PubMed Health⌕ Search

Biomedical subjects

D A Saint

Publications and source records attributed to D A Saint.

At least 19 recordsLinked to original sources
PubMed2006

Gene expression of stretch-activated channels and mechanoelectric feedback in the heart.

1. Mechanoelectric feedback (MEF) in the heart is the process by which mechanical forces on the myocardium can change its electrical properties. Mechanoelectric feedback has been demonstrated in many animal models, ranging from isolated cells, through isolated hearts to whole animals. In humans, MEF has been demonstrated directly in both the atria and the ventricles. It seems likely that MEF provides either the trigger or the substrate for some types of clinically important arrhythmias. 2. Mechanoelectric feedback may arise because of the presence of stretch-sensitive (or mechano-sensitive) ion channels in the cell membrane of the cardiac myocytes. Two types have been demonstrated: (i) a non-specific cation channel (stretch-activated channel (SAC); conductance of approximately 25 pS); and (ii) a potassium channel with a conductance of approximately 100 pS. The gene coding for the SAC has not yet been identified. The gene for the potassium channel is likely to be TREK, a member of the tandem pore potassium channel gene family. We have recorded stretch-sensitive potassium channels in rat isolated myocytes that have the properties of TREK channels expressed in heterologous systems. 3. It has been shown that TREK mRNA is expressed heterogeneously in the rat ventricular wall, with 17-fold more expression in endocardial compared with epicardial cells. This difference is reflected in the TREK currents recorded from endocardial and epicardial cells using whole-cell patch-clamp techniques, although the difference in current density was less pronounced (approximately threefold). Consistent with this, we show here that when the ventricle is stretched by inflation of an intraventricular balloon in a Langendorff perfused rat isolated heart, action potential shortening was more pronounced in the endocardium (30% shortening at 40 mmHg) compared with that in the epicardium (10% shortening at the same pressure). 4. Computer models of the mechanics of the (pig) heart show pronounced spatial variations in strain in the myocardium with large transmural differences (in the left ventricle in particular) and also large differences between the base and apex of the ventricle. 5. The importance of MEF and the non-homogeneous gene expression and strain distribution for arrhythmias is discussed.

Animals↗
PubMed2004

Heterogeneous expression of tandem-pore K+ channel genes in adult and embryonic rat heart quantified by real-time polymerase chain reaction.

1. Many members of the tandem-pore K+ channel gene family have been reported to be present in cardiac cells. However, the pattern of gene expression of these channels in the heart is a matter of some dispute. 2. Here, we used reverse transcription and real-time quantitative polymerase chain reaction to investigate the pattern of gene expression of nine members of the tandem-pore K+ channel genes in adult and embryonic rat heart. The genes (TWIK-1, TWIK-2, TASK-1, TASK-2, TASK-3, TREK-1, TREK-2, TRAAK and KCNK6) were quantified, relative to glyceraldehyde-3-phosphate dehydrogenase (GADPH), in all four chambers of adult rat hearts and in the ventricles of embryonic rat hearts. 3. All these genes were detected in at least one chamber of the heart, with a predominance of TWIK-2, TASK-1 and TREK-1 expression. The expression of TWIK-2 was higher in the right atrium than in other cardiac chambers, TASK-1 was expressed more in atria than in ventricles and TREK-1 was highly expressed in the right ventricle. 4. The expression levels of the three predominant genes in embryonic rat ventricle are much lower than their expression in adult rat ventricles. 5. The physiological implications of the differential gene expression of the tandem-pore K+ channels is discussed.

Animals↗
PubMed2003

Suppression of calcium sparks in rat ventricular myocytes and direct inhibition of sheep cardiac RyR channels by EPA, DHA and oleic acid.

The anti-arrhythmic effects of long-chain polyunsaturated fatty acids (PUFAs) may be related to their ability to alter calcium handling in cardiac myocytes. We investigated the effect of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) on calcium sparks in rat cardiac myocytes and the effects of these PUFAs and the monounsaturated oleic acid on cardiac calcium release channels (RyRs). Visualization of subcellular calcium concentrations in single rat ventricular myocytes showed that intensity of calcium sparks was reduced in the presence of EPA and DHA (15 micro M). It was also found that calcium sparks decayed more quickly in the presence of EPA but not DHA. Sarcoplasmic vesicles containing RyRs were prepared from sheep hearts and RyR activity was determined by either [(3)H]ryanodine binding or by single-channel recording. Bilayers were formed from phosphatidylethanolamine and phosphatidylcholine dissolved in either n-decane or n-tetradecane. EPA inhibited [(3)H]ryanodine binding to RyRs in SR vesicles with K(I) = 40 micro M. Poly- and mono-unsaturated free fatty acids inhibited RyR activity in lipid bilayers. EPA (cytosolic or luminal) inhibited RyRs with K(I) =32 micro M and Hill coefficient, n(1) = 3.8. Inhibition was independent of the n-alkane solvent and whether RyRs were activated by ATP or Ca(2+). DHA and oleic acid also inhibited RyRs, suggesting that free fatty acids generally inhibit RyRs at micromolar concentrations.

Animals↗
PubMed2002

Trek-like potassium channels in rat cardiac ventricular myocytes are activated by intracellular ATP.

Large (111 +/- 3.0 pS) K+ channels were recorded in membrane patches from adult rat ventricular myocytes using patch-clamp techniques. The channels were not blocked by 4-AP (5 mM), intracellular TEA (5 mM) or glybenclamide (100 mM). Applying stretch to the membrane (as pipette suction) increased channel open probability (Po) in both cell-attached and isolated patches (typically, Po approximately equals 0.005 with no pressure; approximately equals 0.328 with 90 cm H2O: Vm = 40 mV, pHi = 7.2). The channels were activated by a decrease in intracellular pH; decreasing pHi to 5.5 from 7.2 increased Po to 0.16 from approx. 0.005 (no suction, Vm held at 40 mV). These properties are consistent with those demonstrated for TREK-1, a member of the recently cloned tandem pore family. We confirmed, using RT-PCR, that TREK-1 is expressed in rat ventricle, suggesting that the channel being recorded is indeed TREK-1. However, we show also that the channels are activated by millimolar concentrations of intracellular ATP. At a pH of 6 with no ATP at the intracellular membrane face, Po was 0.048 +/-0.023, whereas Po increased to 0.22 +/- 0.1 with 1 mM ATP, and to 0.348 +/- 0.13 with 3 mM (n = 5; no membrane stretch applied). The rapid time course of the response and the fact that we see the effect in isolated patches appear to preclude phosphorylation. We conclude that intracellular ATP directly activates TREK-like channels, a property not previously described.

Adenosine Triphosphate↗
PubMed2001

Subconductance states of the cardiac K(ATP) channel revealed by partial block with glybenclamide.

Currents carried by single ATP-sensitive potassium channels (K(ATP) channels) were recorded in membrane patches isolated from adult rat ventricular myocytes. Channel currents were blocked completely by ATP at millimolar concentrations and by glybenclamide at micromolar concentrations. However, at lower glybenclamide concentrations (1-1000 nM), a partial block, manifest as a subconductance state, was often seen. At concentrations of 100-300 nM the mean size of the subconductance state was 33+/-2.7 pS (175 mM potassium in the pipette; n=13). The size of the conductance substate varied slightly with the concentration of glybenclamide, (42 pS at 1 nM, 34 pS at 100 nM and 31 pS at 1 microM), while the open time of the subconductance state decreased with increasing glybenclamide concentration (n=4). ATP (4 mM) completely blocked both the main conductance state of the channel and the subconductance state induced by glybenclamide. Submaximal concentrations of ATP also appeared to induce subconductance states, but these could not be resolved into discrete conductance levels. The observation that subconductance states can be induced by low concentrations of glybenclamide may have implications for models of how the binding of glybenclamide is translated into closure of the Kir6.2 pore.

Adenosine Triphosphate↗
PubMed2000

Interaction of lidocaine with the cardiac sodium channel: effects of low extracellular pH are consistent with an external blocking site.

Brief extracellular application of millimolar concentrations of lidocaine affected sodium currents recorded in isolated rat ventricular myocytes in two ways: 1) a reduction of the maximum current consistent with a channel blocking action, and 2) a negative shift in the voltage dependence of inactivation consistent with an interaction with the inactivated state of the channel. Both effects occurred very rapidly (<< 1 s). Decreasing extracellular pH to 6.4 increased the potency for channel block (EC50 1.8 +/- 0.2 mM at pH 7.4 and 0.8 +/- 0.1 mM at pH 6.5) and decreased the potency to shift inactivation (V(1/2) shift -42 mV by 1 mM lidocaine at pH 7.4 and -12.6 mV at pH 6.5). Channel block was slightly less at +90 mV compared to -40 mV at either pH (not statistically significant). The increase in potency for block at decreased extracellular pH, while intracellular pH is buffered, and the lack of voltage dependence of block, suggest that the charged form of lidocaine can block the channel by interacting with a site near the extracellular mouth, although alternative explanations are discussed.

Animals↗
PubMed1999

Inhibition of cardiac sodium currents in adult rat myocytes by n-3 polyunsaturated fatty acids.

1. The acute effects of n-3 polyunsaturated fatty acids were determined on whole-cell sodium currents recorded in isolated adult rat ventricular myocytes using patch clamp techniques. 2. The n-3 polyunsaturated fatty acids docosahexaenoic acid (22:6, n-3), eicosapentaenoic acid (20:5, n-3) and alpha-linolenic acid (18:3, n-3) dose-dependently blocked the whole-cell sodium currents evoked by a voltage step to -30 mV from a holding potential of -90 mV with EC50 values of 6.0 +/- 1.2, 16.2 +/- 1.3 and 26.6 +/- 1.3 microM, respectively. 3. Docosahexaenoic acid, eicosapentaenoic acid and alpha-linolenic acid at 25 microM shifted the voltage dependence of activation of the sodium current to more positive potentials by 9.2 +/- 2.0, 10.1 +/- 1.1 and 8.3 +/- 0.9 mV, respectively, and shifted the voltage dependence of inactivation to more negative potentials by 22.3 +/- 0.9, 17.1 +/- 3.7 and 20.5 +/- 1.0 mV, respectively. In addition, the membrane fluidising agent benzyl alcohol (10 mM) shifted the voltage dependence of activation to more positive potentials by 7.8 +/- 2.5 mV and shifted the voltage dependence of inactivation to more negative potentials (by -24.6 +/- 3.6 mV). 4. Linoleic acid (18:2, n-6), oleic acid (18:1, n-9) and stearic acid (18:0) were either ineffective or much less potent at blocking the sodium current or changing the voltage dependence of the sodium current compared with the n-3 fatty acids tested. 5. Docosahexaenoic acid, eicosapentaenoic acid, alpha-linolenic acid and benzyl alcohol significantly increased sarcolemmal membrane fluidity as measured by fluorescence anisotropy (steady-state, rss, values of 0.199 +/- 0. 004, 0.204 +/- 0.006, 0.213 +/- 0.005 and 0.214 +/- 0.009, respectively, compared with 0.239 +/- 0.002 for control), whereas stearic, oleic and linoleic acids did not alter fluidity (the rss was not significantly different from control). 6. The potency of the n-3 fatty acids docosahexaenoic acid, eicosapentaenoic acid and alpha-linolenic acid to block cardiac sodium currents is correlated with their ability to produce an increase in membrane fluidity.

Animals↗
PubMed1999

Variability of channel subconductance states of the cardiac sodium channel induced by protease.

Conductance and subconductance levels of voltage-activated sodium channels recorded using patch clamp techniques from isolated cardiac myocytes were accurately determined using signal processing techniques. From the tabulated amplitude distributions of the conductance levels, we inferred the most likely underlying distribution by applying the method of the kernel density estimate. When myocytes were prepared by dissociation of the heart with a solution containing collagenase as the only digestive enzyme, the fully open conductance level of the channel was 23 pS, with two prominent sublevels at 8 and 16 pS (280 mM sodium). When cells were dissociated in an identical manner but with solution containing added protease, the most frequent open levels of the channel were 9 and 15 pS. In these latter recordings, the channel also opened to 22 pS, but did so only rarely. The main conductance levels in cells dissociated with protease were essentially the same as the subconductance states in cells dissociated without protease. We infer that the conductance sublevels normally seen are, within experimental errors, 1/3 and 2/3 of the fully open level, and that the proteolytic enzyme modifies the channel such that it tends to open predominantly to the subconductance levels.

Animals↗
PubMed1998

The effects of propofol on macroscopic and single channel sodium currents in rat ventricular myocytes.

1. The effects of the injectable anaesthetic agent propofol (di-isopropyl phenol) were examined on sodium currents and single sodium channels by use of patch-clamp techniques in ventricular myocytes isolated from rat hearts. 2. Propofol dose-dependently blocked the whole cell sodium currents evoked by a voltage step to -30 mV from a holding potential of -90 mV with an EC50 of 14.8+/-2.3 microM (mean+/-s.e.mean). 3. Propofol caused a substantial hyperpolarizing shift in the voltage-dependence of inactivation of sodium currents (168 microM (30 microg ml(-1)) propofol caused a -14 mV shift (P<0.01); 56 microM caused a -8 mV shift (P<0.05)). A smaller shift in the voltage-dependence of activation was produced (4 mV by 168 microM (not statistically significant)), but this was to more depolarized potentials. The maximal sodium conductance, as judged from the activation and inactivation curves, was reduced by 13% by 168 microM propofol (not statistically significant), but propofol did not affect the reversal potential of the current-voltage relationship. 4. The macroscopic rate of inactivation, as measured by the time constant of the exponential fall of current amplitude from the peak current, was also slowed by propofol, from a control time constant of 1.78+/-0.31 ms to 2.93+/-0.47 ms (mean+/-s.e.mean, n=8, P<0.05) by 168 microM propofol. Despite the increase in the time constant, the macroscopic inactivation remained well fitted by a single exponential. The macroscopic rate of activation was also slowed, but to a lesser degree (<10%, not statistically significant) by 168 microM propofol. 5. Propofol slowed the rate of recovery from inactivation of the sodium current, as measured by a two pulse protocol. Propofol (168 microM) increased the time constant of recovery, measured at -100 mV and room temperature, from a control value of 55+/-5.9 ms to 141+/-24.2 ms (mean+/-s.e.mean, n=8, P<0.01). Although the time constant was increased at all voltages measured, the intrinsic voltage-dependence of the rate of recovery was not changed. 6. Single channel recordings showed that the mean open time of single sodium channels was dramatically reduced by propofol (from 0.50+/-0.02 ms in control to 0.28+/-0.01 ms by 56 +/-M propofol and to 0.24+/-0.01 ms by 168 microM, both significantly different from control, P<0.01). Single channel conductance was not changed by either concentration of propofol.

Anesthetics, Intravenous↗
PubMed1998

Sodium channel-blocking properties of spiradoline, a kappa receptor agonist, are responsible for its antiarrhythmic action in the rat.

Spiradoline (U-62,066E), a selective kappa (kappa) receptor agonist, was examined for actions on the cardiovascular system and on myocardial ionic currents in rats. We initially characterized cardiac, hemodynamic, and antiarrhythmic actions of spiradoline in isolated perfused rat hearts and pentobarbital-anesthetized rats. Electrophysiologic studies in isolated myocytes were used to elucidate the mechanism for changes observed in vivo in the ECG, as well as for antiarrhythmic actions against electrical and ischemia-induced arrhythmias. In isolated rat hearts, spiradoline reduced heart rate and cardiac contractility and increased the PR interval and QRS width of the ECG in a concentration-dependent manner. In anesthetized rats, spiradoline dose-dependently reduced blood pressure and heart rate and prolonged the PR interval and QRS width. At slightly higher doses, it increased the QaT interval of the ECG. RSh, an index of sodium channel blockade in the rat, also was dose-dependently increased. Electrical stimulation of the left ventricle suggested that spiradoline may exert its antiarrhythmic action by blockade of myocardial sodium currents. The electrophysiologic actions of spiradoline on sodium currents, the transient outward (i(to)) and sustained plateau potassium (ik(sus)) currents were studied in isolated cardiac rat myocytes by whole-cell patch-clamp techniques. Spiradoline (15-500 microM) reduced peak sodium current in a rapid, reversible, and concentration-dependent manner; it also increased the rate of decay of I(to) and reduced the amplitude of Ik(sus). At a concentration of 150 microM, spiradoline produced a 24 +/- 2 mV hyperpolarizing shift in sodium current inactivation kinetics but did not alter activation processes. Spiradoline showed both tonic and frequency-dependent components of sodium current block. Thus spiradoline produced its antiarrhythmic actions via sodium channel blockade in myocardial tissue, although higher doses also block potassium currents. This combined ion channel-blocking property may be of added clinical benefit in the setting of myocardial ischemia.

Animals↗
PubMed1998

Pacemaking in the heart: the interplay of ionic currents.

1. There is still a degree of controversy about which currents drive pacemaking in the sinoatrial node or sinus venous. Early attempts to identify a single 'pacemaker current' in these tissues, based on voltage-clamp data, were largely unsuccessful, prompting the search for other mechanisms that may contribute to rhythmic activity. 2. Whole-cell patch-clamp recording from single cells isolated from the sinus venosus of the toad has shown that a voltage-dependent sodium current may play a role in pacemaking. This current has a transient component that contributes to the action potential upstroke and an inactivation-resistant component that contributes to the diastolic depolarization. The relative importance of this current in pacemaking is still controversial. 3. The development of computer models of pacemaking has contributed greatly to our understanding of how ionic currents can interact to produce rhythmic activity. Results are presented from one such model, 'Oxsoft Heart', to illustrate the different contributions of Ir and INa and to highlight the concept that pacemaking is driven by the integrated activity of many processes, rather than by any one current in particular. 4. Present models of pacemaking fail to accurately reproduce biological observations for certain situations. It is becoming clear that many processes contribute to pacemaking and have yet to be fully incorporated into models. Recent results regarding the role of intracellular calcium buffering and release and their implications, are discussed in this context. 5. The control of pacemaking by neurotransmitters is discussed. The limitations of single cell models in reproducing many of the complex responses to nerve stimulation of multicellular tissue, such as postinhibitory rebound, are discussed and possible improvements to models are suggested.

Animals↗
PubMed1998

Propofol block of cardiac sodium currents in rat isolated myocardial cells is increased at depolarized resting potentials.

1. The effect of propofol on cardiac whole-cell sodium currents and single sodium channels in rat isolated ventricular myocytes was examined using patch-clamp techniques. 2. Propofol caused a block of the whole-cell sodium current, the potency of block depending on the holding potential. When cells were held at -90 mV, the EC50 was 2.8 micrograms/mL. When cells were held more hyperpolarized (at -140 mV), the EC50 increased to 44.0 micrograms/mL. 3. Although the degree of block produced by the same concentration of propofol was different at different holding potentials, the time course of onset and recovery from block was the same. 4. The current/voltage relationship for the sodium current showed a pronounced block of peak current by propofol (40-50% block of the maximum current by 30 micrograms/mL propofol), with a minimal shift in the voltage dependence of activation and no shift in reversal potential. 5. The voltage dependence of the steady state inactivation curve was shifted to more hyperpolarized potentials by propofol (shift of 18 and 8 mV by 30 and 10 micrograms/mL propofol, respectively). 6. Single channel records showed that propofol caused a shortening of the mean channel open time (from a mean of 0.59 to 0.38 ms by 10 micrograms/mL propofol), but no change in the channel amplitude. 7. It is concluded that propofol produces a block of sodium currents in cardiac myocytes at concentrations that are comparable to those that may be attained during anaesthesia.

Anesthetics, Intravenous↗
PubMed1996

Hypoxia increases persistent sodium current in rat ventricular myocytes.

1. A persistent inward current activated by depolarization was recorded using the whole-cell, tight seal technique in rat isolated cardiac myocytes. The amplitude of the inward current increased when cells were exposed to a solution with low oxygen tension. 2. The persistent inward current had the characteristics of the persistent Na+ current described previously in rat ventricular myocytes: it was activated at negative potentials (-70 mV), reversed close to the equilibrium potential for Na+ (ENa), was blocked by TTX and was resistant to inactivation. 3. Persistent single Na+ channel currents activated by long (200-400 ms) depolarizations were recorded in cell-attached patches on isolated ventricular myocytes. Hypoxia increased the frequency of opening of the persistent Na+ channels. 4. Persistent Na+ channels recorded during hypoxia had characteristics similar to those of persistent Na+ channels recorded at normal oxygen tensions. They had a null potential at ENa, their amplitude varied with [Na+], they were resistant to inactivation and their mean open time increased with increasing depolarization. 5. The persistent Na+ channels in cell-attached patches were blocked by TTX (50 microM) in the patch pipette and by lidocaine (100 microM). 6. It was concluded that hypoxia increases the open probability of TTX-sensitive, inactivation-resistant Na+ channels. The voltage dependence of these channels, and their greatly increased activity during hypoxia, suggest that they may play an important role in the generation of arrhythmias during hypoxia.

Animals↗
PubMed1996

Tetrodotoxin-sensitive inactivation-resistant sodium channels in pacemaker cells influence heart rate.

There is currently some uncertainty about whether cardiac pacemaker cells contain tetrodotoxin (TTX)-sensitive Na+ channels although TTX is known to slow heart rate. We have recorded transient and persistent single-channel currents activated by depolarization in myocytes isolated from the toad sinus venosus. The myocytes were identified as pacemaker cells by their characteristic morphology, spontaneous action potentials that were blocked by cobalt but not by TTX, and lack of an inwardly rectifying K+ current. The voltage dependence of the single-channel currents, their presence in solutions containing no K+ or Ca2+, or in solutions to which Cs+ and Co2+ had been added, their dependence on [Na+] and their sensitivity to TTX indicated that they were Na+ channel currents. The persistent Na+ channel currents were resistant to inactivation and were activated over the range of potentials that occur during diastole in pacemaker cells: they would therefore contribute to the pacemaker current that sets heart rate. It was concluded that TTX slows heart rate by blocking these channels in pacemaker cells.

Animals↗
PubMed1995

The cardiac electrophysiological effects of sparteine and its analogue BRB-I-28 in the rat.

This study compares the cardiovascular and antiarrhythmic effects of sparteine and a 3,7-diheterobicyclo[3.3.1]nonane analogue of sparteine, BRB-I-28, in pentobarbitone-anaesthetized rats subjected to left-ventricle electrical stimulation and occlusion of the left anterior descending coronary artery. Sparteine and BRB-I-28 produced a dose-dependent reduction in heart rate and blood pressure over the dose range 1-64 mumol/kg/min. As well, the P-R and Q-aT intervals of the electrocardiogram (ECG) were prolonged. The thresholds for induction of premature beats and ventricular fibrillation were dose-dependently increased and both drugs increased refractoriness. While sparteine and BRB-I-28 (at 16 and 64 mumol/kg/min, respectively) did not change the incidence of premature beats or ventricular tachycardia with coronary occlusion, both drugs equally reduced the incidence of ventricular fibrillation. We characterized the actions of sparteine and BRB-I-28 on cardiac Na+, transient outward and sustained outward plateau K+ currents of rat myocytes using the whole-cell patch-clamp. Sparteine and BRB-I-28 produced a concentration-dependent reduction in Na+ current with EC50 values of 110 and 230 microM, respectively. Both drugs produced hyperpolarizing shifts of 8 and 11 mV, respectively, for Na+ channel inactivation while neither produced a change in channel activation. Both drugs produced a concentration-dependent block of the sustained plateau K+ current and increased the rate of decay of the transient outward K+ current. Thus, sparteine and BRB-I-28 possess Na+ and K+ channel blocking properties which may account for their antiarrhythmic actions against electrical and ischaemic arrhythmias.

Animals↗
PubMed1995

Sodium currents in toad cardiac pacemaker cells.

Cells in the pacemaker region of toad (Bufo marinus) sinus venosus had spontaneous rhythmic action potentials. The rate of firing of action potentials, the rate of diastolic depolarization and the maximum rate of rise of action potentials were reduced by TTX (10 nM to 1 microM). Currents were recorded with the whole cell, tight seal technique from cells enzymatically dissociated from this region. Cells studied were identified as pacemaker cells by their characteristic morphology, spontaneous rhythmic action potential activity that could be blocked by cobalt but not by TTX and lack of inward rectification. When calcium, potassium and nonselective cation currents (If) activated by hyperpolarization were blocked, depolarization was seen to generate transient and persistent inward currents. Both were sodium currents: they were abolished by tetrodotoxin (10 to 100 nM), their reversal potential was close to the sodium equilibrium potential and their amplitude and reversal potential were influenced as expected for sodium currents when extracellular sodium ions were replaced with choline ions. The transient sodium current was activated at potentials more positive than -40 mV while the persistent sodium current was obvious at more negative potentials. It was concluded that, in toad pacemaker cells, TTX-sensitive sodium currents contributing both to the upstroke of action potentials and to diastolic depolarization may play an important role in setting heart rate.

Action Potentials↗
PubMed1995

Tonic and use-dependent block of sodium currents in isolated cardiac myocytes by bisaramil.

1. The effects of bisaramil on sodium currents in rat isolated cardiac myocytes were examined by use of tight-seal, whole-cell patch clamp techniques. Bisaramil produced a concentration-dependent, readily reversible reduction in peak transient sodium current. When the sodium current was evoked at 3 s intervals the estimated ED50 for bisaramil was about 11 microM. 2. Bisaramil (16 microM) produced a shift in the inactivation curve to hyperpolarized potentials of about 10 mV, but produced no change in the voltage-dependence of activation. 3. The block of the sodium current by bisaramil showed a profound use-dependence. A concentration of 10 microM produced a considerable block of the current with repeated stimulation. The recovery from block was biphasic, showing fast and slow components which had time constants of about 40 ms and 5 s respectively. 4. Bisaramil produced little tonic block of the sodium current at concentrations of 100 microM; at 300 microM it produced tonic block of around 50%, with extreme use-dependence. 5. Bisaramil appeared not to interact primarily with the inactivated form of the channel, since lengthening the depolarizing pulses did not affect the degree of block produced.

Animals↗