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

Mechanisms responsible for anoxic/ischemic cell death in mammalian CNS grey and white matter involve an increase in intracellular Ca2+, however the routes of Ca2+ entry appear to differ. In white matter, pathological Ca2+ influx largely occurs as a result of reversal of Na+-Ca2+ exchange, due to increased intracellular Na+ and membrane depolarization. Na+ channel blockade has therefore been logically and successfully employed to protect white matter from ischemic injury. In grey matter ischemia, it has been traditionally presumed that activation of agonist (glutamate) operated and voltage dependent Ca2+ channels are the primary routes of Ca2+ entry. Less attention has been directed towards Na+-Ca2+ exchange and Na+ channel blockade as a protective strategy in grey matter. This study investigates mexiletine, a use-dependent sodium channel blocker known to provide significant ischemic neuroprotection to white matter, as a grey matter protectant. Pentobarbital (65 mg/kg) anesthetized, mechanically ventilated Sprague-Dawley rats were treated with mexiletine (80 mg/kg, i.p.). Then 25 min later the animals were subjected to 10 min of bilateral carotid occlusion plus controlled hypotension to 50 Torr by temporary partial exsanguination. Animals were sacrificed with perfusion fixation after 7 days. Ischemic and normal neurons were counted in standard H&E sections of hippocampal CA1 and the ratio of ischemic to total neurons calculated. Mexiletine pre-treatment reduced hippocampal damage by approximately half when compared to control animals receiving saline alone (45 vs. 88% damage, respectively; P<0.001). These results suggest that mexiletine (and perhaps other drugs of this class) can provide protection from ischemia to grey matter as well as white matter.
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PMID:The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury. 1130 14

In this study, the properties of ischemic condition-induced and veratridine-evoked [3H]noradrenaline ([3H]NA) release from rat spinal cord slices were compared. It was expected that ischemia mimicked by oxygen and glucose deprivation results in the impairment of Na+/K+ -ATPase with a consequent elevation of the intracellular Na+ -level which reverses the NA carrier and promotes excessive NA release, and veratridine, by the activation of Na+ channels, releases NA both carrier-mediated and Ca2+ -dependent, i.e. vesicular manner. In our experiments, veratridine (1-100 microM) dose-dependently increased the resting [3H]NA release, and its effect was only partially blocked by low temperature or the lack of external calcium, whereas the sodium channel inhibitor tetrodotoxin (TTX, 1 microM) completely prevented it, indicating that veratridine induces NA release via axonal depolarization and reversing the transporters by eliciting Na+ -influx. In contrast to TTX, the local anesthetic lidocaine (100 microM) only partially blocked the veratridine-induced [3H]NA release due to its inhibitory action on K+ channels. The ischemia-induced [3H]NA release was abolished at 12 degrees C, a temperature known to block only the transporter-mediated release of transmitters. However, lidocaine was also partially effective to reverse the action of ischemia on the NA release, indicating that lidocaine is not a useful compound in the treatment of spinal cord-injured patients against the excessive excytotoxic NA release.
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PMID:Excessive release of [3H] noradrenaline by veratridine and ischemia in spinal cord. 1131 50

Recent studies have established the presence of three distinct cell types in the ventricular myocardium: epicardial, M and endocardial cells. Epicardial and M cell action potentials differ from endocardial cells with respect to the morphology of phase 1. These cells possess a prominent transient outward current (I(to))-mediated notch responsible for the 'spike and dome' morphology of the epicardial and M cell response. M cells are distinguished from the other cell types in that they display a smaller slowly activating delayed rectifier current (I(Ks)), but a larger late sodium current (late I(Na)) and sodium-calcium exchange current (I(Na-Ca)). These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell, which is more pronounced in the presence of antiarrhythmic agents with class III actions. The preferential prolongation of the M cell action potential results in the development of a transmural dispersion of repolarization (TDR), which can be estimated from the electrocardiogram (ECG) as the interval between the peak and the end of the T wave (QTpeak-QTend interval). Using the canine arterially perfused ventricular wedge model, transmembrane action potentials of the various cardiac cell types can be correlated to the waveforms of the ECG, providing insight into the cellular etiology of ECG abnormalities. Two congenital syndromes of sudden cardiac death that have been modeled using this technique are the long QT and Brugada syndromes. The long QT syndrome has been linked to 5 gene mutations on chromosomes 3, 7, 11, and 21. Mutations in the cardiac sodium channel SCN5A have been linked to families with a history of the Brugada syndrome. Although the etiologies of these two syndromes are different, lethal arrhythmias in both are thought to arise due to amplification of intrinsic electrical heterogeneities. Similar mechanisms are likely responsible for life-threatening arrhythmias in a variety of other cardiomyopathies ranging from heart failure and hypertrophy, which involve mechanisms similar to those operative in LQTS, to ischemia and infarction, which may involve mechanisms more closely resembling those responsible for the Brugada syndrome.
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PMID:Electrical heterogeneity within the ventricular wall. 1177 69

Seizurogenic activity develops in many patients following brain injury and may be involved in the pathophysiological effects of brain trauma and stroke. We have evaluated the effects of the use-dependent sodium channel blocker RS100642, an analog of mexiletine, as a neuroprotectant and anti-seizure agent in a rat model of transient middle cerebral artery occlusion (MCAo). Post-injury treatment with RS100642 (0.01-5.0 mg/kg) dose-dependently reduced brain infarction, improved functional recovery of electroencephalographic (EEG) power, and improved neurological outcome following 2 h of MCAo and 24 h recovery. This effect was more potent and offered a larger reduction of brain infarct volume than a maximal neuroprotective dose of mexiletine (10.0 mg/kg). Furthermore, brain seizure activity recorded following 1 h MCAo and 72 h of recovery in injured rats was either completely blocked (30 min pre-MCAo treatment) or significantly reduced (30 min post-MCAo treatment) with RS100642 (1.0 mg/kg) treatment resulting in greater than 60% reduction of core brain infarct. These results indicate that brain seizure activity during MCAo likely contributes to the pathophysiology of brain injury and that RS100642 may be an effective neuroprotective treatment not only to decrease brain injury but also to reduce the pathological EEG associated with focal ischemia.
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PMID:Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. 1191 60

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. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.
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PMID:Neuroprotective agents in acute ischemic stroke. 1203 58

Hypertension is the most prevalent, treatable risk factor for diseases of the heart, brain and kidneys. In this review, we discuss advances in understanding of the genetics of blood pressure regulation, the development of hypertensive complications and the pharmacodynamics of antihypertensive drug responses. Discovery of single gene mutations that cause hypertension or hypotension in humans suggests that the common final pathway for regulation of blood pressure level is via alterations in renal sodium handling. Based on a working hypothesis that common genetic variations contributing to blood pressure variation in the population may also act on this same pathway, we summarize supporting evidence emerging from linkage and selected association studies of candidate genes--including those encoding components of the renin-angiotensin-aldosterone system, the epithelial sodium channel, adrenoceptors, G protein subunits, and other cellular signaling mediators and modifiers. We proceed to distinguish ischemic target organ complications due to arteriolosclerotic changes of the microvasculature from those due to atherosclerosis involving larger conduit and capacitance arteries. Using the example of subcortical white matter ischemia of the brain, we propose that interindividual variation in the arteriolosclerotic complications is more likely than atherosclerotic complications to be related to the same genetic (and environmental) mechanisms that contribute to hypertension. We conclude by summarizing the state-of-the-art of antihypertensive pharmacogenetics, which has succeeded in rejecting the null hypothesis that genetic variation does not influence blood pressure or protective target organ responses to drug therapy. In each of the three areas covered in this review, we indicate the many remaining obstacles to the routine clinical use of genetic measurements in the diagnosis, evaluation and treatment of hypertension.
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PMID:Genetics of blood pressure, hypertensive complications, and antihypertensive drug responses. 1251 86

Although, sodium channel blockers have the ability to suppress nonsustained ventricular arrhythmias, an excessive drug-associated arrhythmic death rate has been reported in patients with coronary heart disease (CHD). Sodium channel blockers should prevent initiation of reentry activation by reducing directional differences in cardiac conduction (anisotropy). However, in vitro data demonstrated, that reduction of membrane excitability, e.g. by lowering the inward Na+ current, increases the risk for conduction failure and associated reentry arrhythmias. In 11 dogs the effects of myocardial ischemia, premature epicardial stimulation (PES) and propafenone on anisotropic conduction properties were tested using three-dimensional mapping techniques. The epicardial (longitudinal and transverse to fiber orientation) and transmural (oblique and straight) spread of activation was reconstructed during constant and PES. At baseline, conduction velocities (CV) were higher along (1.20 +/- 0.41 m/s) than across (0.91 +/- 0.19 m/s; p < 0.05) epicardial muscle fibers as well as along oblique (1.77 +/- 0.75 m/s) compared to straight (0.39 +/- 0.09 m/s, p < 0.05) transmural pathways. Acute ischemia did not significantly reduce tissue anisotropy. PES and additional administration of propafenone epicardially eliminated and transmurally profoundly reduced tissue anisotropy (longitudinal 0.58 +/- 0.09 m/s, transverse 0.69 +/- 0.08 m/s, oblique 0.69 +/- 0.28 m/s, straight 0.27 +/- 0.07 m/s). However, reduced anisotropy was associated with a higher probability for conduction block along myocardial fibers in the epicardium and along oblique transmural pathways. Our data show, that propafenone exhibits both potential pro- and antiarrhythmic effects in dogs with acute myocardial ischemia. These results possibly provide more insights in mechanisms underlying the excessive drug-associated arrhythmic death rate in patients with CHD.
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PMID:Effects of acute ischemia, early extrabeats and propafenone on complex activation patterns in intact and ischemic canine hearts. 1267 92

This study investigated the effects of brain ischemia on sodium channel gene (NaCh) expression in rats. Using quantitative RT-PCR, our findings demonstrated the expression ratio of NaCh genes in normal rat brain to be Na(v)1.1 > Na(v)1.8 > Na(v)1.3 > Na(v)1.7 (rBI > PN3 > rBIII > PN1). In contrast, brain injury caused by middle cerebral artery occlusion (MCAo) for 2 h followed by reperfusion significantly down-regulated Na(v)1.3 and Na(v)1.7 genes in both injured and contralateral hemispheres; whereas the Na(v)1.8 gene was down regulated in only the injured hemisphere (though only acutely at 2 or 2-6 h post-MCAo). However, the time-course of NaCh gene expression revealed a significant down-regulation of Na(v)1.1 only in the ischemic hemisphere beginning 6 h post-MCAo and measured out to 48 h post-MCAo. In a separate preliminary study Na(v)1.2 (rBII) gene was found to be expressed at levels greater than that of Na(v)1.1 in normal rats and was significantly down regulated at 24 h post-MCAo). Our findings document, for the first time, quantitative and relative changes in the expression of various NaCh genes following ischemic brain injury and suggest that the Na(v)1.1 sodium channel gene may play a key role in ischemic injury/recovery.
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PMID:Differential pattern of expression of voltage-gated sodium channel genes following ischemic brain injury in rats. 1282 95

The tumor suppressor gene p53 is a potent transcriptional regulator for genes involved in many cellular activities including cell cycle arrest and apoptosis. In this study, we examined the role of p53 in neuronal death induced by the sodium channel modulator veratridine. We also analyzed the involvement of Ca2+, mitochondria and reactive oxygen species in p53 activation. Exposure of hippocampal neurons to veratridine (0.3-100 microM) resulted in a dose-dependent neuronal death, measured 24 h after treatment. p53-Like immunoreactivity, undetectable in neurons under control conditions, was observed in about 25% of neurons, 7 h after veratridine exposure. Treatments that modified the alkaloid-induced Ca2+ influx including tetrodotoxin or Ca2+ removal, prevented either veratridine-induced cell death or p53 immunoreactivity. Mitochondria were involved in veratridine-induced cell death, as the alkaloid collapsed inner transmembrane mitochondrial potential in a Ca2+ influx dependent manner. Treatments of neuronal cultures with the permeability transitory pore blockers cyclosporin A and bongkrekic acid prevented veratridine-induced p53 immunoreactivity and neuronal death, placing mitochondria upstream of veratridine-induced p53 immunoreactivity. Reactive oxygen species also participated in veratridine-induced neurotoxicity and p53 activation. Antisense knockdown of p53 resulted in a significant increase in neuronal survival after veratridine treatment. This protective effect was maintained on N-methyl-D-aspartate or ischemia-induced death but not on staurosporine cytotoxicity. These results together suggest that p53-expression is involved in veratridine-induced neuronal death and that p53 might be a link between toxic stimuli of different types and neuronal death.
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PMID:Role and regulation of p53 in depolarization-induced neuronal death. 1462 14

The effects of propyl paraben, an antimicrobial preservative, on voltage-dependent sodium current and myocardial ischemia-reperfusion injury were investigated in isolated adult rat cardiomyocytes. Whole cell voltage-clamp recording showed that propyl paraben reversibly blocked the voltage-gated sodium channel both in concentration- and voltage-dependent manners. Propyl paraben (500 microM but not 100 microM) significantly shifted the steady-state inactivation of the sodium channel toward the hyperpolarizing direction at the V(1/2) point. Consistent with the above result, the propidium iodide (PI) uptake test revealed that pretreatment with 500 microM but not 100 microM of propyl paraben significantly reduced cell death induced by 45 min of sustained ischemia followed by 15 h of reperfusion (42.37 +/- 7.01% of cell viability in control and 71.05 +/- 7.06% in the propyl paraben group), suggesting that propyl paraben can protect myocytes from ischemia-reperfusion injury. These results indicate a possible correlation between the inhibition of sodium current and cardioprotection against ischemia-reperfusion injury.
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PMID:Propyl paraben inhibits voltage-dependent sodium channels and protects cardiomyocytes from ischemia-reperfusion injury. 1505 27


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