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Biologia Geral e Experimetal
ELECTROPHYSIOLOGICAL EFFECTS OF SODIUM THIOPENTAL ON THE RIGHT ATRIUM OF THE RABBIT (ORYCTOLAGUS CUNICULUS) Marcli Costa da Silveira Libório1 This study describes the effects of sodium thiopental (40 mg/l) on the rabbit atrium. The electrical endocardial signals and theintracellular action potentials were recorded. The results revealed a reduction in the atrial impulse velocity (from 75 ± 3 cm/secto 63 ± 7 cm/sec), disorganization of the propagated electrical front wave, reduction of the spontaneous atrial pacemaker rate,depolarization of atrial cells (quiescent: 3.46 ± 1.2 mV; under electrical stimulation: 3.1 ± 0.5 mV), and an increase of the atrialcellular refractory period (from 52 ± 5 msec to 117 ± 8 msec). Atropine sulfate (1 mg/l) did not prevent or abolished thebradicardia produced by the sodium thiopental.
Keywords: Electrocardiophisiology, action potentials, atrial cells, sodium thiopental.
O estudo descreve os efeitos do tiopental sódico (40 mg/l) sobre átrios de coelho. Foram registrados os sinais elétricos endocárdicose os potenciais de ação intracelulares. Os resultados mostraram redução da velocidade de propagação do impulso atrial (75 ± 3 cm/sec a 63 ± 7 cm/sec), desorganização da frente de onda propagada, redução da freqüência espontânea do marcapasso atrial,despolarização de células atriais mantidas em repouso (3.46 ± 1.2 mV) ou sob estimulação elétrica (3.1 ± 0.5 mV), e aumento doperíodo refratário das células atriais (52 ± 5 msec a 117 ± 8 msec). O sulfato de atropina (1 mg/l) não preveniu ou aboliu abradicardia produzida pelo tiopental sódico.
Palavras-chave: eletrocardiofisiologia, potencial de ação, células atriais, tiopental sódico.
those with high blood flow demands. In plasma, 85% of NaTHIO is bound to albumin molecules and, as a Sodium thiopental (NaTHIO) is a well-known consequence, patients with severe hypoalbuminemia barbiturate. Its rapid hypnotic properties derive from may need less NaTHIO to lose consciousness during its effective liposolubility, a property due to the presence of a sulfur atom substituting an oxygen atom Becker & Tonnesen (1978) reported some in the ureic residue of the barbiturate ring. At blood cardiovascular effects produced by NaTHIO in patients concentrations of up to 16 mg/ml, conscience is lost anesthetized exclusively by this drug. These effects quickly (Evers & Crowder, 2001). Patients of normal included an increase in heart rate during the induction body weight who receive small doses of NaTHIO phase, a decrease in systolic blood pressure, and an normally wake up around 5 to 10 minutes later. Rapid increase of the ventricular pre-ejection period.
recovery occurs as a consequence of the redistribution Since Beattie et al. (1930) showed that chloroform of NaTHIO among different tissues and organs, mainly facilitates the appearance of ventricular fibrillation, the 1 Departamento de Fisiologia, Laboratório de Biofísica do Coração. Universidade Federal de Sergipe, Av. Marechal Rondon, s/n, Jardim RosaElze, São Cristóvão, Se, 49100-000. [email protected] anesthetic side-effects have been investigated mm, outer diameter: 1 mm) used as a grounded pole.
exhaustively. However, Price & Ohnishi (1980) have The electrode was then mounted on a mechanical emphasized the need for a better understanding of the micromanipulator to allow it to be displaced smoothly effects of NaTHIO on the conduction of electrical (X-Y axes) along the endocardial surface. Electrical impulses and myocardial excitability.
signals captured by this roving electrode were amplified This paper describes the electrophysiological differentially, monitored, and photographed by an effects promoted by this thiobarbiturate. The following oscilloscope camera (Differential Amplifier 5A22N, C- parameters were studied: a) conduction velocity of the 50 Oscilloscope Camera, D44 Dual Beam Oscilloscope, atrial electrical impulse, b) organization of the wave TEKTRONIX, Inc. Beaverton, Oregon, USA).
front of the propagated electrical impulse, c) Intracellular readings were taken with 3M KCl- spontaneous pacemaker rate, d) cellular resting filled glass microelectrodes (DC resistance equal to 40 potential in quiescent and electrically stimulated MW, tip diameter about 0.1mm: Oliveira-Castro & myocardial fibers, e) morphology of propagated action Machado, 1969). Microelectrode signals were sent to a potentials, and f) electrical refractory period of the atrial high input impedance amplifier (M701, W-P Instruments, cells. These parameters are especially important given Inc., New Haven, Connecticut, USA) and then to a the use of NaTHIO in animal research as a hypnotic plug-in oscilloscope amplifier (5A48 Dual Trace drug or as an auxiliary to prevent ischemic/reperfusion- Amplifier, TEKTRONIX, Inc. Beaverton, Oregon, USA).
induced cardiac arrhythmias (Ruigrok et al., 1985; Following the experimental protocol, the atrium was Schultz et al., 1997; Conradie & Coetzee, 1999; Kato & stimulated electrically using ungrounded electrical current pulses (DS2 Isolator Unit, D4030 Pulse Programmer, DIGITIMER Limited, Welwyn Garden City, Hertfordshire, England). The stimuli were delivered through a pair of stainless steal electrodes placed at The present study was carried out on adult rabbits (1.5-2.0 kg) of both sexes. Animals were To evaluate the effect of thiobarbiturate on atrial sacrificed by a blow applied to the base of the skull.
impulse velocity, the atrial pacemaker frequency was Their hearts were removed immediately and immersed set at a rate 20% higher than the spontaneous one.
in a modified Tyrode solution (in mM: NaCl 137, KCl The conduction velocity was measured through 5.0, MgCl2 0.5, NaHCO3 12, CaCl2 1.8, Glucose 6.0, previously selected pathways with uniform conduction NaH2PO4 1.8). The right atrium was separated and of electrical signals. They were placed 4 to 6 mm from mounted in a chamber with its endocardial surface the stimulus electrodes to avoid interference of the facing upwards, superfused in Tyrode at 34.0±0.5°C stimulation field. Atrial impulse speed was estimated (UNITEMP, model 111, FANEM, Cumbica, Guarulhos, by displacing the surface electrode at constant steps Sao Paulo, SP), aerated and buffered with carbogen (0.5 or 0.6 mm) and by simultaneous measurement of mixture (95% oxygen plus 5% carbon dioxide, <1% the time elapsed before the wave reached the electrode.
error). The test solution was prepared by adding It was possible to estimate the velocity of the atrial NaTHIO (Thionembutal, Abbott, Laboratórios do impulse by plotting each displacement against its Brasil, Ltda., São Paulo, SP) to the Tyrode.
corresponding time delay, based on the steepness of Surface records were performed with the aid of a the regression line used to fit the experimental data.
Teflon®-coated silver wire electrode (150 mm) inserted To evaluate the effects of the barbiturate on atrial into a hypodermic stainless steel needle (length:100 pacemaker activity, the electrical impulses recorded by Electrophysiological effects of sodium tiopental the surface electrode were counted, and the were obtained for six other atria in which NaTHIO (40 spontaneous rate was determined in detail (D4030 Pulse mg/l) decreased the impulse velocity from 75 ± 3 cm/ Programmer, DIGITIMER Limited, Welwyn Garden City, sec to 63 ± 7 cm/sec (n = 18 trials, p < 0.001). This effect Hertfordshire, England; 1830 Interval Generator, 1832 had not disappeared completely 30 minutes after Preset Control, 1831 Pulse Control Module, W-P removal of the barbiturate from the organ bath.
Instruments, Inc. New Haven, Connecticut, USA).
To study the effects of NaTHIO on cellular 2. Effects of sodium thiopental on the atrial pacemaker resting potential, special care was taken with regard to the grounding system of the organ bath. For this, the At 60 mg/l, NaTHIO reduced the atrial pacemaker silver electrode was covered with chloride, according rate 16 to 47% (Figure 2). This negative chronotropic to the technique described by Geddes (1972), in order effect was eliminated partially or completely during the to minimize junction potentials. This electrode, washout (n = 13 atria, 25 trials, p < 0.001).
connected to the ground, was immersed in 3M KCl, At a doseage of 40 mg/l, NaTHIO decreased the with an agar/3M KCl bridge connecting it to the organ spontaneous atrial rate progressively, and complete bath. The aim was to obtain electrical stability, and no asystole was observed in several experiments (see electrical drift was recorded in the organ bath when the Figure 3). Initial control rate was 158 bpm, but during Tyrode voltage was monitored during 3 hours.
NaTHIO (40 mg/l), it decreased progressively, Statistical Analysis: Results are presented as means
sometimes to zero (interruptions in the fitting line). This ± standard deviation. Student’s t-test was used to effect was not altered by the application of atropine sulfate (1 mg/l, Sigma Chemical Co., St. Louis, MO, USA) 20 minutes before NaTHIO. However, removal of NaTHIO from the perfusion solution resulted in a return to the control rate. Similar results were obtained for 1. Effects of sodium thiopental on the propagated atrial three other atria (n = 6 trials). In some experiments, NaTHIO (40-60 mg/l) induced the appearance of Figure 1 shows two sets of electrical waves isolated extrasystoles or even activated rapid ectopic recorded from the atrial endocardium by moving the surface electrode at regular steps. The experiments were carried out on a paced right atrium (2 Hz). In the control 3. Effects of sodium thiopental on the resting potential (Figure 1A), the interval between successive waves was highly regular (electrode displacement step = 0.6 Figure 4 shows an intracellular record obtained mm), indicating uniform propagation. Conduction from a quiescent atrial cell (resting potential = 81 mV).
velocity was calculated at 73 cm/sec (r2 = 0.9992). In the Downward pointing arrows indicate the moment when experimental procedure (Figure 1B), waves were NaTHIO (40 mg/l) was added to the bath and upward recorded in the presence of NaTHIO (40 mg/l). The arrows indicate when the barbiturate was removed from.
surface electrode was displaced at steps of 0.5 mm and NaTHIO promoted depolarization (3.46 ± 1.2 mV) when the impulse velocity of the atrium decreased to 56 cm/ present in the solution bath. The depolarizing effect sec (r2 = 0.9954, p < 0.001), 22% lower than the control was not reverted completely by the washout. Similar value. Wave morphology was also less regular, and in effects were observed in five other atria (3.06 ± 1.4, n = several cases, irregularities indicate loose organization of atrial impulses. Figure 1C presents the regression NaTHIO (40 mg/l) also promoted depolarization lines for control and NaTHIO data points. Similar results in electrically stimulated atrial tissue (1.2 Hz). Figure 5 Figure 1. Effect of NaTHIO (40mg/l) on the rabbit atrial conduction velocity. Superimposed electrical waves recorded on theendocadial surface by displacing a surface roving electrode at constant steps. A: control (step=0.6mm); B: test solution (Tyrode +NaTHIO 40mg/l, step=0.5mm); Atrial impulse velocities were determined (C) by the steepness of regression lines. NaTHIO reducedthe impulse velocity about 23 percent from 73cm/sec control (triangles, r2=0.99) to 56cm/sec (squares, r2=0.99, p<0.001). Theexperiment was carried out on paced atrium (2Hz, 34±0.1°C; Horizontal bar: 2msec).
Figure 2. Negative chronotropic effect produced by NaTHIO (40mg/l) on therabbit atrial pacemaker (n=13 atria). This effect ranged from 16 to 47 percentof the control rate. Experiments were performed on spontaneous beating atria(34±0.1°C, p<0.001).
Electrophysiological effects of sodium tiopental Figure 3. NaTHIO (40mg/l) induces asystole (interruption of the fitting line) in the rabbit right atrium. The asystole wasobserved in 4 of 13 rabbit atria assayed but bradycardia was present in all of them. This negative chronotropic effect couldnot be prevented by atropine sulfate (1mg/l) applied 20 minutes before and during the barbiturate action (2Hz, 34±0.1°C).
Figure 4. Effect of NaTHIO (40mg/l) on the quiescent rabbit atrial cell (initialresting potential=81mV). Downward and upward arrows mark when NaTHIOwas added or removed, respectively, from the organ bath. Note that it producedsmall depolarizations (3.46±1.2mV). This effect was not completely abolishedduring washout (34±0.1°C).
Figure 5. Effect of NaTHIO (40mg/l) on the resting potential of a rabbit atrialpaced cell (1.2Hz). Thiobarbiturate depolarized the cell (downward arrows).
Similar result was seen in other 5 atria (3.1±0.5mV, 34±0.1°C). Upward arrowsstand for the washout.
shows intracellular records obtained from a stimulated atrium. The amplitude of action potentials is truncated due to the high gain needed for monitoring resting potential. Up and down arrows indicate, respectively, when NaTHIO (40 mg/l) was added to or removed from the bath. Note that NaTHIO induced depolarization.
Similar results were obtained from five other atria (n = 12 trials) in which NaTHIO depolarized atrial cells 3.1 ± 0.5 mV (p < 0.001). Nevertheless, in contrast to the quiescent myocardium, recovery of control resting potential was faster in the paced atrium, and residual 4. Effects of sodium thiopental on the morphology of the propagated action potential in atrial tissue Figure 6 shows superimposed traces of action potentials that were randomly obtained from atrial cells located in a previously selected myocardium area (Zoom Stereo Microscope, model SZ-III, Olympus Optical Co., Ltd., Tokyo, Japan, ocular with embedded Figure 6. Superimposed traces of propagated action potentialsobtained in different cell of the atrial endocardial suface. A: six reticle). Control action potentials are seen in the Figure action potentials recorded on control solution. All of them 6A, and Figure 6B presents action potentials recorded showed a well-developed fast component (depolarization phase).
B: four action potential were recorded in the same atrial area, when NaTHIO (20 mg/l) was added to the external but after adding NaTHIO (40mg/l). Under the barbiturateaction, several action potentials showed depressed fast medium. Arrows indicate the maximum amplitude of components (arrows), suggesting a partial inhibition of the the fast component of the myocardial action potentials.
sodium current (34±0.1°C, stimuli: 30mV, 1ms, 2Hz).
In the presence of NaTHIO, the amplitude of the fast component was reduced and was exceeded by that of the slow component (Paes de Carvalho et al., 1966, 5. Effects of sodium thiopental on the cellular refractory Figure 7 shows action potentials obtained from an atrial cell. The upper panel presents the control, and the lower panel depicts the effect of NaTHIO (40 mg/l) on the cellular refractory period. Extrasystolic stimuli, applied at different coupling intervals (between normal Figure 7. Effect of NaTHIO (40mg/l) on the cellular refractory and premature stimuli), permitted measurement of the period determined by applying extrasystolic stimuli withdifferent coupling interval. Upper panel: control (refractory cellular refractory period. In the control, the refractory period equal to 73msec); lower panel: test with 40mg/l of NaTHIO period was 73 msec, but it increased to 127 msec when (refractory period equal to 127msec). Experiment carried outat 34±0.1°C. Calibration bars: 20mV (vertical), 20msec (hori- NaTHIO was added to the bath. Similar results were Electrophysiological effects of sodium tiopental obtained in fifteen other cells (n = 4 atria; control : 52 ± patients anesthetized with NaTHIO. However, in the 5 msec; test: 117 ± 8 msec; p < 0.001).
isolated rabbit right atrium, this barbiturate promoted bradycardia, sometimes followed by an asystole. The tachycardic effect related by these authors could be In spite of the development of new hypnotic explained by the depression of myocardial contractility, agents, NaTHIO is still employed as an anesthetic in given that NaTHIO is known to reduce inward calcium many experimental procedures with animals. This paper flow in myocardial cells (Komai & Rusy, 1991, 1994a, contributes to the understanding of its effects on the 1994b; Park & Lynch, 1992; Housmans et al., 1995; mammalian myocardium. The results showed that Bettens et al., 1996; Descorps et al., 2001). This entry NaTHIO promotes arrhythmogenic effects similar to of calcium ions is important for the promotion of electrical wave front fragmentation, reduction of the calcium-induced calcium release in the myocardial cells fast component of action potential amplitude, and (Sitsapesan & Williams, 1994; Bassani et al., 1995; cellular depolarization. On the other hand, the increase López-López et al., 1995; Sipido et al., 1998; Wier & of the refractory period may have an anti- Balke, 1999; Shannon et al., 2000; Bers, 2002) and arrhythmogenic effect associated with NaTHIO.
initiatiation of the contractile process. Depression of myocardial contractility would lead to a decrease in electrical changes in the myocardium that can promote arterial blood pressure, triggering a reflex response from and sustain cardiac arrhythmias. This is because it the aortic pressure baroreceptors. Under such reduces the myocardium impulse velocity and conditions, the sympathetic tonus of the heart would simultaneously disorganizes the propagated wave front be enhanced and the cardiac rate increased. The of the electrical impulse. This could facilitate the depressor effect of NaTHIO on the atrial pacemaker establishment of a chaotic state in electrical wave cells does not seem to be mediated by release of propagation. It is important to note that the irregular acetylcholine from the parasympathetic nervous morphology observed in the surface records during endings, given that the muscarinic blockade with NaTHIO action (Figure 1B) represents a form of wave atropine sulfate did not have any effect.
front fragmentation that is a consequence of micro- accelerations and micro-deaccelerations of the myocardial performance by acting on the ionic cellular propagated impulse. This facilitates re-entry currents responsible for electrogenesis in the cardiac mechanisms in the myocardium tissue, leading to the tissue. To study this, resting potentials from quiescent appearance of cardiac arrhythmia. The thiobarbiturate and non-quiescent myocardial cells were measured also decreased impulse propagation velocity, probably (Figs. 4 and 5). In both cases, thiopental depolarized due to the decrease of the fast sodium currents that are the myocardium. It is known that the resting potential responsible for the depolarization phase of propagated is maintained by a complex balance between action potentials. This effect became clear because depolarizing currents, which are mainly carried by NaTHIO reduced clearly the fast component of the sodium and calcium ions, and hyperpolarizing currents, myocardial action potential (Figure 6B). Similar sodium carried by potassium ions. The depolarizing effect of current inhibition has been recorded for sodium thiopental should thus be due either to an increase of pentobarbital (Wartenberg et al., 2001) – a close the inward sodium-calcium current or to a decrease of the ouward potassium current. The depressor effect of Becker & Tonnesen (1978) observed a cardiac NaTHIO on potassium channels was described recently rate increase during the sleep induction phase in (Pancrazio et al., 1993; Carnes et al., 1997; Martynyuk et al., 1999). In fact, NaTHIO, as demonstrated elegantly of the pro- and anti-arrhythmogenic effects that are by Heath & Terrar (1996), is a selective blocker of the K potassium channels (a subtype of the delayed Acknowledgements ELETROBRÁS - Centrais Elétricas
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