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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years, the results of large randomized and controlled trials of antiarrhythmic agents for primary and secondary prevention of ventricular tachycardia and ventricular fibrillation have changed perceptions of the actions of antiarrhythmic agents regarding both efficacy and risk. The premature termination of the CAST trials of primary prevention in postinfarct patients highlighted the proarrhythmic risk and inefficacy of the sodium channel blockers (class I action), encainide, flecainide, and moricizine, in patients at relatively low risk for death in the long term. The excess mortality with therapy was attributed to proarrhythmia due to facilitation of reentry, especially during acute ischemia. About the same time, European trials with amiodarone, a complex agent with antiadrenergic action and powerful action to prolong refractoriness (class III action), indicated enhanced survival after infarction with amiodarone but not with agents with class I action. Recent verbal reports of larger and placebo-controlled trials (EMIAT and CAM-IAT) confirm a significant reduction in arrhythmia mortality, possibly with a favorable trend in total mortality. While an older trial with dl-sotalol (class III and beta-blocking actions) showed a trend toward improved survival after infarction, a recent trial with d-sotalol in patients with recent infarction or remote infarction and heart failure was prematurely terminated because of excess mortality attributed to proarrhythmia (torsades de pointes), indicating the importance of beta-blocking properties of a class III agent. A secondary prevention trial (ESVEM) in patients surviving an episode of VT or VF showed significant superiority of dl-sotalol compared to an array of agents that block sodium channels with respect to both efficacy and tolerance. Occurrence rates of arrhythmias treated with drugs tested for efficacy either by suppression of inducible arrhythmias or by suppression of spontaneous ectopy were higher and equivalent for both testing methods. A secondary prevention trial of amiodarone and multiple agents that block sodium channels in survivors of cardiac arrest (CASCADE) showed a significant increased efficacy of amiodarone but poorer long-term tolerance compared with the other agents. Comparative analysis of the results of the various trials suggests that class III action coupled with antiadrenergic action is more efficacious in both primary and secondary prevention of life-threatening ventricular arrhythmias and that lethal proarrhythmias may be the predominant effect in attempts at primary prevention in low-risk populations due to class I or so-called pure class III action.
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PMID:From first class to third class: recent upheaval in antiarrhythmic therapy--lessons from clinical trials. 878 Mar 26

Ischemic neuronal injury is supposed to be caused in part by the extracellular accumulation of excitatory amino acids (EAA). Neurotransmitter and metabolic EAA can be released from synaptic vesicles and cytoplasm of neurones and glial cells. In this study the release of the glutamate analogue [3H]D-aspartate ([3H]D-ASP), loaded into 500 microns slices of rat hippocampus, was investigated. The efflux of the label was measured during anoxic-aglycemic ("ischemic") and normoxic K+ depolarization. To identify the pools from which [3H]D-ASP is released we have estimated its calcium dependence and the effects of inhibitors of: (1) Na(+)-dependent transporter of amino acids (100 microM L-trans-pyrrolidine-2,4-dicarboxylic acid/L-trans-PDC/), (2) sodium channel (1 microM tetrodotoxin TTX), and (3) anion channel (1 mM furosemide). [3H]D-ASP released upon normoxic depolarization was 40% inhibited by TTX, nearly 40% by L-trans-PDC and over 50% by furosemide. The "ischemic" release was in 40% calcium dependent, completely TTX independent and in approximately 50% blocked by furosemide treatment. Our data suggest that EAA accumulated in the synaptic cleft during ischemia are mainly released from the cytosolic compartment by mechanisms which are connected with the ischemic increase of extracellular potassium concentration.
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PMID:Enhancement of 3[H]D-aspartate release during ischemia like conditions in rat hippocampal slices: source of excitatory amino acids. 878 12

Myocardial reperfusion is associated with increased influx of activated neutrophils and intracellular accumulation of sodium in the ischemic zone. Lidocaine is a sodium channel blocker that also inhibits several neutrophil functions. We investigated the effect of lidocaine on infarct size in rabbits undergoing 30 minutes of ischemia and 48 hours of reperfusion. Animals randomly received lidocaine (10 mg/kg, n = 11) or saline (n = 11) during occlusion. The area of necrosis (AN) was measured histologically and expressed as a percentage of the area at risk (AR). Myocardial oxygen consumption and the perfusion bed at risk were similar in the two groups. Lidocaine reduced infarct size compared with control (AN/AR = 30% +/- 4% vs 61% +/- 5%, respectively; p = 0.0001). This reduction was associated with a significant decrease in neutrophil infiltration and in the degree of hemorrhage in the reperfused myocardium. Lidocaine also significantly inhibited superoxide anion production by rabbit and human neutrophils in whole blood. Therefore, lidocaine treatment results in a significant reduction in infarct size in the rabbit model, partly through reduction of neutrophil-mediated injury to viable cells, suggesting that lidocaine may be useful to enhance myocardial salvage in patients undergoing pharmacologic or mechanical reperfusion.
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PMID:Reduction of myocardial infarct size in rabbits and inhibition of activation of rabbit and human neutrophils by lidocaine. 906 Aug

Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.
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PMID:Disappearance with ischaemic depolarization of the antifibrillatory activity in a sodium channel blocker and appearance in calcium channel blocker. 912 97

Massive striatal dopamine release during cerebral ischaemia has been implicated in the resulting neuronal damage. Sodium influx is an early event in the biochemical cascade during ischaemia and blockade of sodium channels may increase resistance to ischaemia by reducing energy demand involved in compensation for sodium and potassium fluxes. In this study, we have determined the effects of opening and blockade of voltage-gated sodium channels on hypoxia/hypoglycaemia-induced dopamine release. Slices of rat caudate nucleus were maintained in a slice chamber superfused by an oxygenated artificial cerebrospinal fluid containing 4 mM glucose. Ischaemia (hypoxia/hypoglycaemia) was mimicked by a switch to a deoxygenated artificial cerebrospinal fluid containing 2 mM glucose and dopamine release was measured using fast cyclic voltammetry. In drug-free (control) slices, there was a 2-3 min delay after the onset of hypoxia/hypoglycaemia followed by a rapid dopamine release event which was associated with anoxic depolarization. In slices treated with the Na+ channel opener, veratridine (1 microM), the time to onset of dopamine release was shortened (101 +/- 20 s, compared with 171 +/- 8 s in controls, P < 0.05). Conversely, phenytoin (100 microM), lignocaine (200 microM) and the highly selective sodium channel blocker, tetrodotoxin (1 microM) markedly delayed and slowed dopamine release vs paired controls. In the majority of cases, dopamine release was biphasic after sodium channel blockade: a slow phase preceded a more rapid dopamine release event. The latter was associated with anoxic depolarization. Neither the fast nor the slow release events were affected by pretreatment with the selective dopamine uptake blocker GBR 12935 (0.2 microM), suggesting that uptake carrier reversal did not contribute to these events. In conclusion, sodium channel antagonism delays and slows hypoxia/hypoglycaemia-induced dopamine release in vitro. Furthermore, sodium channel blockade delays anoxic depolarization and its associated neurotransmitter release, revealing an earlier dopamine release event that does not result from reversal of the uptake carrier.
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PMID:Sodium channel blockade unmasks two temporally distinct mechanisms of striatal dopamine release during hypoxia/hypoglycaemia in vitro. 933 Mar 62

Brief periods of global cerebral ischemia are known to produce characteristic patterns of neuronal injury both in human studies and in experimental animal models. Ischemic damage to vulnerable areas such as the CA1 sector of the hippocampus is thought to result from excitotoxic amino acid neurotransmission. The objective of this study was to determine the ability of a novel sodium channel blocking compound, zonisamide, to reduce neuronal damage by preventing the ischemia-associated accumulation of extracellular glutamate. Using a gerbil model, animals were subjected to 5 min ischemic insults. Both pre- and post-ischemic drug administration (zonisamide 150 mg/kg) were studied. Histological brain sections were prepared using a silver stain at 7 and 28 days post ischemia. The animals sacrificed at 28 days also underwent behavioral testing using a modified Morris water maze. In vivo microdialysis was performed on a separate group of animals in order to determine the patterns of ischemia-induced glutamate accumulation in the CA1 sector of the hippocampus. Pyramidal cell damage scores in the CA1 region of the hippocampus were significantly reduced in animals pre-treated with zonisamide compared to saline-treated controls, both at 7 days (drug pre-treated: 0.812 +/- 0.28, n = 8; controls: 1.625 +/- 0.24, n = 8; *P < 0.05) and 28 (drug pre-treated: 0.833 +/- 0.22, n = 12; controls: 1.955 +/- 0.26, n = 11; **P < 0.01) days post ischemia. However, animals receiving zonisamide post-treatment did not display significant differences from controls. Behavioral studies also showed significant preservation of function in drug-treated animals. Microdialysis studies confirmed a reduction in glutamate release in drug-treated animals compared to saline-treated controls. Our data suggest that zonisamide is effective in reducing neuronal damage by a mechanism involving decreased ischemia-induced extracellular glutamate accumulation and interruption of excitotoxic pathways.
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PMID:Zonisamide as a neuroprotective agent in an adult gerbil model of global forebrain ischemia: a histological, in vivo microdialysis and behavioral study. 937 10

Ischemia is believed to induce neuronal damage by causing a sustained increase in the level of extracellular excitatory amino acids. In our study, we have examined the relationship between oxygen/glucose deprivation-induced changes in extracellular glutamate/aspartate level and subsequent neuronal injury by pharmacological manipulation of glutamate receptors and calcium and sodium channels. Cultured hippocampal neurons were exposed to combined deprivation of oxygen/glucose for 40 to 50 min. These cultures developed acute neuronal swelling and widespread neuronal degeneration over the next 20 hr. The extracellular levels of glutamate and aspartate at the end of the oxygen/glucose deprivation period were measured by high-performance liquid chromatography, and neuronal injury was assessed by lactate dehydrogenase efflux assay after subsequent aerobic incubation of the cells in normal medium for 20 hr. Both N-methyl-D-aspartate and non- N-methyl-D-aspartate receptor antagonists attenuated the extracellular level of glutamate/aspartate and the neuronal injury. L-type, N-type and P-type calcium channel blockers each significantly attenuated the neuronal injury, although the increase in the extracellular glutamate/aspartate was not significantly inhibited by any subtype-specific calcium channel blocker alone. A combination of calcium channel blockers of the three subtypes showed the most prominent neuroprotective effect and inhibited glutamate release. The sodium channel blocker tetrodotoxin also attenuated both glutamate efflux and neuronal injury. These observations suggest that the overactivation of glutamate receptors, calcium channels and sodium channels leads to excitotoxic neuronal injury through enhancing glutamate efflux into the extracellular space under the condition of oxygen/glucose deprivation.
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PMID:Role of glutamate receptors and voltage-dependent calcium and sodium channels in the extracellular glutamate/aspartate accumulation and subsequent neuronal injury induced by oxygen/glucose deprivation in cultured hippocampal neurons. 953 8

Spiradoline (U-62,066E), a selective kappa (kappa) receptor agonist, was examined for actions on the cardiovascular system and on myocardial ionic currents in rats. We initially characterized cardiac, hemodynamic, and antiarrhythmic actions of spiradoline in isolated perfused rat hearts and pentobarbital-anesthetized rats. Electrophysiologic studies in isolated myocytes were used to elucidate the mechanism for changes observed in vivo in the ECG, as well as for antiarrhythmic actions against electrical and ischemia-induced arrhythmias. In isolated rat hearts, spiradoline reduced heart rate and cardiac contractility and increased the PR interval and QRS width of the ECG in a concentration-dependent manner. In anesthetized rats, spiradoline dose-dependently reduced blood pressure and heart rate and prolonged the PR interval and QRS width. At slightly higher doses, it increased the QaT interval of the ECG. RSh, an index of sodium channel blockade in the rat, also was dose-dependently increased. Electrical stimulation of the left ventricle suggested that spiradoline may exert its antiarrhythmic action by blockade of myocardial sodium currents. The electrophysiologic actions of spiradoline on sodium currents, the transient outward (i(to)) and sustained plateau potassium (ik(sus)) currents were studied in isolated cardiac rat myocytes by whole-cell patch-clamp techniques. Spiradoline (15-500 microM) reduced peak sodium current in a rapid, reversible, and concentration-dependent manner; it also increased the rate of decay of I(to) and reduced the amplitude of Ik(sus). At a concentration of 150 microM, spiradoline produced a 24 +/- 2 mV hyperpolarizing shift in sodium current inactivation kinetics but did not alter activation processes. Spiradoline showed both tonic and frequency-dependent components of sodium current block. Thus spiradoline produced its antiarrhythmic actions via sodium channel blockade in myocardial tissue, although higher doses also block potassium currents. This combined ion channel-blocking property may be of added clinical benefit in the setting of myocardial ischemia.
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PMID:Sodium channel-blocking properties of spiradoline, a kappa receptor agonist, are responsible for its antiarrhythmic action in the rat. 986 91

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule-1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.
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PMID:Neuroprotective therapy. 993 19

We examined whether the anti-ischemic effect of lamotrigine (LTG), which inhibits the presynapic sodium channel, could be enhanced by the calcium channel blocker-flunarizine (FNR) in cerebral ischemia. Global ischemia was induced in Mongolian gerbils for 5 min under the monitoring of scalp temperature. LTG and FNR were administered intraperitoneally 1 h before ischemia. After 7 days, animals were killed and viable neurons in CA1 area were counted. LTG treated group showed significant protective effects compared to control group (P < 0.01). These effects were more prominent in group treated with LTG and FNR (P = 0.01). Combination of two drugs did not increase the mortality rate compared to single-treated group. These results show that a synergistic reduction of neuronal death can be achieved by combination of LTG and FNR without serious adverse reaction.
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PMID:Neuroprotective effects of lamotrigine enhanced by flunarizine in gerbil global ischemia. 1032 69


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