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)

Calcium is believed to be responsible for initiating a deleterious cascade of events that leads to irreversible cell injury during prolonged ischemia. Theoretically, the calcium-dependent cascade of events can be interrupted at three distinct points: a) by reducing calcium inflow into the cytosol using a calcium channel blocker such as verapamil, b) by increasing the mitochondrial capacity to sequester calcium using ethane-1-hydroxy-1:1-diphosphonic acid (EHDP), and c) by inhibiting the activation of the calcium-calmodulin complex using trifluoperazine (TFP). To evaluate the protective role of these agents in prolonged ischemia, 190 unilaterally nephrectomized rats underwent total occlusion of the renal artery for 90 min. One hour before surgery, all the rats received an i.p. injection of either saline or one of the drugs. Of the 190 rats, 130 were used to determine survival and optimal drug doses; the remaining 60 rats were used to determine blood urea nitrogen and serum creatinine at 40 h and 5 days after surgery. Only 33% of the rats in the control group survived for 10 days. However, 87.5% (P less than 0.005), 90% (P less than 0.005), and 60% (P less than 0.01) of the rats pretreated with verapamil, TFP and EHDP respectively survived for 10 days. No differences, however, were seen in renal function tests among the control, TFP or EHDP groups. This suggests that calcium antagonists are successful in protecting the kidney from prolonged ischemic injury despite impaired renal function tests. It may also indicate that these agents delay or prevent the ischemic cells from undergoing irreversible damage.
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PMID:Blocking the calcium cascade in experimental acute renal failure. 211 82

The pH dependence of the Ca2(+)-transporting ATPase of bovine cardiac sarcolemma was determined in a membrane vesicle preparation. The maximal velocity (Vmax) at saturating external Ca2+ showed a sigmoidal pH dependence with maximal values in the 6.0-6.5 range, a half-maximal value at 7.2 and minimal (less than or equal to 15%) values at pH greater than or equal to 8.0. The apparent affinity for Ca2+ (1/Km) varied over 10(4)-fold for 6.0 less than or equal to pH less than or equal to 8.5, increasing with increasing pH. Plots of log(1/Km) vs. pH were biphasic. In the acid range (6.0 less than or equal to pH less than or equal to 7.2), a slope of 2.6 was observed for the calmodulin-activated form of the pump. For 7.2 less than or equal to pH less than or equal to 8.5, a slope of 0.5 was observed. At pH 7.4, the Km is approx. 48 +/- 19 nM. The Ca2+ pump of cardiac sarcoplasmic reticulum in the same preparation had a Km of 304 +/- 115 nM and showed a similar pH dependence except that the slope in the acid range was 1.7. When calmodulin was removed from the sarcolemmal pump, its Km was raised to approx. 1.0 microM, the slope in the acid range was reduced to 1.7 and the Vmax was markedly reduced. The results are explicable in terms of a model in which each of the two Ca2+ binding sites on the pump contains two buried COO- groups responsible for high affinity. The Km effect is explained by 2 H+ vs. 1 Ca2+ competition for occupation of each of the two cytoplasmically-oriented translocators (4 H+ vs. 2 Ca2+). The Vmax effect is explained by counter-transport of H+. The findings are considered in terms of the published amino acid sequence of the cardiac sarcolemmal pump and recent site-directed mutagenesis vs. function studies identifying the Ca2+ binding site in the skeletal sarcoplasmic reticulum pump. The kinetic data are also applied to pump behavior under conditions of ischemia and acidosis.
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PMID:The pH dependence of the cardiac sarcolemmal Ca2(+)-transporting ATPase: evidence that the Ca2+ translocator bears a doubly negative charge. 214 13

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.
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PMID:Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium. 214 19

We evaluated several doses of cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS-19755), a potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight-arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium-calmodulin binding. High-dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS-19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium-calmodulin binding. We conclude that CGS-19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.
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PMID:CGS-19755, a competitive NMDA receptor antagonist, reduces calcium-calmodulin binding and improves outcome after global cerebral ischemia. 216 37

Many investigations have shown that calcium and adenosine triphosphate are crucial to central nervous system functions. It is probable that alterations of these substances during central nervous system ischemia are involved in the processes that cause irreversible neural damage. Calcium regulates several protein kinases that are responsible for phosphorylation of proteins vital for many central nervous system functions. Using a rabbit spinal cord ischemia model, we found protein kinase C and calcium/calmodulin-dependent kinase were severely affected during the first hour of ischemia. Protein kinase A was not significantly affected. The time course of lost protein kinase C enzyme activity closely corresponded to irreversible loss of neurologic function, and there is evidence that protein kinase C inhibitor activity is generated. Also, drugs that inhibit protein kinase C increased neurologic damage when administered during the early phases of ischemia. These results suggest that protein phosphorylation, particularly by protein kinase C, is critical to maintenance of neurologic function.
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PMID:Protein phosphorylation during ischemia. 223 67

We correlated the efficacy of several clinically relevant pharmacotherapies with their ability to prevent calcium influx into neurons and subsequent binding to calmodulin. We studied the administration of CGS 19755, nimodipine, nicardipine, and combinations of these drugs before or immediately after ischemia in globally ischemic rats. Calcium-calmodulin binding was graded by an immunohistochemical assay after 2 and 24 hours of reperfusion (n = 5-6 at each time period), and histologic damage was graded by light microscopy after 72 hours of reperfusion (n = 6). Calcium-calmodulin binding correlated with the severity of delayed histologic damage in various brain regions. In untreated ischemic control rats, marked calcium-calmodulin binding was seen in CA1 and CA3 after 24 hours of reperfusion (p less than or equal to 0.01). Administered before ischemia, CGS 19755 prevented calcium-calmodulin binding across all brain regions after 2 and 24 hours of reperfusion compared with controls (p less than or equal to 0.05). This effect was most prominent in CA3 and CA1, where the drug also reduced delayed neuronal damage (p less than or equal to 0.05). Lower doses or postischemic administration of CGS 19755, nimodipine, nicardipine, and a combination of postischemic CGS 19755 and nicardipine had a more limited effect on calcium-calmodulin binding and did not protect against delayed neuronal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuronal protection correlates with prevention of calcium-calmodulin binding in rats. 223 82

Effective utilization of nonheartbeating cadaver donor organs is limited by the time required to obtain the necessary family consent prior to organ retrieval (a delay of at least 4-6 hr); this exceeds by far the maximum tolerance of kidneys to warm ischemia. Measures that could theoretically permit use of such organs include: (1) rapid in situ flush cooling; (2) continued in situ kidney cooling until permission for donation is secured; and (3) cell-membrane stabilization of vital organs, with only minimal invasion of the donor body. These measures were tested experimentally in dogs. Hemorrhagic shock was produced in mongrel dogs. One hour after cessation of heartbeat, a rapid perfusion tube was placed into the femoral artery; it was advanced, and its balloon was inflated in the aorta above the renal vessels. The kidneys were then flushed in situ with 1000 cc of cold preservation solution containing a calmodulin inhibitor, trifluoperazine. Two other catheters were inserted percutaneously into the peritoneal cavity for continuous intraperitoneal cold perfusion. Core temperatures of 4 degrees C were maintained in situ in the kidneys for 5 hr. Six hours after cardiac arrest, the kidneys were removed and preserved ex vivo at 4 degrees C for 24 hr, and were then transplanted into their respective hosts (n = 11), where they sustained life uneventfully. This method requires a 2-inch incision in the groin of the prospective donor, and two small stab wounds of the abdomen; i.e., semi-invasive procedures which are commonly performed in emergency rooms. The perfused body could then be released to the family if donation is denied. The recently documented increased willingness of the public to donate organs when the termination of life support is not an issue, and court decisions that have authorized the performance of nondeforming diagnostic procedures in cadavers without consent, suggest that the salvage of transplantable semi-invasive procedures described in this study may be useful in helping to alleviate the current shortage of transplantable organs. This technique can provide the time needed for families to consider the option of organ donation from nonheartbeating cadaver donors in an unhurried and unpressured manner, while preserving the viability of vital organs during the decision-making process.
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PMID:An approach to organ salvage from non-heartbeating cadaver donors under existing legal and ethical requirements for transplantation. 230 58

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.
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PMID:Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy. 234 99

The protective effects of protein kinase inhibitors and a calmodulin kinase inhibitor (W-7) against ischemic neuronal damage were examined in the CA1 subfield of the hippocampus. Staurosporine, KT5720, and KT5822 were used as inhibitors of protein kinase C (PKC), cyclic AMP-dependent protein kinase, and cyclic GMP-dependent protein kinase, respectively. All test compounds were injected topically into the CA1 subfield of the hippocampus. In the gerbil ischemia model, staurosporine (0.1-10 ng) administered 30 min before ischemia prevented neuronal damage in a dose-dependent manner. However, KT5720, KT5822, and W-7 were ineffective, even at a dose of 10 ng. In the rat ischemia model, staurosporine (10 ng) also prevented neuronal damage when administered before ischemic insult, although staurosporine administered 10 or 180 min after recirculation was ineffective. These results suggest the involvement of PKC in CA1 pyramidal cell death after ischemia and that the fate of vulnerable CA1 pyramidal cells through PKC-mediated processes could be determined during the early recirculation period.
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PMID:Staurosporine, a novel protein kinase C inhibitor, prevents postischemic neuronal damage in the gerbil and rat. 238 38

In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.
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PMID:Bepridil: a pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia. 248 9


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