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

There is great concern about the health effects of cocaine use during pregnancy. Cocaine alters maternal physiology and crosses the placenta to interact with fetal tissues including the brain. Neurotoxicity, defined as structural and/or functional changes which result in a neurobehavioral deficit, is not unequivocally documented in the human. It is difficult to ascertain duration, intensity and frequency of cocaine exposure in humans as well as the effects of multiple drug use, poor nutrition, lack of prenatal care, lead exposure and infectious diseases. In addition, plasticity of the central nervous system makes the postnatal environment as important as the intrauterine milieu for the developing organism. Animal studies, which allow quantitation of drug exposure and reduction of confounding variables, suggest several possible mechanisms for neurotoxicity induced by cocaine or its active metabolites. The possible mechanisms include: alteration of sodium channel and monoamine transporter development, release of epinephrine from the adrenal medulla with subsequent hyperglycemia, vasoconstriction with subsequent hypoxia and decrease of nutrient supply, calcium ion chelation, superoxide formation or infarction following repeated ischemia and reperfusion, enzyme inhibition, reduced neurotrophic activity, altered gene expression and plasma membrane changes. Alterations in the above parameters may cause acute and reversible effects as well as chronic and permanent effects. Not all alterations in structure and function are deficits, and no single mechanism may explain a given alteration.
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PMID:Potential mechanisms of cocaine-induced developmental neurotoxicity: a minireview. 760 37

Release of the excitatory amino acid (EAA) neurotransmitter glutamate has been implicated in secondary tissue damage following central nervous system (CNS) trauma and ischemia. The present study evaluated the neuroprotective actions of 619C89, a sodium channel blocker that inhibits ischemia-induced glutamate release, on traumatic brain injury (TBI) in rats using a lateral fluid percussion model. Various motor-related behavioral outcomes were used to evaluate neurologic function. Glial fibrillary acidic protein (GFAP) immunostaining and Cresyl violet staining were used to assess the histological changes. Treatment with 619C89, at a dose of 30 mg/kg administered intravenously 15 min before brain injury, significantly attenuated behavioral deficits at 24 h and 1 week. At 2 weeks, neuronal loss in the CA1 and CA3 pyramidal cell layers of the hippocampus was significantly decreased by 619C89 administration. Treatment with this compound also significantly attenuated increases in GFAP-immunoreactivity in both ipsilateral and contralateral CA1 regions. The present results suggest a potential therapeutic role for sodium channel blockade and/or glutamate release inhibition in the treatment of TBI.
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PMID:Neuroprotective effects of 619C89, a use-dependent sodium channel blocker, in rat traumatic brain injury. 775 66

The present study was undertaken to test the hypothesis that the degree of sodium channel blockade by class-I-type antiarrhythmic agents accounts for enhancement of postischemic contractile recovery of ischemic/reperfused hearts. Electrophysiological studies showed that the class-I-type antiarrhythmic agents quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide and pilsicainide suppressed the Vmax value of the rat left ventricular muscle cell, a marker of sodium channel blockade, in a concentration-dependent manner. Isolated rat hearts were subjected to 35 min of ischemia and 60 min of reperfusion. Postischemic contractile recovery, which was never detected in untreated hearts, was enhanced in hearts pretreated with these antiarrhythmic agents during the last 3 min before ischemia at concentrations ranging from 3 to 300 microM. Tissue Na, but not Ca, accumulation was also detected in the ischemic heart, and tissue Na and Ca accumulation was observed in the reperfused heart, which suggests that sodium overload occurs during ischemia, followed by sodium and calcium overload during reperfusion. The degree of postischemic contractile recovery seen in the presence of these antiarrhythmic agents was inversely related to tissue Na or Ca accumulation after reperfusion, which suggests that class-I-type antiarrhythmic agents inhibit sodium overload occurring in ischemic/reperfused myocardial cells. A close relationship between postischemic contractile recovery of the perfused heart and depression in the Vmax value of the ventricular muscle was also observed. These results suggest that the ability class-I-type antiarrhythmic agents to inhibit myocardial sodium channels plays a significant role in the enhancement of postischemic contractile recovery of the ischemic/reperfused heart.
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PMID:A possible involvement of sodium channel blockade of class-I-type antiarrhythmic agents in postischemic contractile recovery of isolated, perfused hearts. 779 Nov 14

In vitro ischemia (IVI) was simulated with rat hippocampal slices in medium lacking D-glucose, equilibrated with 95% nitrogen, 5% carbon dioxide. Within 5-8 min, synaptic potentials disappeared and a DC negative shift (5-15 mV) occurred. Prolonged application of 95% oxygen and D-glucose 12 min later did not allow synaptic potentials to recover. Slices pretreated with sodium channel blocking drugs allowed synaptic potentials to recover after IVI. Tetrodotoxin (TTX, 100-600 nM), the anticonvulsant phenytoin (5.0 to 100 microM) and the local anesthetic lidocaine (2.0 to 200 microM) each delayed or prevented negative DC shifts from IVI. Histological examination showed that drug treatments also prevented CA1 pyramidal cell damage from IVI. Neuroprotection occurred without blocking synaptic potentials or presynaptic fiber volleys, suggesting relevance for treatment of brain ischemia.
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PMID:Damage from oxygen and glucose deprivation in hippocampal slices is prevented by tetrodotoxin, lidocaine and phenytoin without blockade of action potentials. 789 26

The effects of sodium channel blockers, propafenone and disopyramide, on post-ischemic contractile dysfunction of perfused rat hearts were examined. Isolated hearts were subjected to 35 min ischemia, followed by 60 min reperfusion with and without administration of either drug during 3 min of pre-ischemia. Ischemia/reperfusion induced complete cardiac dysfunction, rise in left ventricular end-diastolic pressure, increase in perfusion pressure, accumulation of Na+ and Ca2+ and loss of K+ and Mg2+, and release of creatine kinase and purine nucleosides and bases from the heart. These observations suggest that ischemia/reperfusion in the current study induces cardiac cell necrosis or an increase in cell membrane permeability to ions, substrates and macromolecules. Treatment of perfused hearts with either propafenone at concentrations ranging from 5 to 70 microM, or disopyramide at concentrations of 100 microM or higher resulted in a pronounced contractile recovery of the heart, associated with suppression of reperfusion-induced tissue ion alteration and inhibition of reperfusion-induced release of creatine kinase and purine nucleosides and bases. Ischemic insult itself caused tissue Na+ accumulation and K+ loss without any change in tissue Ca2+ and Mg2+. The alterations in the electrolytes were attenuated by treatment with either agent. The results suggest that prevention of ischemia- and reperfusion-induced ionic disturbance of cardiac cells by propafenone and disopyramide plays a role in the improvement of post-ischemic contractile dysfunction.
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PMID:Propafenone and disopyramide enhance post-ischemic contractile and metabolic recovery of perfused hearts. 811 96

In the isolated, perfused working rat heart, ischemia (15 min) decreased mechanical function and also the tissue levels of ATP and creatine phosphate, and increased the tissue levels of lactate and free fatty acids including arachidonic acid. Reperfusion (20 min) did not restore mechanical function, but restored changes of metabolites incompletely except for free fatty acids, which changed further during reperfusion. Drugs were given 5 min before ischemia until the end of ischemia or for the first 10 min after reperfusion. Both dl- and d-propranolol (10 and 30 microM) decreased mechanical function, accelerated the recovery of mechanical function during reperfusion following ischemia, and attenuated ischemia reperfusion-induced metabolic changes. The attenuation of reperfusion-induced metabolic changes was more marked when these drugs were present during reperfusion. d-Propranolol showed a cardioprotection similar to that by dl-propranolol. Timolol (50 microM) did not accelerate the recovery of mechanical function during reperfusion, and did not attenuate the reperfusion-induced metabolic changes. These results suggest that d-propranolol, like dl-propranolol, has a cardioprotective effect which is probably due to its membrane stabilizing (or sodium channel blocking) action.
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PMID:Cardioprotective effect of d-propranolol in ischemic-reperfused isolated rat hearts. 831 54

The local anesthetic-class antiarrhythmic drugs produce greater depression of conduction in ischemic compared with normal myocardium. The basis for this relatively selective action is uncertain. A model of the pH-dependent interaction of tertiary amine drugs with the sodium channel suggests that the low pH occurring during ischemia slows drug dissociation from the channel by changing the drug's protonation. The importance of the proton exchange reaction and the effect of overall slowing of drug dissociation on steady-state sodium channel blockade is uncertain. We have measured whole cell sodium channel current in rabbit atrial myocytes during control and exposure to lidocaine while external pH was varied between 6.8 and 7.8 at membrane potentials of -140, -120, and -100 mV. Tonic blockade was little influenced by external pH. Decreasing the external pH from 7.8 to 6.8 slowed both the rate of development of phasic block and recovery from the block. Decreasing the membrane potential from -140 to -100 mV increased the degree of phasic block attained in the steady state. Block was further enhanced when low pH was combined with membrane depolarization. Experiments in which deuterium ions were substituted for protons suggest that the kinetics of proton exchange is not rate limiting in the dissociation of drugs from the sodium channel. We conclude that it is the combined effect of low pH and membrane depolarization that may be critical in the enhanced blocking action of local anesthetic-class drugs during ischemia.
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PMID:pH dependence of kinetics and steady-state block of cardiac sodium channels by lidocaine. 838 58

Gerbil cerebral cortical synaptosomes loaded with the fluorescent calcium probe FURA-2 were used to study depolarization-induced presynaptic cytosolic free calcium concentration, as an in vitro model of cerebral ischemia. The depolarization-induced increase in intrasynaptosomal cytosolic free calcium concentration is not sodium-dependent or sodium channel-dependent and may be due to an influx of extrasynaptosomal calcium resulting from a cadmium- and omega-conotoxin-sensitive, nickel-, nifedipine-, and nimodipine-insensitive voltage-regulated channel. The depolarization-induced increase in intrasynaptosomal free cytosolic calcium concentration is also inhibited by flunarizine, a calcium antagonist that has protective effects in animal models of cerebral anoxia and ischemia. Our results suggest that presynaptic calcium uptake following depolarization may be mediated in part by an N-type channel. Flunarizine may block presynaptic calcium accumulation, in part, by blocking this N-type channel; this blockade may be just one of several mechanisms by which flunarizine exerts protective effects following cerebral ischemia.
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PMID:Flunarizine blocks elevation of free cytosolic calcium in synaptosomes following sustained depolarization. 840 19

The prevention of ventricular fibrillation raises a special problem when related to myocardial ischaemia, since class I antiarrhythmic drugs are then ineffective and may even behave as profibrillatory agents: the usual antifibrillatory properties of these drugs which are inhibitors of sodium channel, activated at high potentials, disappear with the disappearance of the role of sodium channel caused by ischaemic depolarization. Calcium channel then replacing sodium channel, calcium channel inhibitors should tend to prevent ischaemic ventricular fibrillation. Therefore, vulnerability to ventricular fibrillation was assessed in open-chest pigs by the threshold for fibrillation electrically induced with impulses of 100 ms duration at the rate of 180 beats/min. Ischaemia was produced by total occlusion of the left anterior descending coronary artery near its origin. Electrical fibrillation threshold was measured at the end of ischaemic period of increasing duration (30, 60, 120, 180, 240, 360 s) under control conditions and after i.v. administration of verapamil (50 micrograms/kg loading dose and 2 micrograms/kg/min infusion). Unaffected by verapamil when coronary circulation was normal, fibrillation threshold was raised by the drug when lowered by ischaemia, increasingly with the prolongation of ischaemia responsible for depolarization of the fibres, up to 500%. The rise of fibrillation threshold resulted in a delay in the triggering of fibrillation which occurs when the fibrillation threshold (6-8 mA) falls down to the pacing threshold (0.3-0.4 mA). These experiments tend to confirm the positive results recently obtained in man with verapamil in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, in these experiments, left ventricular dP/dt max was not reduced by more than 15%, even just after the loading dose and returned to its control values within a few minutes.
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PMID:[Value of calcium channel blockers in the prevention of ventricular fibrillation of ischemic etiology: experimental arguments]. 869 77

Drugs that prolong cardiac refractoriness exert antiarrhythmic effects, probably by reducing dispersion of refractoriness and thereby reducing the likelihood of reentrant excitation. This electrophysiologic effect can be achieved in fast-response tissues by sodium channel block or by action potential prolongation; drugs with either attribute can exert antiarrhythmic effects. However, both types of drugs can also cause proarrhythmic effects. For sodium channel blockers, proarrhythmic actions can be attributed to conduction slowing and include increased frequency of episodes of ventricular tachycardia as well as slowing of atrial flutter with 1:1 atrioventricular conduction and increases in ventricular rate. In addition, sodium channel block has been implicated as the mechanism underlying increased mortality with sodium channel blockers in the Cardiac Arrhythmia Suppression Trial (CAST); some data suggest that intercurrent ischemia increases this risk. For drugs that prolong action potentials, torsades de pointes is the most common proarrhythmic syndrome, occurring most often with underlying bradyarrhythmias and hypokalemia. The mechanism(s) underlying normal refractoriness and its modulation by antiarrhythmic drugs, as well as the mechanism(s) underlying these proarrhythmic syndromes, are discussed.
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PMID:Ionic mechanisms for prolongation of refractoriness and their proarrhythmic and antiarrhythmic correlates. 878 Mar 24


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