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

In the rat model of transient cerebral ischemia induced by intraluminal occlusion of the middle cerebral artery, we investigated the respective roles of ischemia and reperfusion in endothelium-dependent relaxation and smooth muscle relaxation related to the inward rectifier potassium current (Kir2.x), using the Halpern arteriography technique and/or patch-clamp technique. We first demonstrated that reperfusion is necessary to induce a significant impairment of smooth muscle Kir2.x, since ischemia alone has no effect on Kir2.x current density and function. In addition, we demonstrated that both ischemia and reperfusion are necessary for the occurrence of maximal post-ischemic endothelial dysfunction. The crucial role of reperfusion in post-ischemic vascular impairment prompted us to characterize the effect of a new antioxidant synthetic flavonoid derivate, 3'5'di- tert-butylhydroxyphenyl (dt-BC), on both neuronal and vascular injuries. Dt-BC (10 mg/kg) induced a neuroprotective effect as demonstrated by a significant decrease in infarct size, while there was no protective effect with the doses of 3 mg/kg and 30 mg/kg. Parallel to neuroprotection, dt-BC at a dose of 10 mg/kg, but not with doses of 3 mg/kg and 30 mg/kg, prevented post-ischemic impairment of smooth muscle Kir2.x current density and function, while dt-BC had no effect on the post-ischemic alteration of endothelial function whatever doses are used. These data demonstrate the potential of a new synthetic flavonoid derivate to induce neurovascular protection and support a possible relationship between vascular and neuronal protection via pharmacological modulation of oxidative stress.
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PMID:The neuroprotective effect of the antioxidant flavonoid derivate di-tert-butylhydroxyphenyl is parallel to the preventive effect on post-ischemic Kir2.x impairment but not to post-ischemic endothelial dysfunction. 1550 71

ATP-sensitive K+ (K(ATP)) channels play many important roles in cellular functions, including control of membrane excitability of skeletal muscle and neurons, K+ recycling in renal epithelia, cytoprotection in cardiac ischemia, and insulin secretion from pancreatic beta-cells. K(ATP) channels are composed of pore-forming inwardly rectifying potassium channel (Kir6.2 or Kir6.1) subunits and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Kir6.2 or Kir6.1 subunits conjoined with a SUR subunit constitute the various tissue-specific K(ATP) channels with distinct pharmacological properties. Both sulfonylureas and non-sulfonylurea hypoglycemic agents are used in treatment of type 2 diabetes mellitus. While the sulfonylurea receptor (SUR) is the target molecule of all of these hypoglycemic agents, the binding sites differ according to the moiety containing in the agent, and alter the pharmachological properties. In addition, chronic exposure of pancreatic beta-cells to the various agents affects the agent-specific sensitivities differently. Here we distinguish differences in pharmacological profile among the various hypoglycemic agents that reflect their chemical composition. We also suggest possible risk in the use of certain hypoglycemic agents in patients with ischemic heart disease.
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PMID:Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity. 1556 85

The T-wave of the electrocardiogram (ECG) is generated both from the left and the right ventricles of the heart. Each ventricle may produce a normal, an "ischemic", or a "secondary" T-wave, depending on segmental perfusion, intraventricular pressure, or QRS complex duration. The direction of the T-wave is determined by the particular inward rectifier potassium channels recruited by various layers and segments in the two ventricles. The observed T-wave in the clinical ECG is the summation of the left and right ventricular T waves, and is thus biventricular. Clinical observations in right bundle branch block (RBBB) and in right ventricular hypertensive states such as pulmonary embolism suggest that many ECG's interpreted as inferior or anterior left ventricular ischemia are in fact examples of abnormal potassium channel recruitment in the right ventricle. Consideration of the right ventricular component of the T-wave in every electrocardiographic interpretation improves diagnostic understanding and accuracy, as the possible right ventricular origin of observed anterior or superior T waves will not be overlooked.
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PMID:T waves are independently generated in both right and left ventricles: the clinically recorded T is a summation of two separate repolarizations, and is thus always biventricular. 1608 69

Resveratrol (trans-3, 4', 5-trihydroxystilbene), a natural antioxidant derived from grapes, has beneficial effects against coronary heart disease. Its electrophysiological characteristics for antiarrhythmic efficacy are largely unknown; thus, this study aims to explore the resveratrol's antiarrhythmic effects and conduction system in isolated hearts as well as its electrophysiological effects on cardiac myocytes. In the experiment, resveratrol suppressed the ischemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts. In the current clamp study of the experiment, resveratrol prolonged the action potential duration (APD(50) and APD(90)) and suppressed the upstroke velocity of the action potential (V(max)). In the voltage clamp study, resveratrol inhibited sodium inward current (I(Na)) in a concentration-dependent manner and negative-shifted the voltage-dependent inactivation curve. Resveratrol also reduced the calcium inward current (I(Ca), 51.2+/-13.3% at 100 microM). Furthermore, the transient (I(to)) and sustained (I(ss)) outward potassium currents were decreased 60.2+/-5.7% and 42.3+/-5.2% after exposure to resveratrol (100 microM), respectively. The inward rectifier potassium current (I(K1)) was also reduced 24.2+/-7.0% in the presence of resveratrol (100 microM). In the isolated heart perfusion model, resveratrol (100 microM) prolonged AV nodal refractory period, the Wenckebach cycle length and the conduction through AV node and His-Purkinje system. In conclusion, resveratrol increased the cardiac effective refractory period mainly through inhibiting the ionic channels including I(Na), I(to) and I(ss) which could contribute to the conversion of ischemia/reperfusion-induced lethal arrhythmias.
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PMID:In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant. 1710 72

ATP-sensitive potassium channels (K(ATP)) couple cell metabolism to electrical activity by regulating potassium movement across the membrane. These channels are octameric complex with two kind of subunits: four regulatory sulfonylurea receptor (SUR) embracing four poreforming inwardly rectifying potassium channel (Kir). Several isoforms exist for each type of subunits: SUR1 is found in the pancreatic beta-cell and neurons, whereas SUR2A is in heart cells and SUR2B in smooth muscle; Kir6.2 is in the majority of tissues as pancreatic beta-cells, brain, heart and skeletal muscle, and Kir6.1 can be found in smooth vascular muscle and astrocytes. The K(ATP) channels play multiple physiological roles in the glucose metabolism regulation, especially in beta-cells where it regulates insulin secretion, in response to an increase in ATP concentration. They also seem to be critical metabolic sensors in protection against metabolic stress as hypo or hyperglycemia, hypoxia, ischemia. Persistent hyperinsulinemic hypoglycaemia (HI) of infancy is a heterogeneous disorder which may be divided into two histopathological forms (diffuse and focal lesions). Different inactivating mutations have been implicated in both forms: the permanent inactivation of the K(ATP) channels provokes inappropriate insulin secretion, despite low ATP. Diazoxide, used efficiently in certain cases of HI, opens the K(ATP) channels and therefore overpass the mutation effect on the insulin secretion. Conversely, several studies reported sequencing of KCNJ11, coding for Kir6.2, in patients with permanent neonatal diabetes mellitus and found different mutations in 30 to 50% of the cases. More than 28 heterozygous activating mutations have now been identified, the most frequent mutation being in the aminoacid R201. These mutations result in reduced ATP-sensitivity of the K(ATP) channels compared with the wild-types and the level of channel block is responsible for different clinical features: the "mild" form confers isolated permanent neonatal diabetes whereas the severe form combines diabetes and neurological symptoms such as epilepsy, deve-lopmental delay, muscle weakness and mild dimorphic features. Sulfonylureas close K(ATP) channels by binding with high affinity to SUR suggesting they could replace insulin in these patients. Subsequently, more than 50 patients have been reported as successfully and safely switched from subcutaneous insulin injections to oral sulfonylurea therapy, with an improvement in their glycated hemoglobin. We therefore designed a protocol to transfer and evaluate children who have insulin treated neonatal diabetes due to KCNJ11 mutation, from insulin to sulfonylurea. The transfer from insulin injections to oral glibenclamide therapy seems highly effective for most patients and safe. This shows how the molecular understan-ding of some monogenic form of diabetes may lead to an unexpected change of the treatment in children. This is a spectacular example by which a pharmacogenomic approach improves the quality of life of our young diabetic patients in a tremendous way.
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PMID:Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences. 1729 10

In a model of 1 hour-intraluminal occlusion of rat middle cerebral artery (MCA), we investigated the spontaneous recovery of vascular functions and functional deficit together with ischemia volume evolution at 24 h, 3 days and 7 days of reperfusion. Infarct cerebral volumes and edema were quantified with histological methods. Endothelium-dependent and smooth muscle potassium inward rectifier current (Kir2.x)-dependent relaxing responses of MCA were tested using Halpern arteriograph and Kir2.x current density evaluated on MCA myocytes with whole-cell patch-clamp technique. Sensorimotor recovery was estimated according to performances obtained with adhesive removal test and prehensile traction test. A time-dependent improvement of smooth muscle K(+)-dependent vasorelaxation and Kir2.x current density is observed at 7 days of reperfusion while endothelium-dependent relaxation is still impaired. In parallel a significant reduction of functional deficit is observed at 7 days of reperfusion together with a time-matched reduction of striatal infarct and edema volumes. Administration of an antioxidant agent, stobadine, at time of reperfusion and 5 h later allowed: (i) a neuroprotective effect with a significant reduction of infarct size compared to vehicle-treated rats; (ii) a prevention of endothelial-dependent relaxation and Kir2.x current density reductions of MCA ipsilateral to occlusion; (iii) a hastening of the functional recovery. The beneficial effect of stobadine underlines a link between vascular protection, neuronal protection and sensorimotor recovery that could become a promising pharmacological target in the treatment of cerebral ischemia.
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PMID:Stobadine-induced hastening of sensorimotor recovery after focal ischemia/reperfusion is associated with cerebrovascular protection. 1837 75

Ventricular arrhythmias are commonly observed in patients with ischemia. It is reported that the electrophysiological changes evoked by ischemia are greater in the epicardium than in the endocardium. To investigate the effects of this heterogeneity on transmural reentry, the computer simulation method is used. A two-dimensional model which can reproduce the endocardial, epicardial and middle cell types, approximate the ischemic characteristics and distribution of the ischemic severity is developed by setting different ratios of the maximum conductance of the rapid and slow inward rectifier potassium currents and considering the three major component conditions of acute ischemia at the ionic level. The results demonstrate that action potentials of the ischemic cells have elevated resting potential, shortened duration, slowed upstroke and declined amplitude. Conduction velocity is much more depressed in the epicardium because of the ischemia-induced transmural gradient of excitability. The epicardially initiated activation has wider vulnerable window and more possibility to cause unidirectional propagation even reentry. Dispersion of the excitability is proposed to be the underlying mechanism.
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PMID:Effects of electrical heterogeneity on transmural reentry during acute global ischemia. 2037 76

Atrial and ventricular tachyarrhythmias can be perpetuated by up-regulation of inward rectifier potassium channels. Thus, it may be beneficial to block inward rectifier channels under conditions in which their function becomes arrhythmogenic (e.g., inherited gain-of-function mutation channelopathies, ischemia, and chronic and vagally mediated atrial fibrillation). We hypothesize that the antimalarial quinoline chloroquine exerts potent antiarrhythmic effects by interacting with the cytoplasmic domains of Kir2.1 (I(K1)), Kir3.1 (I(KACh)), or Kir6.2 (I(KATP)) and reducing inward rectifier potassium currents. In isolated hearts of three different mammalian species, intracoronary chloroquine perfusion reduced fibrillatory frequency (atrial or ventricular), and effectively terminated the arrhythmia with resumption of sinus rhythm. In patch-clamp experiments chloroquine blocked I(K1), I(KACh), and I(KATP). Comparative molecular modeling and ligand docking of chloroquine in the intracellular domains of Kir2.1, Kir3.1, and Kir6.2 suggested that chloroquine blocks or reduces potassium flow by interacting with negatively charged amino acids facing the ion permeation vestibule of the channel in question. These results open a novel path toward discovering antiarrhythmic pharmacophores that target specific residues of the cytoplasmic domain of inward rectifier potassium channels.
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PMID:Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets. 2058 26

ATP-sensitive K(+) (K(ATP)) channels, composed of inward rectifier K(+) (Kir)6.x and sulfonylurea receptor (SUR)x subunits, are expressed on cellular plasma membranes. We demonstrate an essential role for SUR2 subunits in trafficking K(ATP) channels to an intracellular vesicular compartment. Transfection of Kir6.x/SUR2 subunits into a variety of cell lines (including h9c2 cardiac cells and human coronary artery smooth muscle cells) resulted in trafficking to endosomal/lysosomal compartments, as assessed by immunofluorescence microscopy. By contrast, SUR1/Kir6.x channels efficiently localized to the plasmalemma. The channel turnover rate was similar with SUR1 or SUR2, suggesting that the expression of Kir6/SUR2 proteins in lysosomes is not associated with increased degradation. Surface labeling of hemagglutinin-tagged channels demonstrated that SUR2-containing channels dynamically cycle between endosomal and plasmalemmal compartments. In addition, Kir6.2 and SUR2 subunits were found in both endosomal and sarcolemmal membrane fractions isolated from rat hearts. The balance of these K(ATP) channel subunits shifted to the sarcolemmal membrane fraction after the induction of ischemia. The K(ATP) channel current density was also increased in rat ventricular myocytes isolated from hearts rendered ischemic before cell isolation without corresponding changes in subunit mRNA expression. We conclude that an intracellular pool of SUR2-containing K(ATP) channels exists that is derived by endocytosis from the plasma membrane. In cardiac myocytes, this pool can potentially play a cardioprotective role by serving as a reservoir for modulating surface K(ATP) channel density under stress conditions, such as myocardial ischemia.
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PMID:Endosomal KATP channels as a reservoir after myocardial ischemia: a role for SUR2 subunits. 2105 44

Sudden cardiac death remains one of the most prevalent modes of death and is mainly caused by ventricular fibrillation (VF) in the setting of acute ischemia resulting from coronary thrombi. Animal experiments have shown that platelet activation may increase susceptibility of ischemic myocardium to VF, but the mechanism is unknown. In the present study, we evaluated the effects of activated blood platelet products (ABPPs) on electrophysiological properties and intracellular Ca(2+) (Ca(2+)(i)) homeostasis. Platelets were collected from healthy volunteers. After activation, their secreted ABPPs were added to superfusion solutions. Rabbit ventricular myocytes were freshly isolated, and membrane potentials and Ca(2+)(i) were recorded using patch-clamp methodology and indo-1 fluorescence measurements, respectively. ABPPs prolonged action potential duration and induced early and delayed afterdepolarizations. ABPPs increased L-type Ca(2+) current (I(Ca,L)) density, but left densities of sodium current, inward rectifier K(+) current, transient outward K(+) current, and rapid component of the delayed rectifier K(+) current unchanged. ABPPs did not affect kinetics or (in)activation properties of membrane currents. ABPPs increased systolic Ca(2+)(i), Ca(2+)(i) transient amplitude, and sarcoplasmic reticulum Ca(2+) content. ABPPs did not affect the Na(+)-Ca(2+) exchange current (I(NCX)) in Ca(2+)-buffered conditions. Products secreted from activated human platelets induce changes in I(Ca,L) and Ca(2+)(i), which result in action potential prolongation and the occurrence of early and delayed afterdepolarizations in rabbit myocytes. These changes may trigger and support reentrant arrhythmias in ischemia models of coronary thrombosis.
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PMID:Activated human platelet products induce proarrhythmic effects in ventricular myocytes. 2165 13


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