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Biomedical subjects

T J Colatsky

Publications and source records attributed to T J Colatsky.

30 records · Page 2Linked to original sources
PubMed1990

Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes.

Block of the delayed rectifier potassium current, IK, by the class IC antiarrhythmic agent, flecainide, and by the novel selective class III antiarrhythmic agent, E-4031, were compared in isolated cat ventricular myocytes using the single suction-pipette, voltage-clamp technique. Flecainide (10 microM) markedly reduced IK elicited on depolarization steps to plateau voltages (+10 mV) and nearly completely blocked the "tail currents" elicited on repolarization to -40 mV (93 +/- 4% block at +40 mV, n = 3). E-4031 (1 microM) produced similar effects (96 +/- 3% block at +40 mV, n = 3). Slow voltage ramps from -100 to +40 mV confirmed inward rectifying properties of IK and showed that flecainide and E-4031 have no effects on the background potassium current, IK1. Thus, the results demonstrate that block of IK is a common feature of flecainide and E-4031. IK block by E-4031 most likely underlies the drug's potent class III antiarrhythmic properties. On the other hand, flecainide block of IK during an action potential would tend to prolong repolarization, but this effect may be obscured by concomitant block of plateau Na+ channels to produce little or no change in action potential duration, consistent with its class IC classification.

Animals↗
PubMed1990

Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias.

Although work on class III antiarrhythmics remains at an early stage, these agents still appear to possess greater efficacy and less proarrhythmia than conventional class I agents in those experimental arrhythmia models considered to be most representative of the clinical situation. Although prolongation of repolarization carries with its own tendency for pause-dependent arrhythmogenesis (i.e., torsade de pointes), available data suggest that this may be a function of nonspecificity in potassium channel block rather than a general characteristic of class III activity. The availability of new and more selective blockers of specific cardiac potassium channels under development as class III agents have already helped to clarify basic questions about the ionic mechanism of repolarization in the heart, and one hopes that a growing clinical data base will eventually determine the relative safety and efficacy of these agents in preventing symptomatic and life-threatening arrhythmias.

Animals↗
PubMed1990

Electrical properties of canine subendocardial Purkinje fibers surviving in 1-day-old experimental myocardial infarction.

The passive electrical properties of subendocardial Purkinje fibers surviving in infarcted regions of canine ventricle 24 hours after coronary ligation were studied by using microelectrode techniques and cable theory. In normal hearts, cells within the subendocardial Purkinje fiber strands were found to be well coupled to each other but electrically isolated from neighboring myocardium. Voltage response to intracellular current injection was consistent with one-dimensional cable behavior and yielded estimates of passive electrical properties in general agreement with previous work on free-running Purkinje strands (membrane length constant, 1.2 +/- 0.1 mm; membrane time constant, 7.3 +/- 0.8 msec; input resistance, 67.4 +/- 7.4 K omega; membrane resistance, 8.2 +/- 0.7 K omega.cm; axial resistance, 0.52 +/- 0.06 M omega/cm; membrane capacitance, 960 +/- 102 nF/cm) (n = 21). On the day after coronary ligation, subendocardial Purkinje fiber action potentials were prolonged and slightly depolarized. Significant increases were measured in input resistance (+40.5%), membrane resistance (+43.9%), and axial resistance (+47.5%), whereas membrane capacitance was found to be significantly decreased (-24.3%) (n = 19). Conduction velocity, membrane length constant, membrane time constant, and the time constant and capacitance for the foot of the action potential remained unchanged. These results are consistent with electrical uncoupling between adjacent cells, which will increase internal resistivity, accompanied by changes in cellular phospholipid content, which can increase membrane resistance and alter membrane capacitance. Alternatively, the results can be explained by a simple model in which the apparent electrical structure is altered by changes in electrical coupling alone, with specific electrical properties remaining constant. Although the mechanisms underlying the observed changes remain uncertain, the present study indicates that myocardial infarction is associated with alterations in the passive electrical structure of surviving subendocardial Purkinje fibers, which, together with changes in action potential configuration, may provide a substrate for the generation of ventricular arrhythmias 24 hours after coronary ligation.

Action Potentials↗
PubMed1988

Cardiac electrophysiology of the antiarrhythmic agent recainam (Wy-42,362) in anesthetized dogs: relation to plasma and myocardial concentrations.

The present study was undertaken to characterize the cardiac electrophysiologic effects of the investigational class I antiarrhythmic agent recainam (Wy-42,362) on the canine heart in situ, and to determine the possible relationship between these effects and the concentration of drug in plasma and myocardium. Cardiac conduction times and refractory periods were measured at a paced cycle length of 300 ms in open-chest anesthetized dogs by recording atrial, ventricular, and His bundle electrograms. Recainam was infused intravenously (as a loading + maintenance dose) at either (a) 7.5 mg/kg/20 min + 5 mg/kg/60 min (low-dose group) or (b) 15 mg/kg/20 min + 10 mg/kg/60 min (high-dose group). Samples of plasma and ventricular myocardium were removed at selected times for subsequent analysis. At the end of the maintenance infusion, low-dose recainam produced a plasma concentration of 4.1 +/- 0.5 micrograms/ml and significantly increased atrial conduction time only. Plasma levels with high-dose recainam reached 9.4 +/- 3.5 micrograms/ml at end infusion, and produced significant increases in all measured electrophysiologic parameters except ventricular refractory period. Myocardial levels of recainam were undetectable in the low-dose group, but increased linearly with plasma concentration in the high-dose group with a myocardium/plasma ratio of nearly 1:1. Changes in ventricular conduction time, H-V interval, atrial and ventricular refractory periods, and Wenckebach cycle length correlated significantly with recainam concentration in plasma. In addition, drug levels in the ventricle correlated with the observed changes in both ventricular conduction time and ventricular refractory period. The data suggest that recainam plasma levels may serve as a useful guide in monitoring electrophysiologic response to this agent.

Anesthesia↗
PubMed1987

Cellular electrophysiology of the new antiarrhythmic agent recainam (Wy-42,362) in canine cardiac Purkinje fibers.

Recainam, [N-2,6-dimethylphenyl-N'-3-(1-methylethyl-amino)propylurea] hydrochloride (Wy-42,362), is a new class I antiarrhythmic agent that has been shown to be very effective in suppressing premature ventricular contractions in humans. To clarify the mechanism of antiarrhythmic action, the electrophysiologic effects of recainam were examined in canine cardiac Purkinje fibers using standard microelectrode techniques. Recainam at 3-100 microM (1-30 micrograms/ml) produced concentration-dependent decreases in action potential duration (APD), membrane responsiveness, and maximal upstroke velocity (Vmax). The reduction in Vmax was strongly modulated by the frequency of stimulation--i.e., Vmax block was use dependent. The rate of development of use-dependent block produced by recainam was much slower than typically seen with lidocaine, but comparable with that of the class Ia agents disopyramide and procainamide. However, unlike agents of the Ia subclass, recainam did not prolong APD at any concentration or cycle length tested. In summary, recainam appears to possess a novel cardiac cellular electrophysiologic profile, in that it shares characteristics with all three current class I antiarrhythmic subclasses.

Action Potentials↗
PubMed1986

Efficacy of the antidepressant iprindole against experimental arrhythmias.

The antiarrhythmic activity of iprindole was compared to that of imipramine in a variety of experimental arrhythmia models. Iprindole at 20 mg/kg i.v. showed efficacy in reverting ouabain- and aconitine-induced arrhythmias in pentobarbital anesthetized dogs, and at 15-30 mg/kg i.v. reduced the severity of the ventricular arrhythmias following acute coronary artery occlusion in anesthetized pigs. Imipramine (5-10 mg/kg i.v.) was also effective in reverting ouabain- and aconitine-induced arrhythmias, but appeared to exacerbate arrhythmias during coronary occlusion. In microelectrode experiments on isolated dog Purkinje fibers, iprindole reduced maximal upstroke velocity (Vmax) and action potential duration (characteristics of Class Ib antiarrhythmic agents) at concentrations greater than 1 microgram/ml. Significant decreases in Vmax occurred at lower iprindole concentrations when membrane potential was reduced by increasing external potassium from 4 to 10 mM, suggesting that electrical activity in depolarized cells may be selectively suppressed by iprindole. The present data indicate that iprindole may exert beneficial therapeutic effects in the treatment of cardiac arrhythmias, mediated, at least in part, through a Class I mechanism of action.

Aconitine↗
PubMed1981

Tetrodotoxin block of sodium channels in rabbit Purkinje fibers. Interactions between toxin binding and channel gating.

Tetrodotoxin (TTX) block of cardiac sodium channels was studied in rabbit Purkinje fibers using a two-microelectrode voltage clamp to measure sodium current. INa decreases with TTX as if one toxin molecule blocks one channel with a dissociation constant KD approximately equal to 1 microM. KD remains unchanged when INa is partially inactivated by steady depolarization. Thus, TTX binding and channel inactivation are independent at equilibrium. Interactions between toxin binding and gating were revealed, however, by kinetic behavior that depends on rates of equilibration. For example, frequent suprathreshold pulses produce extra use-dependent block beyond the tonic block seen with widely spaced stimuli. Such lingering aftereffects of depolarization were characterized by double-pulse experiments. The extra block decays slowly enough (tau approximately equal to 5 s) to be easily separated from normal recovery from inactivation (tau less than 0.2 s at 18 degrees C). The amount of extra block increases to a saturating level with conditioning depolarizations that produce inactivation without detectable activation. Stronger depolarizations that clearly open channels give the same final level of extra block, but its development includes a fast phase whose voltage- and time-dependence resemble channel activation. Thus, TTX block and channel gating are not independent, as believed for nerve. Kinetically, TTX resembles local anesthetics, but its affinity remains unchanged during maintained depolarization. On this last point, comparison of our INa results and earlier upstroke velocity (Vmax) measurements illustrates how much these approaches can differ.

Animals↗
PubMed1980

Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres.

1. Voltage clamp studies of the excitatory sodium current, INa, were carried out in rabbit cardiac Purkinje fibres using th two-micro-electrode technique. Previous work has shown the rabbit Purkinje fibre to have relatively simple morphology (Sommer & Johnson, 1968) and electrical structure (Colatsky & Tsien, 1979a) compared to other cardiac preparations. 2. Non-uniformities in membrane potential were kept small by reducing the size of INa to less than 50 microA/cm2 of total membrane surface area through prepulse inactivation or removal of external sodium, Nao. Temporal resolution was improved by cooling to 10-26 degrees C. These adjustments did not greatly alter the measured properties of the sodium channel. 3. Under these conditions, sodium currents were recorded satisfying a number of criteria for adequate voltage control. Direct measurement of longitudinal non-uniformity using a second voltage electrode showed only small deviations at the time of peak current. 4. The properties of the sodium channel were examined using conventional protocols. Both peak sodium permeability, PNa, and steady-state sodium inactivation, h infinity, showed a sigmoidal dependence on membrane potential. PNa rose steeply with small depolarizations, increasing roughly e-fold per 3.2 mV, and reaching half-maximal activation at -30 +/- 2 mV. The h infinity -V curve had a midpoint of -74.9 +/- 2 mV and a reciprocal slope of 4.56 +/- 0.13 mV at temperatures of 10-19.5 degrees C, and showed a dependence on temperature, shifting to more negative potentials with cooling (approximately 3 mV/10 degrees C). Recovery of INa from inactivation in double pulse experiments followed a single exponential time course with time constants of 108-200 msec at 19 degrees C for holding potentials near -80 mV. No attempt was made to describe the activation kinetics because of uncertainties about the early time course of the current. 5. These data predict a maximum duration for INa of less than 1-2 msec and a maximum peak current density of about 500 microA/cm2 under physiological conditions, i.e. 37 degrees C and 150 mM-Nao. This current magnitude is sufficient to discharge the membrane capacitance at rates comparable to those measured experimentally (311 +/- 27 V/sec, Colatsky & Tsien, 1979a). 6. The limitations of the method are discussed. The major problem is the longitudinal cable delay which limits the speed of voltage control. This makes it difficult to separate the activation of INa from the decay of the capacity transient for potentials positive to -15 mV. 7. It is concluded that the approach described is valid for measurements of sodium currents in the potential range where action potentials are initiated, making it possible to study cardiac sodium channels in an adult mammalian preparation which is free of enzymatic treatment.

Animals↗
PubMed1979

Electrical properties associated with wide intercellular clefts in rabbit Purkinje fibres.

1. Rabbit Purkinje fibres were studied using micro-electrode recordings of electrical activity or a two-micro-electrode voltage clamp. Previous morphological work had suggested that these preparations offer structural advantages for the analysis of ionic permeability mechanisms. 2. Viable preparations could be obtained consistently by exposure to a K glutamate Tyrode solution during excision and recovery. In NaCl Tyrode solution, the action potential showed a large overshoot and fully developed plateau, but no pacemaker depolarization at negative potentials. 3. The passive electrical properties were consistent with morphological evidence for the accessibility of cleft membranes within the cell bundle. Electrotonic responses to intracellular current steps showed the behaviour expected for a simple leaky capacitative cable. Capacitative current transients under voltage clamp were changed very little by an eightfold reduction in the external solution conductivity. 4. Slow current changes attributable to K depletion were small compared to those found in other cardiac preparations. The amount of depletion was close to that predicted by a cleft model which assumed free K diffusion in 1 micron clefts. 5. Step depolarizations over the plateau range of potentials evoked a slow inward current which was resistant to tetrodotoxin but blocked by D600. 6. Strong depolarizations to potentials near 0 mV elicited a transient outward current and a slowly activating late outward current. Both components resembled currents found in sheep or calf Purkinje fibres. 7. These experiments support previous interpretations of slow plateau currents in terms of genuine permeability changes. The rabbit Purkinje fibre may allow various ionic channels to be studied with relatively little interference from radial non-uniformities in membrane potential or ion concentration.

Action Potentials↗