Biomedical subjects

J Toyama

Publications and source records attributed to J Toyama.

At least 73 records · Page 4Linked to original sources

PubMed1996

Electropharmacology of Ro 22-9194, a new antiarrhythmic agent.

1. Ro 22-9194 (> or = 10 microM) caused a concentration-dependent decrease in the maximum upstroke velocity (Vmax) and shortening of action potential duration in guinea-pig ventricular cells. 2. The Vmax inhibition by Ro 22-9194 was enhanced in a use-dependent manner. A time constant for Vmax recovery from the use-dependent block was 9.3 sec. Conditioning depolarizing clamp experiments in ventricular cells indicated that Ro 22-9194 may block sodium channels, mainly during the activated state. 3. Ro 22-9194 > or = 30 microM inhibited calcium inward current (Ica) of the ventricular cells. 4. In dogs in vivo Ro 22-9194 (0.1-3 mg/kg, IV) caused a dose-dependent prolongation of atrioventricular conduction time with greater prolongation of His-ventricular (HV) than atrio-His (AH) intervals. Ro 22-9194 had a potent inhibitory action against various types of model arrhythmias. 5. Ro 22-9194 may exert its antiarrhythmic activity primarily by a use-dependent sodium channel block. From the onset and offset kinetics of the use-dependent block, it belongs to the intermediate kinetic Class I drugs. From the state-dependence of the channel block, it belongs to activated channel blockers.

Action Potentials↗

PubMed1996

Protective effects of dimethyl amiloride against postischemic myocardial dysfunction in rabbit hearts: phosphorus 31-nuclear magnetic resonance measurements of intracellular pH and cellular energy.

The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na(+)-H+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, beta-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37 degrees C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 mumol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of reperfusion in control hearts (n = 6) up to 99% +/- 1.9% in hearts treated with dimethyl amiloride (n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 +/- 0.05 in control hearts compared with 5.24 +/- 0.17 in hearts treated with dimethyl amiloride (p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and beta-adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na(+)-H+ exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na+ and secondary Ca2+ overload. Specific Na(+)-H+ exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia.

Acidosis↗

PubMed1996

Ion channel blockers in the treatment of chronic heart failure.

Strategies for pharmacological treatment of chronic congestive heart failure (CHF) are discussed from the viewpoint of cardiac ion channel modulations. It remains controversial as to whether Na channel blockers, which are the most effective drugs to suppress ventricular arrhythmias, can improve the prognosis of chronic CHF. As far as recent knowledge of interactions between the Na channel and its blocker is concerned, lidocaine-like agents such as mexiletine, which inhibit the Na channel current by binding to the channel in the inactivated state, are recommended because they can suppress premature ventricular contractions without prolongation of QRS complexes of sinus beats. To develop a new agent for the treatment of chronic CHF, we extracted the common features of electropharmacologic actions shared by amiodarone and vesnarinone, both of which have been reported to reduce the mortality of patients with chronic CHF. It is concluded that increases in the action potential duration (APD) of ventricular muscle mediated through an inhibition of the delayed rectifier K channel (IK channel) and a reduction of sinus node firing through an inhibition of L type Ca channel in addition to IK channel inhibition, are essential for the treatment of chronic CHF.

Amiodarone↗

PubMed1996

Changes in action potentials and ion currents in long-term cultured neonatal rat ventricular cells.

A primary culture of neonatal ventricular myocytes isolated from day-old rats was established for investigating the changes in action potentials and ion currents over long periods. Cells at days 5 and 15 in culture were studied. These changes in vitro were compared with those in situ derived from the age-matched freshly isolated cells. During primary culture, quiescent cells demonstrated shortening of action potential durations (APD) resembling the developmental changes observed in situ. The beating cultured cells were not associated with APD shortening. Despite constant current amplitudes, the densities of Ca2+ currents (ICa) decreased in the quiescent cultures at later ages as a result of cell enlargement. ICa densities were maintained in the beating cultured and freshly isolated cells. Acceleration in the inactivation of ICa was observed during developments both in vitro and in situ. In addition, the densities of transient outward currents (Ito) tripled and doubled in the quiescent and beating cells during 15-day cultures. However, Ito in beating cultured cells made less contribution to APD in contrast to the quiescent cultured and freshly isolated myocytes. These findings demonstrate that electrophysiological properties differ between two types of long-term cultured cells. ICa densities remained constant in the beating cultures, suggesting that cell beating may be required for the maintenance of ICa density in developing cardiomyocytes.

Action Potentials↗

PubMed1996

Roles of Cl- channels and Ca2+ mobilization in stretch-induced increase of SA node pacemaker activity.

Ionic mechanisms underlying the enhancement of cardiac pacemaking activity by mechanical stretch were investigated in the isolated rabbit sinoatrial (SA) node. A 5-s stretch of 0.2-2.0 g was applied to small tissue strips (1.5 mm x 3.0 mm) of the SA node using a mechanical stimulator. Spontaneous excitation cycle length (SPCL) was monitored by recording endocardial surface potential through modified bipolar electrodes with high-gain amplification. Influence of neurotransmitters released from nerve terminals was eliminated by atropine and propranolol. A stretch > 0.2 g caused a significant shortening of SPCL; there was a positive correlation between the force and the maximum shortening of SPCL. Treatment of the preparation with gadolinium (10 microM) or glibenclamide (1 microM) did not affect the force-response relationship. The positive chronotropic response to mechanical stretch > 0.5 g was reduced significantly by treatment with 4,4'-dinitrostilbene-2,2'-disulfonic acid (5mM), 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (1 mM), or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (50 microM). The positive chronotropic response was also reduced in a low-Ca2+ (0.36 mM) medium and by bath application of ryanodine (0.1 microM) or thapsigargin (2 microM). These findings suggest the possible involvement of mechanosensitive Cl- channels and intracellular Ca2+ mobilization in the stretch-induced enhancement of pacemaking activity in the mammalian SA node, although other conceivable mechanisms cannot be ruled out.

Animals↗

PubMed1996

Inactivation of the calcium current is involved in overdrive suppression of rabbit sinoatrial node cells.

The contribution of inactivation of the L-type Ca2+ current (iCa) to overdrive suppression was investigated in rabbit sinoatrial (SA) node cells by use of the whole cell patch-clamp technique. In the current-clamp mode, rapid stimulation (6.7 Hz) for 30 s was followed by a transient increase in the cycle length of spontaneous action potentials of 135 +/- 52% (n = 3), i.e., "overdrive suppression." The iCa was measured in the voltage-clamp mode in the presence of 30 microM tetrodotoxin. An increase in the rate of depolarizing pulses (to 0 mV for 100 ms) from 1 to 6.7 Hz from a holding potential (HP) of -40 mV resulted in an abrupt, followed by a progressive, decrease in iCa; after 30 s of stimulation at 6.7 Hz, iCa was reduced to 15.5 +/- 1.8% (n = 4) of the control at 1 Hz. With an HP of -80 mV, a similar increase in the pulse rate caused much less reduction in iCa. When spontaneous action potentials were interrupted by a 30-s train of high-frequency voltage-clamp pulses (to 0 mV for 100 ms; 6.7 Hz) from an HP of -40 mV, there was again a marked decrease in iCa during the train, and after the train there was a transient suppression of spontaneous activity. In contrast, a similar interruption by high-frequency voltage-clamp pulses from an HP of -80 mV caused no decrease in iCa, and there was no suppression of spontaneous activity after the train. Neither delayed rectifier K+ current nor hyperpolarization-activated current was affected after a train of high-frequency voltage-clamp pulses. These findings suggest that overdrive suppression in the SA node is, in part at least, the result of a rate- and voltage-dependent inactivation of iCa.

Action Potentials↗

PubMed1996

Effects of long-term oral administration of amiodarone on the ventricular repolarization of rabbit hearts.

The chronic effects of amiodarone on ventricular repolarization were investigated in Langendorff-perfused rabbit hearts in comparison with the acute effects of other Class III antiarrhythmic drugs. Forty to fifty electrograms were recorded through modified bipolar electrodes from the anterior to the lateral epicardial surface of the ventricles under His-bundle pacing (1.0 Hz). In control hearts, epicardial activation proceeded from the apex to the base. The interval from the initial sharp negative deflection of the QRS complex to the apex of the T-wave (Q-aT), which reflects the action potential duration (APD) at the recording site, was longest in the apex and shortest in the base. Therefore, repolarization proceeded from the base to the apex. In hearts treated with oral amiodarone (100 mg/kg, 4 weeks), Q-aT was uniformly prolonged by 14-16% throughout the entire mapped area, whereas the activation sequence was unaffected, and a normal Q-aT gradient was well preserved from the apex to the base. The spatial inhomogeneity of left ventricular repolarization was not enhanced by drug treatment. Acute application of sotalol (30 mumol/L), E-4031 (0.1 mumol/L) or MS-551 (1.0 mumol/L) caused a much greater Q-aT prolongation in the apex than in the base, resulting in a marked enhancement of the spatial inhomogeneity of repolarization. These findings suggest that the propensity of chronic amiodarone to induce torsade de pointes less often than other Class III agents may result at least in part from its favorable effect on the spatial homogeneity of ventricular repolarization.

Administration, Oral↗

PubMed1996

Acute and chronic effects of amiodarone on mammalian ventricular cells.

This article reviews experimental studies on the electrophysiological effects of amiodarone on mammalian hearts. Acute application of amiodarone (0.1-10 microM) to papillary muscles or single ventricular cells isolated from rabbits or guinea pigs caused a significant decrease in action potential duration (APD) as well as a marked use-dependent inhibition of the maximum upstroke velocity (Vmax) of action potential with fast recovery kinetics. Acute amiodarone also caused a concentration-dependent decrease in the calcium current (ICa) and the delayed-rectifier potassium current (IK). Action potentials recorded from papillary muscles or single ventricular cells isolated from the rabbits treated with oral amiodarone (100 mg/kg daily, 4 weeks) were characterized by a moderate frequency-independent prolongation of APD. There was no use-dependent Vmax inhibition. The ventricular cells treated with chronic amiodarone showed a significant decrease in the current density of ICa, IK and Ito. The amount of mRNA for Kv1.5, a Shaker-related potassium channel from the rats treated with chronic oral amiodarone was significantly lower than that from control rats. These results suggest that the major and consistent effects of chronic amiodarone is repolarization delay (Class III action) through a decrease in IK and Ito density, probably due to a modulation of gene expression of potassium channels. When amiodarone above a certain concentration is present in the extracellular space, fast kinetic Class I and Class IV actions would be added as acute effects.

Action Potentials↗

PubMed1996

Effects of chronic hypoxia on the developmental changes in action potential of cultured neonatal rat ventricular myocytes.

The action potentials of rat ventricular myocytes are known to become progressively shortened within several weeks after birth. We studied the effects of long-term exposure to hypoxia on these developmental changes in cardiac action potentials. Single ventricular myocytes isolated from day-old neonatal rat hearts were cultured in normoxic conditions (21% O2) for more than 15 days. To test the influence of long-term exposure to hypoxia, O2 tension was lowered to 7.5% in some cells at day 6. Action potentials were measured at day 5 and day 15 in both the normoxic and hypoxic groups. Under normoxic conditions, action potential durations decreased by 44% between day 5 and day 15, while cell capacitance doubled (n=10-11). Under hypoxic conditions, action potential durations decreased slightly by 16% (n=6). This shortening was significantly attenuated when compared to that observed during normoxic conditions. Cell capacitance was not altered under the hypoxic conditions. These results suggest that 1) shortening of the action potential during normoxic culturing is prevented under hypoxic conditions, and 2) cell capacitance as seen in normoxic conditions is unaffected by hypoxic culturing.

Action Potentials↗

PubMed1996

Negative dromotropic effects of class I antiarrhythmic drugs in anisotropic ventricular muscle.

OBJECTIVE: In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis. METHODS: Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy. RESULTS: F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency-dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation. CONCLUSION: Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle.

Action Potentials↗

PubMed1996

Differential effects of MS-551 and E-4031 on action potentials and the delayed rectifier K+ current in rabbit ventricular myocytes.

OBJECTIVE: The frequency-dependent effects of MS-551 on the action potential duration (APD) and the underlying ionic mechanisms were investigated in comparison with those of E-4031. METHODS: Whole-cell clamp techniques were used to study action potentials and ionic currents in enzymatically isolated rabbit ventricular myocytes. RESULTS: The frequency-response obtained within the range of 0.1 to 3.3 Hz was different for MS-551 and E-4031. The APD prolongation by MS-551 (10 microM) was significant at 0.5-3.3 Hz, whereas that by E-4031 (1 microM) was significant at 0.1-1.0 Hz. The prolongation by MS-551 (10 microM) of APD of a test action potential, which was preceded by a train of 1.0 Hz stimulation, decreased progressively as the rest duration increased, whereas that by E-4031 (1 microM) remained at the same level. Both MS-551 (10 microM) and E-4031 (1 microM) significantly decreased IK, but showed no effects on the transient outward current (Ito) and the inward rectifier K+ current (IKl). The development of the block on IK and the recovery from the block by MS-551 were voltage dependent. At a holding potential of -50 mV, MS-551 reduced the tail current to a similar extent (21-34%, n = 6) across all the tested durations of the depolarizing pulses to +10 mV, whereas at -75 mV, the intensity of the block progressively increased as the durations of depolarizing pulses were prolonged. The recovery from the block by MS-551 was absent at -50 mV, but occurred at -75 mV with a time constant of 577 +/- 179 ms (n = 6). The development of the block on IK by E-4031 was voltage and time independent. No recovery from the block was observed for E-4031 at either -50 or -75 mV. CONCLUSIONS: These findings suggest that MS-551 produces frequency-dependent class III action, presumably due to the voltage-dependent binding and unbinding to the IK channels. The reverse frequency dependence of class III action by E-4031 cannot be explained by the effects on IK.

Action Potentials↗

PubMed1996

[Autonomic regulation of pacemaker activity in the sinoatrial node].

Recent technical advances have made it possible to investigate quantitatively the ionic events underlying pacemaker activity in the sinoatrial node. Various time-dependent currents through ion channels such as the delayed rectifier K current, two types of Ca currents and the hyperpolarization-activated current have been found to play an important role in the generation of the pacemaker activity of sinoatrial node cells. Time-independent background currents, transporter-mediated current and pump current also contribute to pacemaker activity. In this article, the physiological significance of these currents for the pacemaker depolarization and their modulation by autonomic nerves and humoral factors are discussed.

Autonomic Nervous System↗

PubMed1996

Modulated expression of transient outward current in cultured neonatal rat ventricular myocytes: comparison with development in situ.

OBJECTIVES: Developmental changes of cardiac ion channels have been characterized in freshly isolated mammalian heart cells. To investigate the regulatory factors of postnatal development in transient outward current (Ito) in cardiomyocytes, the modulated expression of Ito was studied in cultured neonatal rat ventricular cells. These changes in vitro were compared with those in situ in acutely isolated ventricular myocytes. METHODS: Ventricular cells were enzymatically isolated from day-old Wistar rats and cultured under various growth conditions from day 6 to 15. Whole-cell patch-clamp recording was used to study the functional expression of Ito. RESULTS: During development in situ from 5- to 15-day-old stages, Ito density was doubled at day 15 with a significant increase in membrane capacitance (Cm) of the myocytes. Some cells were incubated in serum-rich medium from day 6 to 15 during primary culture, revealing marked increases in both Cm and Ito density at day 15. However, no developmental changes in the Cm and Ito density were observed in serum-free medium. Under the serum-free condition, neither the addition of acidic fibroblast growth factor (aFGF) nor basic FGF (bFGF) to culture medium influenced the Cm. aFGF (10-60 ng/ml) failed to stimulate Ito expression. 72-h treatment with bFGF significantly promoted the Ito density in a concentration-dependent manner; nevertheless, prolonged administration from day 6 to 15 did not induce a further increase, resulting in lower Ito density than in age-matched freshly isolated and serum-treated preparations. The increase in Ito in cultured cells induced by serum and bFGF may be attributable to paralleling changes in the ionic selectivity of the channel, but was not caused by changes in the voltage-dependence of steady-state Ito activation and inactivation. CONCLUSIONS: bFGF and some other unknown serum factors may play important roles in the postnatal expression of Ito in the neonatal cardiomyocytes. The developmental increase in Ito and postnatal cell hypertrophy of neonatal cardiomyocytes can be regulated independently.

Animals↗

PubMed1995

bFGF promotes functional expression of transient outward currents in cultured neonatal rat ventricular cells.

To investigate the effect of basic fibroblast growth factor (bFGF) on ion channel expressions in developing cardiac cells, a short-term primary culture of ventricular myocytes isolated from day-old newborn rats was established. Functional expressions of the transient outward currents (Ito) were measured by whole-cell voltage-clamp method. Addition of 40 ng/ml bFGF to the serum-free culture medium for 72 hours increased the Ito density without influences on membrane capacitance of the myocytes, an estimate of cell size. bFGF also promoted expressions of the steady-state outward currents. Methyl 2,5-dihydroxycinnamate (3 microM), a tyrosine kinase inhibitor, showed preferential inhibition of the bFGF-stimulated increase in Ito density. These results suggest that bFGF may play a role in regulating ion channel expressions of developing cardiac cells via activation of bFGF receptor tyrosine kinase activity.

Animals↗

PubMed1995

Computer simulation of the electrotonic modulation of pacemaker activity in the sinoatrial node by atrial muscle.

Electrotonic interaction between the sinoatrial (SA) node and surrounding atrial muscle was investigated in a computer simulation using a modified Oxsoft HEART model (Oxsoft, Oxford, UK). When an SA node cell model was coupled to a passive atrial membrane model (RC circuit) with various coupling conductances (Gc), there was a Gc-dependent prolongation of spontaneous cycle length (SCL). At a sufficiently high value of Gc, the spontaneous activity was finally stopped. A nonlinear relationship between Gc and SCL was obtained, similar to that observed in experiments on rabbit SA node cells. When the muscarinic potassium current (iK,ACh) was activated in the SA node cell model, the coupling-induced inhibition of pacemaker activity was potentiated. Although coupling current and iK,ACh were additive, their effects on SCL were more than additive because of the nonlinear dependence of SCL on net current. A decrease in the input resistance of the atrial membrane model to stimulate the activation of iK,ACh in atrial muscle was also shown to potentiate the coupling-induced inhibition of SA node spontaneous activity.

Action Potentials↗

PubMed1995

Complex frequency-dependent interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction.

We investigated the interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction of human hearts in vivo. QRS duration in signal-averaged electrocardiograms and standard electrocardiograms were measured as an index of intraventricular conduction time in 17 patients with implanted pacemakers at various pacing rates (100-180 ppm, VVI mode). Single intravenous administration of lidocaine, disopyramide or aprindine prolonged the QRS of signal-averaged electrocardiograms in a frequency-dependent manner. Lidocaine (n = 17) produced significant QRS prolongation from pre-drug control at rates > or = 120 ppm (6.2 +/- 1.4% at 180 ppm), whereas disopyramide (n = 17) and aprindine (n = 17) did so from the lowest rate (8.9 +/- 1.8% to 12.3 +/- 2.9% at 100-180 ppm with disopyramide; 14.7 +/- 1.3% to 19.3 +/- 2.2% at 100-180 ppm with aprindine). Addition of lidocaine to disopyramide (n = 17) showed an additive effect; QRS prolongation was enhanced significantly by 1.4-2.8% at rates > or = 150 ppm. In contrast, addition of lidocaine to aprindine (n = 17) showed a subtractive effect; the QRS prolongation was attenuated significantly by 1.6-2.4% at rates < 150 ppm. Combined intravenous administration of class-I antiarrhythmic drugs causes not only additive but also subtractive effects on the intraventricular conduction of the human heart, probably through their interaction on the sodium channel receptor.

Aged↗

PubMed1995

Morphology of a cytochrome c-adsorbed stearic acid monolayer on Brewster angle microscopy.

The morphologies of stearic acid and cytochrome c (cyt.c)-adsorbed stearic acid monolayers were investigated by Brewster angle microscopy (BAM) with various molecular areas of stearic acid. With an area of more than 0.38 nm2/molecule, many blight island domains and some bright circles were observed in the BAM image of the stearic acid monolayer. The blight site part became to occupy all the surface with compression, and then became more closely packed with an area of 0.22 nm2/molecule. On the other hand, a different BAM image was obtained for the cyt.c-adsorbed stearic acid monolayer, as follows: (i) a striped pattern was only observed in the presence of cyt.c; (ii) the number of bright circles in the presence of cyt.c was less than that in its absence. Furthermore, when a uniform BAM image was observed for the stearic acid monolayer with cyt.c, the intensity of the absorbance at 409 nm of cyt.c was the highest. By calculating the amount of cyt.c adsorbed on a stearic acid monolayer from the absorbance value, it was shown that cyt.c was most closely packed when an uniform BAM image was observed. These results suggest that the use of BAM and visible absorption spectroscopy together is useful for studying the morphology of a monolayer.

Adsorption↗

PubMed1995

Electrophysiological effects of SD-3212, a new antiarrhythmic agent with vasodilator action, on guinea-pig ventricular cells.

1. The effects of SD-3212 on transmembrane action potentials were examined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea-pig hearts. 2. In papillary muscles, SD-3212 > or = 3 microM caused a significant decrease in the maximum upstroke velocity (Vmax) of action potential without affecting resting membrane potential. The inhibition of Vmax was enhanced at higher stimulation frequencies. 3. In the presence of SD-3212, trains of stimuli at rates > or = 0.5 Hz led to a use-dependent inhibition of Vmax. The time constant for the recovery of Vmax from the use-dependent block was 1.3 s. 4. Voltage-dependence of Vmax inhibition by SD-3212 was investigated in single myocytes. The curves relating membrane potential and Vmax were shifted by SD-3212 (10 microM) in a hyperpolarizing direction by 6.2 mV. 5. In myocytes treated with SD-3212 (10 microM), the Vmax of test action potentials preceded by conditioning clamp to 0 mV was decreased progressively as the clamp pulse duration was prolonged. Vmax of test action potentials following a long (1 s) 0 mV clamp recovered at a time constant ranging from 1.01 to 1.22 s, being shorter at the more negative potential within a range from -70 to -90 mV. 6. These findings suggest that the primary electrophysiological effect of SD-3212 is a use- and voltage-dependent inhibition of sodium channels. From the onset and offset kinetics of the use-dependent block, SD-3212 is located between fast and intermediate kinetic Class-I drugs. From the state-dependence of sodium channel block, SD-3212 belongs to inactivated channel blockers.

Action Potentials↗