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

Our purpose in this article is to examine the hypothesis that both myocardial disease and ischemia can alter the electrophysiologic function of the ion channels responsible for the cellular electrical activity of the heart. Changes in the intracellular and extracellular milieus occur during ischemia and can alter the electrophysiology of several species of ionic channels and the cellular electrophysiologic activity of cardiac myocytes. Included are 1) changes in extracellular [K+] and pH and in intracellular [Na+], [Ca2+], and pH; 2) accumulation of noxious metabolic products such as lysophosphatidylcholine; and 3) depletion of intracellular ATP. Finally, ischemia or disease (e.g., hypertrophy) can alter the electrophysiology of at least two types of K+ channels, the A-like channels underlying the transient outward current and the inward rectifier, by mechanisms that apparently do not involve alteration of either the intra- or extracellular milieus. Findings suggest that the expression of cardiac A-like channel function can be altered by hypertrophy and that at least one intrinsic conductance property of the inward rectifier can be altered by ischemia. We speculate that the control of expression, function, and regulation of cardiac ion channels can be affected at the molecular level by heart disease and myocardial ischemia.
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PMID:Connections: heart disease, cellular electrophysiology, and ion channels. 137 69

The effects of trimetazidine on membrane potentials and membrane currents of enzymatically isolated guinea-pig ventricular cells were studied with the use of giga-seal suction pipettes for patch clamp. Trimetazidine (3 X 10(-5) M) decreased the action potential duration from 433 +/- 179 ms (mean and S.D., n = 9) to 319 +/- 156 ms within 8 mins. In voltage clamp experiment, trimetazidine at a concentration of 1.5 X 10(-4) M decreased the peak amplitude of calcium current by 40% (0.92 +/- 0.46 nA to 0.55 +/- 0.19 nA, mean +/- S.D., n = 5). The effect on calcium current was rate-dependent, e.g., at 1 Hz, trimetazidine blocked a larger fraction of the calcium current than at 0.2 Hz. The drug decreased the conductance of potassium current which flows via inward rectifier potassium channel from 28 +/- 11 nS to 19 +/- 10 nS, n = 5, P less than 0.05). Trimetazidine shifted the steady state current-voltage relationship outward at potentials positive to -20 mV. This shift was not due to the enhanced time- and voltage-dependent outward current (Ik). From these findings, it was concluded that trimetazidine shortens action potential duration by blocking the calcium channels with increases in steady state outward current or a possible blockade of non-inactivated component of the calcium current, at the plateau potentials. The reduction of calcium current and of inward rectifier potassium current may protect the cardiac cells from accumulation of calcium ions and from loss of potassium ions, in the presence of ischemia.
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PMID:Effects of trimetazidine on action potentials and membrane currents of guinea-pig ventricular myocytes. 243 60

Recent investigations have demonstrated substantial reductions in internal [K+] in cardiac Purkinje fibers during myocardial ischemia (Dresdner, K.P., R.P. Kline, and A.L. Wit. 1987, Circ. Res. 60: 122-132). We investigated the possible role these changes in internal K+ might play in abnormal electrical activity by studying the effects of both internal and external [K+] on the gating of the inward rectifier iK1 in isolated Purkinje myocytes with the whole-cell patch-clamp technique. Increasing external [K+] had similar effects on the inward rectifier in the Purkinje myocyte as it does in other preparations: increasing peak conductance and shifting the activation curve in parallel with the potassium reversal potential. A reduction in pipette [K+] from 145 to 25 mM, however, had several dramatic previously unreported effects. It decreased the rate of activation of iK1 at a given voltage by several-fold, reversed the voltage dependence of recovery from deactivation, so that the deactivation rate decreased with depolarization, and caused a positive shift in the midpoint of the activation curve of iK1 that was severalfold smaller than the associated shift of reversal potential. These changes suggest an important role of internal K+ in gating iK1 and may contribute to changes in the electrical properties of the myocardium that occur during ischemia.
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PMID:Internal and external K+ help gate the inward rectifier. 293 Aug 21

Lysophosphatidylcholine, a putative biochemical mediator of ischemia-induced arrhythmias, reduces the resting potential of ventricular muscle. To elucidate possible mechanisms of lysophosphatidylcholine-induced depolarization, we investigated the effects of lysophosphatidylcholine on the electrophysiological properties of cat ventricular muscle, using potassium ion-selective electrodes and conventional microelectrode, current-, and voltage-clamp techniques. Lysophosphatidylcholine (50 microM) decreased the sensitivity of the resting potential to changes in extracellular potassium concentration. Hyperpolarization of lysophosphatidylcholine-depolarized fibers by current-clamp methods failed to reveal two stable levels of resting potential. Depolarizing concentrations of lysophosphatidylcholine did not reduce the potassium equilibrium potential, as determined from the reversal potential of the time-dependent potassium current and measurements of intracellular potassium activity using potassium ion-selective electrodes. Lysophosphatidylcholine induced a depolarizing shift of the reversal potential for steady state current, and did not induce the formation of a negative slope region in the steady state current-voltage or background current-voltage relationships. Lysophosphatidylcholine induced an inward shift and linearization of the background current-voltage relationship negative to -30 mV, and the lysophosphatidylcholine-sensitive component of the background current was an inward rectifier with a reversal potential approximately equal to the potassium equilibrium potential. Lysophosphatidylcholine also reduced the amplitudes of the time-dependent potassium current, slow inward current, and the potassium accumulation and depletion currents. These results indicate that lysophosphatidylcholine-induced depolarization is due, in part, to reduced potassium conductance at voltages near the normal resting potential, and that lysophosphatidylcholine may act as a nonspecific depressant of membrane channels.
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PMID:On the mechanism of lysophosphatidylcholine-induced depolarization of cat ventricular myocardium. 685 Oct 9

We investigated the effect of lysophosphatidylcholine (lysoPtdCho) and palmitoylcarnitine (PamCar), ischemia-induced amphipathic lipid metabolites, on the inward rectifier K+ channel in guinea-pig ventricular cells, under whole-cell and cell-attached configurations with patch-clamp techniques. (a) Both lysoPtdCho (10-50 microM) and PamCar (10-50 microM) depolarized the resting membrane potential (RP), retarded the repolarization of action potential, provoked spontaneous action potential discharges from oscillatory afterpotentials, and eventually caused a sudden rise of the RP to plateau levels. (b) These lysoPtdCho- or PamCar-induced depolarizations of RP were due to a decrease in the inward rectifier K+ current (IK1), and the sudden rise of the RP could be accounted for by a crossover of N-shaped current-voltage relationship on the voltage axis (zero current line) more than once. (c) Single-channel studies in the cell-attached mode revealed that lysoPtdCho (5-100 microM) decreased the conductance of the single IK1 channel with little change in its open probability, whereas PamCar (10-50 microM) did so by decreasing the open probability, with the channel conductance unaltered. (d) A short-chain acylcarnitine, l-propionylcarnitine (PpCar, 100 microM), prevented the depressant effect of lysoPtdCho (50 microM), but not of PamCar (50 microM), on the IK1. (e) Both lysoPtdCho and PamCar produced identical electrophysiological alterations on the membrane potential and IK1 in whole-cell recordings. However, molecular mechanisms involved in the effects of these toxic metabolites on single IK1 channels differ.
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PMID:Differential mechanism of block of palmitoyl lysophosphatidylcholine and of palmitoylcarnitine on inward rectifier K+ channels of guinea-pig ventricular myocytes. 825 27

Free radical-induced oxidant stress has been implicated in a number of physiological and pathophysiological states including ischemia and reperfusion-induced dysrhythmia in the heart, apoptosis of T lymphocytes, phagocytosis, and neurodegeneration. We have studied the effects of oxidant stress on the native K+ channel from T lymphocytes and on K+ channels cloned from cardiac, brain, and T-lymphocyte cells and expressed in Xenopus oocytes. The activity of three Shaker K+ channels (Kv1.3, Kv1.4, and Kv1.5), one Shaw channel (Kv3.4), and one inward rectifier K+ channel (IRK3) was drastically inhibited by photoactivation of rose bengal, a classical generator of reactive oxygen species. Other channel types (such as Shaker K+ channel Kv1.2, Shab channels Kv2.1 and Kv2.2, Shal channel Kv4.1, inward rectifiers IRK1 and ROMK1, and hIsK) were completely resistant to this treatment. On the other hand tert-butyl hydroperoxide, another generator of reactive oxygen species, removed the fast inactivation processes of Kv1.4 and Kv3.4 but did not alter other channels. Xanthine/xanthine oxidase system had no effect on all channels studied. Thus, we show that different types of K+ channels are differently modified by reactive oxygen species, an observation that might be of importance in disease states.
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PMID:Susceptibility of cloned K+ channels to reactive oxygen species. 852 51

The presence of left ventricular hypertrophy (LVH) is associated with an increased incidence of arrhythmias. Our previous study on hypertrophied rat hearts has demonstrated that regression of LVH prevents ischemia-induced lethal arrhythmias. To elucidate the underlying mechanism of the reduced incidence of arrhythmias in regression of LVH, we examined electrophysiological properties of both hypertrophied and regressed left ventricular cells. Hearts from spontaneously hypertensive rats (SHR) were used as LVH, and those from Wistar-Kyoto rats (WKY) served as control. SHR with regression of LVH (REG) was produced by captopril treatment. Action potentials and membrane currents of subendocardial left ventricular cells were compared by the whole-cell patch-clamp techniques. Although the membrane capacitance of SHR cells was significantly greater than that of WKY cells, that of REG cells was normalized to the control level. Prolonged action potential duration (APD) and reduced density of transient outward current (ito) in SHR cells was normalized by LVH regression (APD at 75% repolarization (ms) and ito density at +60 mV (pA/pF): WKY 36.1 +/- 4.2, 11.9 +/- 1.3, SHR 73.1 +/- 12.9, 5.2 +/- 0.7, REG 29.5 +/- 3.9, 10.4 +/- 2.0, P = 0.015, P = 0.001 v WKY). No significant differences were observed in the densities of steady-state outward current, inward rectifier current, and L-type Ca2+ current. The restoration of ito density by regression of LVH could normalize the prolonged APD in hypertensive LVH, which may be causally related to the reduced incidence of arrhythmias in LVH regression.
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PMID:Restoration of action potential duration and transient outward current by regression of left ventricular hypertrophy. 920 19

Prolongation of action potential duration is the most consistent electrophysiological abnormality in myocardium and myocytes from hypertrophied and failing hearts. Measurements of currents in myocytes from hypertrophied and failing hearts indicate that, in most cases, this is due to a decrease in outward potassium currents. If present, a calcium-independent transient outward current is usually substantially reduced, but delayed rectifier and inward rectifier currents have also been found to be diminished. There is increasing evidence that potassium current down-regulation contributes significantly to the enhanced lability of the repolarization process in heart failure, predisposing to early after-depolarizations, dispersion of repolarization and ventricular arrhythmias. The reduction of outward potassium currents may also be involved in the enhanced sensitivity of failing myocardium to triggering factors like hypokalemia, ischemia, and antiarrhythmic agents with Class III effects. A thorough understanding of the mechanisms of cardiac excitability and arrhythmogenesis at the cellular and molecular level under normal and pathological conditions will be essential for the development of new pharmacological strategies to prevent sudden cardiac death in heart failure.
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PMID:Potassium channel down-regulation in heart failure. 961 89

It has been well established that alterations in polyamine metabolism are associated with animal models of global ischemia. Recently, this has been extended to include models of focal ischemia and traumatic brain injury. There is much evidence to support the idea that polyamines may play a multifaceted detrimental role following ischemia reperfusion. Due to the deficit of knowledge about their physiology in the CNS, the link between ischemia-induced alterations in polyamine metabolism and neuronal injury remains to be substantiated. With the recent revelation that polyamines are major intracellular modulators of inward rectifier potassium channels and certain types of NMDA and AMPA receptors, the long wait for the physiologic relevance of these ubiquitous compounds may be in sight. Therefore, it is now conceivable that the alterations in polyamines could have major effects on ion homeostasis in the CNS, especially potassium, and thus account for the observed injury after cerebral ischemia.
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PMID:Polyamines and cerebral ischemia. 967 Jul 80

We examined the blocking effects of terfenadine, an antihistaminic agent, on the ATP-sensitive K+ current (IK,ATP) in rabbit ventricular cells. IK,ATP was induced by cromakalim or NaCN. Terfenadine blocked the IK,ATP with an IC50 of 1.7 microM at -10 mV. This blockage was voltage dependent; depolarization induced a stronger blockage. According to the transmembrane electrical field model, terfenadine interacts with the site located 15 to 18% from the cytoplasmic membrane surface. In line with the assumption that the binding site is near the cytoplasmic surface, terfenadine applied to the cytoplasmic solution potently inhibited the single-channel activity for IK,ATP in the inside-out configuration (IC50 0.19 microM). In contrast, terfenadine applied to the external solution did not affect the channel activity in the cell-attached configuration, but inhibited it when applied into the pipette. The inhibition of the single channels by terfenadine was accompanied by flickering of the channels. These findings suggest that 1) terfenadine blocks the ATP-sensitive K+ channel in the open state, 2) the binding site is near the internal membrane surface and 3) terfenadine is poorly diffusible into the lipid biomembrane and accesses the binding site via the hydrophilic pathway. Terfenadine also inhibited the transient outward K+ current, inward rectifier K+ current and E4031-sensitive rectifier K+ current. However, the inhibition of these repolarization currents by terfenadine at 1 microM was not sufficient to prolong the action potential duration significantly. Whereas, terfenadine (1 microM) prolonged the action potential duration which had been shortened by cromakalim. Terfenadine may modify the ischemia-induced arrhythmias by blocking IK,ATP.
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PMID:Blockage by terfenadine of the adenosine triphosphate (ATP)-sensitive K+ current in rabbit ventricular myocytes. 976 49


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