Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The ability of lifarizine (RS-87476) to block human voltage-sensitive Na+ channel currents was studied by use of whole cell patch clamp recording from differentiated neuroblastoma cells (SH-SY5Y). 2. The Na+ conductance in differentiated SH-SY5Y cells (24.0 +/- 2.4 nS, n = 11) was half-maximally activated by 10 ms depolarizations to -37 +/- 2 mV and was half-maximally inactivated by predepolarizing pulses of 200 ms duration to -86 +/- 3 mV (n = 11). 3. At low stimulus frequencies (0.1 to 0.33 Hz) voltage-dependent sodium currents were completely blocked, in a concentration-dependent manner, by extracellular application of either tetrodotoxin (EC50 = 4 +/- 1 nM, n = 12) or by lifarizine (EC50 = 783 +/- 67 nM, n = 9). The onset of block by lifarizine (tau = 91 +/- 14 s at 10 microM) was considerably slower than that of tetrodotoxin (tau = 16 +/- 3 s at 100 nM). 4. Lifarizine (1 microM) reduced the peak sodium conductance in each cell (from 26.4 +/- 2.0 nS to 15.1 +/- 2.7 nS, n = 4) without changing the macroscopic kinetics of sodium current activation or inactivation (V1/2 = -35 1 mV and -87 +/- 4 mV respectively, n = 4). Similarly, lifarizine (1 microM) did not affect the reversal potential of the macroscopic sodium current (+14 +/- 5 mV in control and +16 +/- 2 mV in 1 microM lifarizine; n = 4) or reactivation time-constant (tau = 14.0 +/- 4.4 ms). 5. Block of the sodium channel open state by tetrodotoxin (30 nM) did not prevent the inhibition caused by a subsequent application of lifarizine (3 micro M). In contrast the depression caused by lifarizinewas readily reversible after pretreatment of cells with the local anaesthetic, lignocaine (1O mM).6. These data demonstrate that lifarizine is a use- and voltage-dependent antagonist of human voltage sensitive sodium currents. The slow kinetics and pharmacology of the block by lifarizine indicate that access of this drug to the channel is more restricted than that of tetrodotoxin and may involve an allosteric site or state of the channel that is also regulated by local anaesthetics.
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PMID:Block of human voltage-sensitive Na+ currents in differentiated SH-SY5Y cells by lifarizine. 783 13

The cardiotoxicity of long acting local anaesthetics is still a matter of controversy. Therefore, the effects of bupivacaine and ropivacaine on cardiac contractility and electrophysiologic parameters were evaluated in the presence of different extracellular potassium concentrations. METHODS. In strips from left atria of guinea pigs action potentials were induced to obtain cumulative dose response curves for bupivacaine (racemic mixture) and ropivacaine (S-enantiomer). Effects on force of contraction and parameters of the action potential (especially maximum upstroke velocity, dV/dtmax, as an indirect measure of fast sodium channel function) were compared for low (2.7 mM) and high (8.7 mM) extracellular K+ concentrations (n = 7-8). RESULTS. At low K+ concentration, bupivacaine and ropivacaine depressed force of contraction and dV/dtmax in a dose-dependent manner. At higher local anaesthetic concentrations, action potential amplitude decreased and action potential duration was prolonged. There was no influence on the resting membrane potential (Tables 2, 3). At high K+ concentration, both local anaesthetics induced effects similar to those observed with low K+, but the dose-response curves for contractility and dV/dtmax were shifted leftward. The EC50 of bupivacaine for the negative inotropic effect and, analogously, for dV/dtmax was approximately 10 times lower. Similar results were observed for ropivacaine (Figs. 1, 2). CONCLUSION. This study confirms the dependence of the cardiodepressive effects of bupivacaine on the extracellular K+ concentration (i.e. membrane potential). The present investigation shows a similar dependence for the effects of ropivacaine, a new long-lasting local anaesthetic. Our results concerning the potential dependency of dV/dtmax depression are compatible with the binding of bupivacaine to the inactivated state of the sodium channel protein preferentially (modulated receptor hypothesis). Thus accumulation of block will occur if stimulation frequency is in an appropriate range. Though we found striking analogies between potential dependency of dV/dtmax depression and negative inotropic effect, there is no firm evidence that the sodium channel block by bupivacaine or ropivacaine substantially participates in the latter effect. An influence on other ionic channels such as the calcium channel remains to be evaluated.
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PMID:[The potential dependence of the effect of bupivacaine and ropivacaine on the heart. In-vitro studies on the effect of local anesthetics on the force of contraction and the action potential in left guinea pig atria]. 836 72

Sodium salts reverse the clinical cardiotoxicity of class 1c antiarrhythmic agents, but the underlying mechanisms are unknown. We studied the modulation of flecainide's action by changes in extracellular sodium concentration ([Na+]e) produced by isotonic substitution of choline for sodium. Increasing [Na+]e by 25 mM attenuated the depressant effects of 3.2 microM flecainide of Vmax in canine cardiac Purkinje fibers, whereas decreasing [Na+]e enhanced drug action. The voltage dependence of Vmax was shifted by flecainide (activation potential for 50% decrease in Vmax, V50: -77.4 +/- 3.5 mV at 3.2 microM flecainide) compared to control (V50: -73.7 +/- 2.8 mV, mean +/- S.D., P < .05). Increasing [Na+]e in the presence of flecainide returned V50 toward control (-75.8 +/- 3.1 mV, P < .05 vs. flecainide at normal [Na+]e). Increased [Na+]e shifted the flecainide concentration-response curve to the right (EC50 19.0 microM) compared to normal (EC50 14.6 microM) and low (EC50 10.8 microM) [Na+]e. [Na+]e modulated the concentration-dependent displacement by flecainide of [3H]batrachotoxin-A-benzoate, with increased [Na+]e shifting the binding curve to the right and decreased [Na+]e shifting it to the left compared to normal [Na+]e. There was a strong linear correlation (r = 0.99) between flecainide's EC50 for Vmax depression and its IC50 for [3H]batrachotoxin-A-benzoate displacement at various [Na+]e. We conclude that [Na+]e modulates flecainide's interaction with the sodium channel. Sodium's ability to displace blocking drug from the sodium channel may underlie the efficacy of sodium salts in treating flecainide toxicity, and could play a similar role in antagonizing cardiotoxicity of other class 1 compounds.
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PMID:Modulation of flecainide's cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity. 838 39

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

The present study is part of ongoing investigations into activity-related synaptic plasticity in the intact animal. In this investigation we sought to determine whether the previously reported increase in synaptic efficacy at the Ia-motoneuron connection following nerve conduction blockade could be attributed to changes in circuitry external to the monosynaptic pathway. Specifically, we used the phenomena of low-frequency depression of the extracellularly recorded group I monosynaptic reflex (MSR) as an indirect measure of presynaptic inhibition. Tibial nerve conduction blockade was achieved by superfusion of the sodium channel blocker tetrodotoxin (TTX). An osmotic pump delivered the TTX to the tibial branch of the sciatic nerve for a period of either 3 or 10 days. Control rats were either unoperated or received implants of pumps not containing TTX. Data collection consisted of tibial nerve stimulation (0.1-20 Hz) with bilateral recordings of the MSR from the L5 ventral roots. The extent of low-frequency depression was compared between treated and untreated sides of TTX-treated animals and between treated and untreated animals. Results showed that the extent of low-frequency depression was unchanged by either 3 or 10 days of complete blockade of tibial afferents. On the basis of this finding, it is concluded that the previously reported TTX-induced increase in Ia excitatory postsynaptic potential amplitude is unlikely to be due to changes in presynaptic inhibitory pathways.
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PMID:Low-frequency depression of the monosynaptic reflex is not altered by tetrodotoxin-induced nerve conduction blockade. 924 56

Poisoning by drugs that block voltage-gated sodium channels produces intraventricular conduction defects, myocardial depression, bradycardia, and ventricular arrhythmias. Human and animal reports suggest that hypertonic sodium bicarbonate may be effective therapy for numerous agents possessing sodium channel blocking properties, including cocaine, quinidine, procainamide, flecainide, mexiletine, bupivacaine, and others.
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PMID:Poisoning by sodium channel blocking agents. 933 Aug 43

The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell patch-clamp recordings from freshly dissociated neurons, we found that nucleus accumbens neurons are less excitable in cocaine withdrawn rats because of a novel form of plasticity: reduced whole-cell sodium currents. Three days after discontinuation of repeated cocaine injections, nucleus accumbens neurons recorded in brain slices were less responsive to depolarizing current injections, had higher action potential thresholds, and had lower spike amplitudes. Freshly dissociated nucleus accumbens neurons from cocaine-pretreated rats exhibited diminished sodium current density and a depolarizing shift in the voltage-dependence of sodium channel activation. These effects appear to be related to enhanced basal phosphorylation of sodium channels because of increased transmission through the dopamine D1 receptor/cAMP-dependent protein kinase pathway. The effects of repeated cocaine administration were not mimicked by repeated injections of the local anesthetic lidocaine and were not observed in neurons within the motor cortex, indicating that they did not result from local anesthetic actions of cocaine. Because nucleus accumbens neurons are normally recruited to coordinate response patterns of movement and affect, the decreased excitability during cocaine withdrawal may be related to symptoms such as anergia, anhedonia, and depression.
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PMID:Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. 1197 3

Effects of ketamine on the sodium (INa) and L-type calcium currents (ICa) were examined by using whole-cell patch clamp techniques in guinea pig single ventricular myocytes. The mode of action of ketamine was compared with those of quinidine, a sodium channel blocker, and verapamil, a calcium channel blocker. Ketamine (30-300 microM) inhibited both INa and ICa in a concentration-dependent manner. Quinidine (30 microM) and verapamil (0.1 microM) produced use-dependent depression of INa and ICa, respectively. The amplitude of INa elicited by the first depolarizing pulse after a long quiescent period was slightly decreased by quinidine. During a train of depolarizing pulse the current amplitude decreased gradually, and reached a steady state level in the quinidine-treated cell (use-dependent block, UDB). Verapamil produced a similar mode of inhibition of ICa, i.e., UDB. In contrast, ketamine produced significant decrease in INa and ICa elicited by the first depolarizing pulses and the decreases of both currents were not augmented during a train of depolarizing pulses. From these results, it can be concluded that ketamine produces tonic block of the cardiac sodium and calcium channels and the mode of inhibition is clearly different from UDB by quinidine and verapamil.
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PMID:Tonic block of the sodium and calcium currents by ketamine in isolated guinea pig ventricular myocytes. 959 21

The effect of zinc ions on presynaptic currents and transmitter release was studied at the neuromuscular junction of the frog cutaneous pectoris muscle preparation with using an extracellular microelectrode. It has been shown that zinc (100 mkM) amplified MEPP frequency at first, but suppressed it later. Zinc affected the presynaptic spike waveform and transmitter release in a concentration-dependent manner. Depending on concentration and time of exposure zinc increased or suppressed transmitter release. Increase of transmitter release was shown to be resulted by blockade voltage gated and calcium activated potassium channels in nerve ending, leading to broad of both presynaptic spike and action potential. Strong change of presynaptic spike waveform after high concentration zinc treatment supposed that under this condition zinc depressed voltage gated calcium and sodium channel leading to decrease of transmitter release. It was concluded that the final and irreversible depression of acetylcholine release by zinc was due to alteration of whole ion conductances in nerve ending and to change of configuration of proteins included in structure of ion channels. It is discussed possible mechanisms of various effects of zinc ions at the neuromuscular synapse.
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PMID:[Presynaptic mechanisms of zinc effects on the neuromuscular transmission]. 1051 83

The effects of thimerosal, a sulfhydryl oxidizing agent, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. Thimerosal blocked the two types of sodium channels in a dose-dependent manner. The inhibitory effect of thimerosal was much more pronounced in TTX-R sodium channels than TTX-S sodium channels. The effect of thimerosal was irreversible upon wash-out with thimerosal-free external solution. However, dithiothreitol, a reducing agent, partially reversed it. Thimerosal shifted the steady-state inactivation curves for both types of sodium channels in the hyperpolarizing direction. The voltage dependence of activation of both types of sodium channels was shifted in the depolarizing direction by thimerosal. The inactivation rate in both types of sodium channels increased after thimerosal treatment. All these effects of thimerosal would add up to cause a depression of sodium channel function leading to a diminished neuronal excitability.
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PMID:Inhibitory action of thimerosal, a sulfhydryl oxidant, on sodium channels in rat sensory neurons. 1079 92


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