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Biomedical subjects

J Toyama

Publications and source records attributed to J Toyama.

At least 127 records · Page 7Linked to original sources
PubMed1990

[Cardiotoxicity study of ME2303 with the interval intravenous injections to rats].

Cardiotoxic effects of ME2303 were studied upon interval intravenous administrations to rats in comparison with those of doxorubicin (ADR). ME2303 at two dose levels of 3 and 9 mg/kg/day or ADR at a dose levels of 3 mg/kg/day was injected once a week for 3 weeks to female Sprague-Dawley rats (SPF) of 5-weeks of age. ADR depressed body weight gain, decreased food intake and increased water intake. Microscopic observation on the myocardial tissues revealed that ADR caused necrosis and cell infiltration, edema and disarrangement of myofibrils in some of ADR-treated rats. On the other hand, ME2303 showed no significant effects except that some decrease of food intake was observed at a dose level 9 mg/kg/day. No changes in left ventricular functions were observed in perfused hearts isolated from ADR- or ME2303-treated rats. However, about 133 ng/g of ADR remained in the hearts even at 1 week after the final administration whereas ME2303 or its metabolites were not detected, suggesting that ADR may cause disturbance of ventricular function and more cardiomyopathy after a longer term than 1 week following the final administration. These results suggest that the cardiotoxicity of ME2303 is weaker than that of ADR in rats.

Animals↗
PubMed1989

Fluctuations of membrane potential in isolated single ventricular myocytes of guinea-pig upon resumption of oxidative phosphorylation.

Electrical and mechanical activities of guinea-pig single ventricular myocytes were investigated under conditions simulating hypoxia-reoxygenation. The localized movement of sarcomere was recorded simultaneously with membrane potential, and analyzed using microcomputer-based image processing. Exposure to 5 mM CN- caused progressive shortening of action potential duration and attenuation of twitch contraction. The myocytes became inexcitable about 30 to 70 min after the CN- treatment. On removal of CN-, the myocytes exhibited periodic miniature membrane depolarizations from the resting potential level (-95 mV). When depolarizations were smaller than 6 mV in amplitude and longer than 500 ms in duration, they were accompanied by localized sarcomere shortening like a propagating contractile wave (unifocal oscillation). Membrane depolarizations of larger amplitude and shorter duration were associated with a more uniform pattern of localized sarcomere shortening (multifocal oscillation). Trains of electrical stimuli applied during the washing out period caused transient augmentation of potential fluctuation and enhancement of synchronization of sarcomere shortening. These results suggest that non-uniform elevation of intracellular calcium concentration on the resumption of oxidative phosphorylation may initiate oscillatory fluctuations of membrane potential leading to abnormal spontaneous excitation.

Action Potentials↗
PubMed1989

Effects of propafenone on electrical and mechanical activities of single ventricular myocytes isolated from guinea-pig hearts.

1. The effects of propafenone on the transmembrane action potential and sarcomere shortening during twitch contraction were investigated in single ventricular myocytes isolated from guinea-pig hearts. 2. Propafenone at low concentrations (3-5 x 10(-7) M) slightly lengthened action potential duration (APD), but shortened it at higher concentrations. The shortening of APD was accompanied by an attenuation of sarcomere shortening during twitch contraction. 3. Propafenone (greater than 10(-6) M) caused a concentration-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential. In the presence of propafenone (3 x 10(-6) M), trains of stimuli led to an exponential decline in Vmax. A time constant for the recovery of Vmax from the use-dependent block was 4.8 s. 4. In myocytes treated with propafenone (3 x 10(-6) M), the Vmax of test action potentials preceded by the conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of single clamp pulse or by increasing the number of multiple brief clamp pulses. 5. These findings suggest that propafenone has use-dependent inhibitory action on the sodium channel by binding to the channel during both activated and inactivated states, and that the unbinding rate is comparable to that of Class-I antiarrhythmic drugs with intermediate kinetics. Propafenone may also have an inhibitory action on calcium and potassium channels.

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PubMed1989

Electrophysiological effects of OPC-88117, a new antiarrhythmic agent on papillary muscles and single ventricular myocytes isolated from guinea-pig hearts.

1. The effects of OPC-88117, a new antiarrhythmic agent, 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, OPC-88117 above 3 x 10(-6) M caused a dose-dependent prolongation of action potential duration (APD). 3. OPC-88117 above 3 x 10(-5) M caused a significant decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting membrane potential. The inhibition of Vmax was enhanced at higher stimulation frequencies. 4. In the presence of OPC-88117, trains of stimuli at rates greater than or equal to 1.0 Hz led to a use-dependent inhibition of Vmax with rapid onset. The time constant for the recovery of Vmax from the use-dependent block was 456 ms. 5. The curves relating membrane potential and Vmax were shifted by OPC-88117 to the direction of more negative potentials (9 mV at 10(-4) M). 6. In single ventricular myocytes treated with OPC-88117 (1-3 x 10(-4) M), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was decreased progressively as the clamp pulse duration was prolonged. 7. These findings suggest that the primary electrophysiological effect of OPC-88117 on the cardiac muscle cell is prolongation of APD (Class III action) and that at high concentrations, it may also possess a lignocaine-like sodium channel inhibitory effect (Class I action).

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PubMed1989

Effects of OPC-88117, a new antiarrhythmic agent, on the electrophysiological properties of rabbit isolated hearts.

1. Effects of a new antiarrhythmic agent, OPC-88117, on the conduction properties and excitability of Langendorff-perfused rabbit hearts were compared with those of lignocaine. 2. OPC-88117 above 10(-5) M caused a significant prolongation of atrio-His bundle conduction time (A-H interval) as well as His bundle-ventricular conduction time (H-V interval). Lignocaine above 10(-5) M caused a similar prolongation of H-V interval with a minimum change of A-H interval. The conduction time from His bundle stimulus to the left ventricle (St-LV) at a low frequency (1 Hz) was also prolonged by these drugs around 10(-4) M. 3. OPC-88117 above 3 x 10(-6) M prolonged the effective and functional refractory periods of His bundle (ERPHB, FRPHB) as well as the effective refractory period of left ventricular muscle (ERPVM) in a dose-dependent manner. ERPHB, FRPHB and ERPVM were shortened by low concentrations of lignocaine (3 x 10(-6)-10(-5) M), but were prolonged by high concentrations (3 x 10(-5)-10(-4) M). 4. Lignocaine (3 x 10(-6)-10(-4) M) induced an upward displacement of the His bundle refractory curve, indicating a greater intraventricular conduction delay for premature excitation. In experiments with OPC-88117, such an upward displacement was observed only at 10(-4) M. 5. These results suggest that the primary electrophysiological effect of OPC-88117 is a lengthening of ventricular refractoriness, and that at high concentrations it may also exert lignocaine-like inhibition of ventricular conduction.

Animals↗
PubMed1989

Electrophysiologic effects of TYB-3823, a new antiarrhythmic agent, on isolated guinea pig ventricular muscles.

The effects of a newly synthesized antiarrhythmic agent, TYB-3823 on the transmembrane action potential were examined in isolated papillary muscles of guinea pig. TYB-3823 (3 x 10(-6)-3 x 10(-5)M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of action potential duration (APD). In the presence of TYB-3823, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 12.6-13.4 s. The curves relating membrane potential and Vmax were shifted by TYB-3823 (3 x 10(-5)M) to the direction of more negative potentials (5.7 mV). In preparations treated with TYB-3823 (10(-5)-3 x 10(-5) M), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of a single clamp pulse or by increasing the number of multiple brief clamp pulses. These findings suggest that TYB-3823 has use- and voltage-dependent inhibitory action on the fast sodium channel by binding to the channel during its activated and inactivated states, and that the unbinding rate of the drug from the channel is very slow. Such characteristics of sodium channel block in combination with APD shortening effect would provide unique antiarrhythmic activities of this substance.

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PubMed1988

Frequency and voltage dependent effects of AN-132, a new class I anti-arrhythmic agent, on Vmax of action potential upstroke in guinea pig ventricular muscles.

The in vitro electrophysiological properties of a newly synthesised antiarrhythmic agent, AN-132, were evaluated by recording transmembrane action potentials from guinea pig papillary muscles. AN-132 (10-100 mumol.litre-1) caused a dose dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of AN-132, trains of stimuli at rates greater than or equal to 0.1 Hz led to an exponential decline in Vmax. This use dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use dependent block was 39.5-41.2 s. The curves relating membrane potential and Vmax were shifted by AN-132 (100 mumol.litre-1) in the direction of more negative potentials (6.1 mV). In preparations treated with AN-132 (30 and 100 mumol.litre-1), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased with an increasing number of pulses. A single prolonged clamp pulse to 0 mV reduced Vmax much less than multiple brief clamp pulses. These findings suggest than AN-132 has use dependent inhibitory action on the fast sodium channel by binding to the channel mainly during its activated state and that the unbinding rate of the drug during diastole is very slow. This use dependency and its greater inhibition of Vmax in depolarised muscles through the increase in tonic block may play a major role in preventing ventricular arrhythmias.

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PubMed1988

Electrophysiological effects of KT-362, a new antiarrhythmic agent with vasodilating action, on isolated guinea pig ventricular muscle.

The effects of KT-362, a newly synthesized vasodilating and antiarrhythmic agent, on transmembrane action potentials were examined in isolated papillary muscles of guinea pig. KT-362 (3 x 10(-6) to 3 x 10(-5) M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of KT-362, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 2.8-2.9 s. The curves relating membrane potential and Vmax were shifted by KT-362 (10(-5) M) in the direction of more negative potentials (8.6 mV). In papillary muscles treated with KT-362 (10(-5) M), the Vmax of test action potential preceded by conditioning clamp pulses to 0 mV was progressively decreased with increasing number of pulses, while it was little affected by the duration of each clamp pulse within the range from 10 to 700 ms. These findings suggest that KT-362 has quinidine-like use-dependent inhibitory action on the fast sodium channel of cardiac muscles by the binding to the channel mainly during its activated state. At high concentrations (greater than or equal to 3 x 10(-5) M), KT-362 also suppressed the slow action potential in K+ depolarized papillary muscles.

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PubMed1988

Effects of bepridil on ventricular depolarization and repolarization of rabbit isolated hearts with particular reference to its possible proarrhythmic properties.

1. Effects of bepridil on ventricular depolarization and repolarization sequences were examined in rabbit Langendorff-perfused hearts. 2. In distant bipolar electrograms (DBEs), bepridil, 10(-6) M, caused a significant prolongation of QT intervals. At 10(-5) M, the QT prolongation was further enhanced, and a significant prolongation of QRS duration was also observed. Polymorphous ventricular tachycardia was frequently induced by a single premature stimulus at the higher concentration. 3. In epicardial electrograms recorded through modified bipolar electrodes, bepridil, 10(-6) M, prolonged the interval from the peak negative deflection of the QRS complex to the apex of the T wave (Q-aT), which corresponded to the intracellular action potential duration at 90% repolarization (APD90). The Q-aT prolongation was larger in the base than in the apex, resulting in a marked distortion and dispersion of repolarization. The epicardial activation sequence was unaffected. 4. At 10(-5) M bepridil, the dispersion of repolarization was much more enhanced by activation delay in the epicardial surface. 5. These findings suggest that bepridil causes regionally different lengthening of APD in ventricular muscle leading to an increase in temporal dispersion of repolarization, and that this dispersion may be inducive for re-entrant arrhythmias when accompanied by slow conduction at toxic doses.

Animals↗
PubMed1988

Diverse characteristics in potential waveform of His-Purkinje system--experimental and simulation studies.

Reflection to the body surface of the single beat-potentials of the His-Purkinje system (HPS) was analysed by a single beat recording of the epicardial HPS potentials from the Langendorff perfused canine heart and by the reconstruction of HPS potentials on the basis of the cable concept. Unipolar epicardial HPS potentials from 8 leads distributed equidistantly over the basal region of the ventricles were amplified by a high gain (120 dB) amplifiers with an active bandpass filter (40-2400 kHz). The waveform of these HPS potentials differed in each lead. The largest (42 +/- 8 microV, mean +/- SE, n = 5) of these HPS potentials, which was obtained from the anterior free wall of the right ventricle, was composed of two peaks: the initial slow- and positive-peak and the late sharp- and negative-peak. The former peak appeared 12 +/- 3 msec (mean +/- SE, n = 5) ahead of the spike of the His-bundle electrogram (HBE) recorded from the close bipolar electrodes which were attached intracavitally along the membrane portion of the His-bundle. The latter appeared in coincidence with the spike of HBE. The extracellular potentials generated by HPS excitation were calculated by assuming that the excitation proceeds along the three dimensionally reconstructed HPS. The simulated waveform was in agreement with those of the epicardial HPS potentials. Thus, the HPS potentials on the body surface may inscribe a diverse waveform as a reflection of the complexed architecture of the whole HPS.

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PubMed1988

Block of cardiac sodium channels by antiarrhythmic drugs.

The effects of seven Class-I antiarrhythmic drugs on the maximum upstroke velocity (Vmax) of action potential were examined in isolated guinea pig ventricular muscles in order to characterize their use- and state-dependent sodium channel blocking action. From the onset and offset kinetics of the use-dependent Vmax inhibition during stimulation trains, the seven drugs were subdivided into two groups; fast drugs (lidocaine, mexiletine, and tocainide), and slow drugs (quinidine, aprindine, disopyramide and flecainide). In experiments to assess the state-dependent sodium channel block, a conditioning clamp pulse to 0 mV was applied by using the single sucrose-gap voltage-clamp technique, and the Vmax of test action potential 100 msec after the clamp pulse was measured. The decrease in Vmax by 10 msec clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 msec was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 for quinidine, disopyramide and flecainide, and much greater than 1.0 for aprindine, lidocaine, mexiletine, and tocainide. These characteristics may contribute to the differences in efficacy of each drug in treating various types of arrhythmias.

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PubMed1987

Block of activated and inactivated sodium channels by class-I antiarrhythmic drugs studied by using the maximum upstroke velocity (Vmax) of action potential in guinea-pig cardiac muscles.

The inhibitory effect of disopyramide, quinidine, mexiletine, lidocaine, tocainide and aprindine on the maximum upstroke velocity (Vmax) of action potential was examined in isolated guinea-pig cardiac muscles in terms of their sodium channel block during activated and/or inactivated state. In right ventricular papillary muscles, a conditioning clamp pulse was applied from the resting potential to 0 mV level using the single sucrose-gap voltage clamp technique, and Vmax of test action potential elicited 100 ms after termination of the clamp pulse was measured as an index of sodium channel availability. Such clamp pulses caused various Vmax decreases in the presence of the six drugs. The decrease in Vmax by 10 ms clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 ms was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 (0.36-0.51) for disopyramide and quinidine, and much greater than 1.0 (2.61-11.23) for mexiletine, lidocaine, tocainide and aprindine. From these findings it was suggested that the former group of drugs may block the sodium channel mainly during the upstroke phase of action potential, while the latter do so mainly during the plateau phase. This assumption was confirmed by experiments comparing the potency of Vmax inhibition in atrial and ventricular muscles isolated from the same guinea-pig heart.

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PubMed1987

Frequency- and voltage-dependent effects of aprindine on the upstroke velocity of action potential in guinea pig ventricular muscles.

The effects of aprindine on transmembrane action potentials were examined in isolated papillary muscles of guinea pig. Aprindine (10(-6)-10(-5) M) caused a dose-dependent decrease in the Vmax of the action potential without affecting the resting potential. In the presence of aprindine, trains of stimuli at rates greater than 0.1 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at the higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block (offset) was 6.2-7.8 s. In depolarized papillary muscles with high [K+]o, the inhibitory action of aprindine on Vmax after a long quiescent period (tonic block) was augmented markedly, but the rates of onset and offset of the use-dependent block were similar to those in normally polarized preparations. The curves relating membrane potential and Vmax were shifted by 7.3 mV with aprindine at 3 X 10(-6) M in the direction of more negative potentials. These findings suggest that aprindine has quinidinelike use-dependent inhibitory action on the fast sodium channels of cardiac muscles. This use-dependency and its greater inhibition of Vmax in depolarized muscles through the augmentation of tonic block may play a major role for the drug action to prevent ventricular arrhythmias.

Action Potentials↗
PubMed1987

Effects of activation sequence and anisotropic cellular geometry on the repolarization phase of action potential of dog ventricular muscles.

The influence of activation sequences on action potential configuration, especially in the repolarization phase, was examined in isolated canine ventricular muscles. Action potentials were recorded from the epicardial surface in the center of a preparation having nearly uniform fiber orientation (25 X 25 mm). Stimuli applied just adjacent to the recording site produced nearly centrifugal propagation. An activation sequence either parallel (longitudinal) or perpendicular (transverse) to the long axis of the muscle fibers was produced by peripheral stimulation. Action potential duration at -60 mV (APD-60 mV) during centrifugal propagation was significantly longer than that during longitudinal propagation. Further shortening of APD-60 mV was observed during transverse propagation. When a collision of longitudinal or transverse wavefronts (longitudinal or transverse collision) was produced at the action potential recording site, the shortest APD was recorded. During centrifugal propagation, action potential mapping around the stimulating electrodes revealed that APD-60 mV shortened gradually as the recording site was moved further from the stimulation site. The spatial gradient of APD was steeper in the transverse than in the longitudinal direction, causing a distortion in the repolarization sequence and the recovery of excitability near the center of the tissue. Premature stimuli applied to an area near the central stimulation site induced one-way block and circus movement of the wavefront, indicating reentry of excitation. We concluded that the activation sequence and anisotropic cellular geometry substantially affect APD, and that such a change contributes to the spatial inhomogeneity of refractoriness leading to reentrant arrhythmias.

Action Potentials↗
PubMed1987

Effects of KW-3049, a newly developed calcium antagonist, on rabbit sinus nodes and guinea pig ventricular muscles.

The effects of KW-3049, a newly developed dihydropyridine-type calcium antagonist, were studied on the electrophysiological properties of isolated rabbit sinus node tissues and guinea pig ventricular muscles. In spontaneously firing sinus node pacemaker cells, KW-3049 (greater than or equal to 10(-8) M) prolonged the cycle length, and decreased the maximum upstroke velocity (Vmax) and overshoot (OS) of action potential. KW-3049 (greater than or equal to 10(-6) M) produced a shortening of action potential duration (APD) of normally polarized ventricular muscles without affecting other parameters. Vmax, OS, and APD of slow action potentials, which had been induced by isoproterenol or by barium in K+-depolarized ventricular muscles, were reduced dose-dependently by KW-3049 (greater than 10(-9) M). The relative potency of KW-3049 for the Vmax inhibition of slow responses was 20 times higher than verapamil, but 0.32 times less than nifedipine. In voltage calmp experiments on ventricular muscles, KW-3049 (10(-6) M) caused a decrease of slow inward current by 52.7%, but did not affect the net outward current. These findings suggest that KW-3049 may have a potent and highly selective inhibitory action on cardiac slow channels.

Action Potentials↗
PubMed1987

Endocardial excitation and conduction during reperfusion arrhythmias.

In order to clarify the role of Purkinje fibers in the occurrence of reperfusion arrhythmias, endocardial mapping was performed on perfused canine hearts by attaching 42 close bipolar electrodes to the endocardial surface of the left ventricular septum. Reperfusion with oxygenated Krebs-Ringer solution following 30 min of coronary occulusion induced ventricular tachycardia (VT) in 14 out of 23 preparations. These VT degenerated into ventricular fibrillation (VF) within 1 min after the reperfusion in all but 3 cases. Endocardial mapping revealed that the excitations during VT were always initiated by the Purkinje activities and that myocardial excitations were expanded in a centrifugal manner through Purkinje-muscle junctional area. Furthermore, this excitation pattern was preserved, in the early phase of VT, even though the propagation pattern was distorted. VF was always induced by reperfusion following 30 min of ischemic condition, that is, coronary perfusion with a hyperkalemic (K = 10 mM), acidic (pH = 6.8) and hypoxic (PO2 = 20-40 mmHg) solution (4/4 cases). Elimination of hyperkalemia from the ischemic condition markedly prevented occurrence of VF (1/6 cases) during reperfusion but it did not affect occurrence of VT (4/6 cases); this implies that hyperkalemia causes the onset of VF but has less effect on the occurrence of VT. It has been separately confirmed by micro-electrode experiment, using the dissected papillary muscle of the canine right ventricle, that abnormal impulse formation during re-oxygenation was triggered in Purkinje fibers around Purkinje-muscle junction.

Animals↗
PubMed1987

Use-dependent blocking action of newly developed lidocaine-analogs on maximum rate of rise of action potentials in guinea pig papillary muscle.

The mode of antiarrhythmic actions of the newly developed antiarrhythmic drugs, tocainide, mexiletine and SUN1165, which bear the N-2,6-dimethylbenzene ring as a common structural unit, were examined by comparing the use-dependent blocking actions on the maximum rate of rise of action potentials (Vmax) in guinea pig ventricular muscle. The time course of the use-dependent reduction of Vmax after stimulation and its recovery after cessation of stimulation were fitted by double exponential curves to avoid the effects of the rapid stimulation (2 Hz) on the level of the membrane diastolic potential. The onset rates constants of the use-dependent block were 0.29 +/- 0.07 per action potential for tocainide (10(-4) M), 0.07 +/- 0.02 (mean +/- SE, n = 5) per action potential for SUN1165 (10(-5) M) and were too rapid to be accurately fitted for mexiletine (10(-5) M). The time constants of the Vmax recovery from the use-dependent block were prolonged to 0.67 +/- 0.32, 0.27 +/- 0.13 and 96 +/- 11 (mean +/- SE, n = 5) sec in the presence of tocainide, mexiletine and SUN1165, respectively. These data indicate that tocainide and mexiletine should be classified as lidocaine-like drugs, while SUN1165 may be a quinidine-like drug which interacts with Na+ channels and has slower kinetics than lidocaine-like drugs.

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