UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superfusion with 3 microM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 +/- 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 +/- 0.3 beats in guinea pig ventricular muscle (n = 6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations.
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PMID:Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers. 271 42

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. Vmax was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of Vmax depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on Vmax. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on Vmax but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 +/- 535 ms and 15.7 +/- 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when Vmax depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.
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PMID:Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers. 276 2

The effects of two novel antiarrhythmic drugs, cibenzoline and flecainide, known to exert potent inhibitory effects on sodium channel, were investigated on intraventricular conduction in anaesthetized, closed-chest dogs. During this study, in which the heart was electrically stimulated, the pacing period was gradually reduced in the 500-200 msec range, and the pacing rate was abruptly altered (2 sec) or sustained (8 to 10 sec) in order to study the possible frequency- and time-dependency of the depression of conduction. In addition to the electrocardiogram, the conduction time was recorded in the ventricular contractile tissue between an electrode advanced to the apex and the pacing electrode positioned near the base. Effective refractory period (ERP) was concurrently measured according to the extrastimulus method, and the monophasic action potential (MAP) recorded. The drugs were infused at a rate of 0.2 mg/kg/min over a 10 min period after a 4.0 mg/kg loading dose. Conduction time was lengthened by approximately 50% at low frequencies and 100% at high frequencies. Widening of the ORS complexes paralleled this lengthening, whereas the drugs tended only to prolong ERP, without preventing its shortening induced by acceleration. Cardiac disorders were aggravated when high pacing rates were maintained for 8 to 10 sec.
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PMID:Frequency- and time-dependent depression of ventricular distal conduction by two novel antiarrhythmic drugs, cibenzoline and flecainide. 313 54

Our previous study demonstrated that class I antiarrhythmics (fast sodium channel blockers) increased sinoatrial conduction time (SACT) in a dose-related fashion, indicating that a fast sodium current might play an important role in sinoatrial conduction. To assess a role of a slow calcium current in sinoatrial conduction, we examined effects of calcium channel blockers (diltiazem, verapamil, AQ-A 39, dilazep and bepridil) on SACT estimated by the constant atrial pacing in addition to on sinus cycle length (SCL) and on atrial developed tension (DT), using the isolated and blood-perfused dog right atrium. These calcium entry blockers except for bepridil were administered into the cannulated sinus node artery at an infusion rate of 0.2, 0.4 and 1.0 micrograms/min and bepridil at a rate of 0.6, 1.2 and 3.0 micrograms/min. The calcium antagonistic agents produced a dose-dependent decrease in DT and increase in SCL. The observed order of depression of inotropism was verapamil greater than diltiazem greater than bepridil = dilazep greater than AQ-A 39, while the order of negative chronotropism was diltiazem greater than verapamil greater than AQ-A 39 greater than dilazep greater than bepridil. However, as to dromotropism none of the five drugs exerted significant influences on SACT. From the previous and present results it is concluded that the fast sodium current may be predominantly important in sinoatrial conduction.
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PMID:Effects of calcium channel blockers on sinoatrial conduction in the isolated and blood-perfused dog atrium. 348 62

Increasing the hydrogen ion concentration of the bathing medium reversibly depresses the sodium permeability of voltage-clamped frog nerves. The depression depends on membrane voltage: changing from pH 7 to pH 5 causes a 60% reduction in sodium permeability at +20 mV, but only a 20% reduction at +180 mV. This voltage-dependent block of sodium channels by hydrogen ions is explained by assuming that hydrogen ions enter the open sodium channel and bind there, preventing sodium ion passage. The voltage dependence arises because the binding site is assumed to lie far enough across the membrane for bound ions to be affected by part of the potential difference across the membrane. Equations are derived for the general case where the blocking ion enters the channel from either side of the membrane. For H(+) ion blockage, a simpler model, in which H(+) enters the channel only from the bathing medium, is found to be sufficient. The dissociation constant of H(+) ions from the channel site, 3.9 x 10(-6) M (pK(a) 5.4), is like that of a carboxylic acid. From the voltage dependence of the block, this acid site is about one-quarter of the way across the membrane potential from the outside. In addition to blocking as described by the model, hydrogen ions also shift the responses of sodium channel "gates" to voltage, probably by altering the surface potential of the nerve. Evidence for voltage-dependent blockage by calcium ions is also presented.
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PMID:Ionic blockage of sodium channels in nerve. 454 Oct 78

The electrophysiological effects of amiodarone were studied in guinea pig papillary muscle by means of the single sucrose gap voltage clamp technique. The first time derivative of the upstroke of the action potential was measured as an indicator of the sodium current. The preparations were not voltage clamped during the action potential upstroke. Acute effects of amiodarone (4.4 X 10(-5) M and 8.8 X 10(-5) M; six experiments each) and effects of chronic administration at a single dose level (nine experimental vs. eight control animals) were studied. Results were qualitatively the same for all experimental conditions, and concentration dependent in the acute studies. Amiodarone caused marked use-dependent depression of the first time derivative of the upstroke of the action potential during stimulus trains. For example, at normal resting potential, chronic amiodarone treatment reduced the first time derivative of the upstroke of the action potential of the 16th beat of trains of cycle length 300 msec to 70 +/- 15% (mean +/- SD) of the initial value. This blocking effect was accentuated at more depolarized holding potentials and reduced at hyperpolarized holding potentials. Reduction of the first time derivative of the upstroke of the action potential was found to depend upon sodium channel inactivation. For all experiments, the mean normalized first time derivative of the upstroke of the action potential following a 1-second clamp in the -20 to +20 mV range was 0.92 +/- 0.08 in the control condition and 0.66 +/- 0.20 in the presence of amiodarone (less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone. 608 14

When frog sartorius muscles are exposed to methadone (2-4 X 10(-4) M) the action potential recorded intracellularly is depressed and eliminated in 3 to 4 hr. This is due to a decrease in the sodium conductance as measured by the maximum rate of rise of the action potential. When the calcium concentration in frog Ringer's solution (normally 1.08 mM) was either lowered to 0.54 mM or raised to 2 mM, the effect of methadone on excitability was unchanged. However, increasing the extracellular calcium to 4 mM decreased the action of methadone. As this would also increase the intracellular calcium concentration, in other experiments the free intracellular Ca+ concentration was raised by adding 0.4 mM caffeine to the Ringer's solution. This also antagonized the depressant action of methadone. The antagonistic action of caffeine was not due to a direct effect of caffeine on sodium conductance because the administration of caffeine by itself caused a 10% depression of the action potential maximum rate of rise and caffeine did not antagonize the action of tetrodotoxin, which is a specific sodium channel blocking agent. Finally, it was shown that the calcium ionophore, A23187, in low concentrations antagonized the depressant actions of methadone and meperidine on action potential production. It was concluded that increasing the intracellular free calcium concentration antagonized the depressant effect on excitability produced by opiate drugs acting on an intracellularly oriented opiate drug receptor.
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PMID:Calcium antagonism of an opiate drug effect on an excitable cell membrane. 629 65

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase O maximal rate of depolarization (Vmax) by fast sodium channel blockade. The marked rate dependence of Vmax depression may explain mexiletine's lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is 9 to 11 hours after intravenous or oral administration. Microsomal enzyme induction shortens mexiletine's elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response.
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PMID:Pharmacology, electrophysiology, and pharmacokinetics of mexiletine. 632 58

The effects of Class I antiarrhythmic drugs on the maximum rate of depolarization (Vmax) of guinea-pig ventricular action potentials were studied by standard microelectrode techniques. The ability of seven different drugs to depress Vmax in unstimulated tissue ('resting block') was found to correlate poorly with the lipophilicity (log P) of the compounds and only a little better with their molecular weights. Depression of Vmax in stimulated tissue was studied for 11 drugs and found, in all cases, to increase with stimulation frequency ('rate-dependent block'). The rapidity of onset of rate-dependent block (at approximately equipotent concentrations) varied markedly between drugs. It correlated well with molecular weight (r = 0.83; P less than 0.01). The time constant of recovery from rate-dependent block (tau re) also correlated very well with molecular weight (r = 0.94; P less than 0.001) for the seven drugs thus studied. A simplified model for the interaction of Class I drugs with the fast sodium channel is proposed in which the drugs all act as 'inactivation enhancers' (as suggested by other workers) but in which their molecular weight plays a central role in determining the kinetics of this interaction.
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PMID:Importance of physico-chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea-pig ventricle. 665 73

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

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