypoglycemic damage. Epidermal growth factor did not protect against hypoglycemic damage. Both IGFs and insulin were effective when administered 24 hr before or immediately following the onset of glucose deprivation. Direct measurements of intraneuronal calcium levels and manipulations of calcium influx demonstrated that calcium influx and sustained elevations in intraneuronal calcium levels mediated the hypoglycemic damage. IGF-I and IGF-II each prevented the hypoglycemia-induced elevations of intraneuronal free calcium. Studies with excitatory amino acid receptor antagonists and calcium channel blockers indicated that NMDA receptors did, and L-type calcium channels did not, play a major role in hypoglycemic damage. Taken together, these findings indicate that IGFs can stabilize neuronal calcium homeostasis and thereby protect against hypoglycemic damage.
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PMID:IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage. 131 98

The activities of Ca2+/calmodulin (CaM)-dependent, Ca2+/phospholipid-dependent, and cyclic AMP-dependent protein kinases (CaM-KII, PKC, and PKA, respectively) were determined in rat brains after global ischemia. Both CaM-KII and PKC activities were significantly depressed in both hippocampal and cerebral cortical regions of ischemic animals, whereas no change was detected in PKA activity. The loss of CaM-KII activity was more dramatic and more sustained than the loss of PKC activity and correlated with the duration of ischemia. These decreases in enzyme activity were found in both supernatant and pellet fractions from crude homogenates. When the supernatant and pellet were analyzed for the amount of CaM-KII 50-kDa protein, a significant decrease was detected in supernatant fractions that paralleled a gain in the amount of CaM-KII in the pellet. Thus, the loss of CaM-KII activity in the supernatant can be explained by translocation of the enzyme to the pellet. Whether inactivation of CaM-KII occurs during or after the enzyme translocates from the supernatant to the pellet is unknown. Our results indicate that loss in CaM-KII activity parallels neuronal damage associated with ischemia; down-regulation of CaM-KII activity coincided with translocation of the enzyme to the particulate fraction, and it is proposed that this may be, in fact, a mechanism for controlling excessive CaM-KII phosphorylation.
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PMID:Ischemia-induced translocation of Ca2+/calmodulin-dependent protein kinase II: potential role in neuronal damage. 131 52


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