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Biomedical subjects

I Kodama

Publications and source records attributed to I Kodama.

At least 199 records · Page 11Linked to original sources
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.

Action Potentials↗
PubMed1987

Competitive inhibition of cardiac sodium channels by aprindine and lidocaine studied using a maximum upstroke velocity of action potential in guinea pig ventricular muscles.

An interaction between aprindine and lidocaine on cardiac fast sodium channels was investigated in isolated guinea pig ventricular muscles. A conditioning clamp pulse was applied from -90 to 0 mV through the single sucrose gap voltage clamp, and the maximum upstroke velocity (Vmax) of action potential elicited after the clamp pulse was measured as an index of sodium channel availability. In the presence of aprindine (2 and 5 microM) or lidocaine (20 and 40 microM), Vmax of test action potential 100 msec after the clamp pulse was decreased progressively as the clamp pulse duration was prolonged. The time constant of this inactivated channel block by aprindine was much slower than by lidocaine. Vmax after a 1000 msec clamp pulse recovered exponentially with a time constant of 4.75 to 4.81 sec for aprindine and 254 to 260 msec for lidocaine. In the presence of both aprindine and lidocaine, Vmax recovered in dual exponential function, where the short and the long time constant corresponded to the values for single treatment with each drug. In preparations treated with aprindine alone the use-dependent decrease of Vmax was observed during stimulation trains at rates higher than 0.1 Hz. This use-dependent block was attenuated significantly after additional application of lidocaine resulted in a net increase in Vmax at 0.5 to 1.0 Hz. These findings suggest that aprindine and lidocaine may block the sodium channels by binding to a common receptor site with different kinetics, leading to a competitive displacement with each other at their high concentrations.

Action Potentials↗
PubMed1986

Effects of calcium, calcium entry blockers and calmodulin inhibitors on atrioventricular conduction disturbances induced by hypoxia.

Effects of hypoxia on atrioventricular conduction were investigated in the Langendorff-perfused isolated heart of the rabbit with various extracellular calcium concentrations ([Ca2+]) as well as in the presence of verapamil, nifedipine, N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7) and chlorpromazine. The prolongation of the atrio-His (AH) interval by hypoxia for 7 min was greater with increasing [Ca2+]o ranging from 1.2 to 5.2 mM. At [Ca2+]o of over 3.2 mM under hypoxic conditions, AH block of the Wenckebach type was observed in some cases. Verapamil (5 X 10(-8) M) and nifedipine (5 X 10(-8) M) caused a significant prolongation of AH intervals before hypoxia. However, the intensity of AH prolongation due to hypoxia was significantly attenuated in the presence of the calcium entry blocker, and AH block was not induced even at 3.2 mM [Ca2+]o. W-7 (5 X 10(-6) M) and chlorpromazine (10(-6) M) did not affect the AH intervals before hypoxia. The hypoxia-induced prolongation of the AH interval or AH block was prevented in the presence of these drugs. W-5, a chlorine-deficient derivative of W-7, showed no protection against hypoxia-induced AV nodal conduction disturbances. These findings suggest that hypoxia-induced AV nodal conduction disturbance is explained, at least in part, by the electrical uncoupling of nodal cells, probably due to the calcium overload. This conduction disturbance is protected by calcium entry blockers or by calmodulin inhibitors, but the mode of protective action is not the same for these different categories of drugs.

Animals↗
PubMed1986

Electromechanical effects of okadaic acid isolated from black sponge in guinea-pig ventricular muscles.

Okadaic acid is a monocarboxylic acid with a unique molecular structure of C44H66O13. Okadaic acid, at concentrations above 10(-5) M, caused a dose-dependent increase of contractile force in guinea-pig isolated ventricular muscles. The increase of contractile force by okadaic acid (1-4 X 10(-5) M) was accompanied by a prolongation of action potential duration (a.p.d.), while a.p.d. was shortened by okadaic acid at above 10(-4) M. The okadaic-acid-induced changes in contractile force and a.p.d. were abolished by pre-treatment with verapamil (2 X 10(-6 M) or nifedipine (10(-6) M). In a low-Ca2+ medium (0.12 mM), the contractile response to okadaic acid (4 X 10(-5) M) was inhibited, whereas the a.p.d. was more prolonged by the drug than in a control medium (containing 1.2 mM-Ca2+). In a low-Na+ (70 mM) medium or in a low-Na+ (70 mM) and low-Ca2+ (0.12 mM) medium both the contractile force and a.p.d. were unaffected by okadaic acid (4 X 10(-5) M). The positive inotropic effect of okadaic acid (4 X 10(-5) M) was not inhibited by treatment with tetrodotoxin (TTX, 2 X 10(-6) M) or with ryanodine (2 X 10(-6) M). In voltage-clamp experiments using a single sucrose-gap technique, okadaic acid (4 X 10(-5) M), caused a significant increase of slow inward current, while it did not affect the net outward current. These findings suggest that okadaic acid has a positive inotropic effect on the heart, probably due to the enhancement of slow Ca2+ and/or Na+ inward current through the cell membrane.

Action Potentials↗
PubMed1986

Endocardial mapping of ventricular tachycardia in one-day-old myocardial infarction.

Endocardial mapping of ventricular tachycardia (VT) was performed in one-day-old myocardial infarction using a matrix electrode (6 X 7 = 42) placed on the endocardial surface of the perfused isolated canine heart. Spontaneous focal VT was observed in all 7 dogs. It was neither affected nor terminated by electrical stimulation. Focal VT was induced in 5 dogs by constant pacing or premature programmed stimulation of the main left bundle. It was terminated by electrical stimulation and induction of the VT was suppressed by verapamil (5 X 10(-7)). Endocardial mapping of the spontaneous focal VT and induced focal VT showed initiation of activation from the surviving Purkinje fiber in the infarcted or border zone with subsequent circular expansion of excitation. Reentrant VT was induced in 3 dogs by bursts of rapid pacing and deteriorated into ventricular fibrillation. Endocardial mapping showed a continuous arc of functional conduction block and slowly circulating activation front around the block. It is suggested that in experimental one-day-old myocardial infarction VT resulted from abnormal automaticity and triggered activity in the surviving Purkinje fiber and reentry in the subendocardial muscle layer.

Animals↗
PubMed1986

[Electrophysiological effects of KW-3049, a new dihydropyridine type Ca antagonist, on isolated rabbit hearts, sinus nodal tissues and guinea-pig ventricular muscles].

Effects of KW-3049 on electrophysiological properties of the heart were examined using Langendorff-perfused hearts and superfused sinus nodal tissues of rabbits and superfused guinea-pig ventricular muscles. In rabbit hearts, KW-3049 at concentrations above 10(-7) M caused a dose-related prolongation of atrio-His bundle conduction time (AH), whereas His bundle-ventricular conduction time (HV) was unaffected. In spontaneously firing rabbit sinus nodal tissues, KW-3049 at concentrations above 10(-8) M prolonged cycle length significantly. At 10(-6) M, amplitude and the maximum upstroke velocity of sinus nodal action potential were decreased as well. In normally polarized guinea-pig ventricular muscles under 4 mM [K+]0, KW-3049 at concentrations above 10(-6) M shortened the action potential duration without affecting the resting membrane potential and the maximum upstroke velocity of action potential (Vmax). The Vmax of slow action potentials induced by isoproterenol at 10(-7) M was inhibited significantly by additional application of KW-3049 at concentrations above 10(-9) M. At above 10(-8) M, the amplitude and duration of slow action potentials were reduced significantly. The potency of this slow action potential inhibition by KW-3049 was slightly less than that of nifedipine, while it was 10 to 100 times greater than that of verapamil. Spontaneous activity of ventricular muscles induced by BaCl2 at 1 mM was abolished completely at 16 min after application of KW-3049 at 10(-7) M. These results suggest that KW-3049 may have a potent and selective inhibitory action on cardiac slow calcium channels.

Animals↗
PubMed1986

Open and inactivated sodium channel block by class-I antiarrhythmic drugs.

Inhibitory action of six Class-I antiarrhythmic drugs on cardiac sodium channel was examined in isolated guinea-pig ventricular muscles. Transmembrane potential of the tissue was controlled by single sucrose gap voltage clamp technique. Following 30 sec quiescent period, a conditioning clamp pulse was applied from resting potential level to 0 mV for 10 msec to 800 msec. 100 msec after returning to the resting potential, voltage clamp was released and an action potential was elicited to measure its maximum upstroke velosity (Vmax) as an index of sodium channel availability. Under control condition such clamp pulse application did not affect the value of Vmax. In preparations treated with quinidine, and disopyramide, Vmax was decreased appreciably by the shortest clamp pulse application, but the Vmax reduction was enhanced only slightly by prolongation of the clamp pulse duration. In cases with lidocaine, mexiletine, tocanide and aprindine, the decrease in Vmax was enhanced much more remarkably by similar prolongation of the clamp pulse duration. These findings suggest the quinidine and disopyramide may block sodium channel mainly during open state. In contrast, lidocaine, mexiletine, tocainide and aprindine may block the channel mainly during inactivated state. Such a difference would cause wide variety of action potential duration dependency for the effects of Class-I drugs.

Action Potentials↗
PubMed1985

Regional differences in the electrical activity of the rabbit sinus node.

In order to study regional differences in membrane properties within the sinus node, we have investigated the electrical activity of small specimens of tissue (approximately 0.3 mm in diameter) that have been prepared from the central, transitional and peripheral areas of the rabbit sinus node. The action potential upstroke velocity and overshoot as well as the maximum diastolic potential were significantly greater in tissue from the peripheral area. Paradoxically, the rate of spontaneous activity was slowest in tissue from the central area (normally the leading pacemaker site in the intact heart). Recovery of excitability was slowest in tissue from the central area and fastest in tissue from the peripheral area. The depression of electrical activity produced by rapid stimulation (overdrive) was most marked in the central region. Raising the bathing K concentration depresses spontaneous activity and this effect was again most marked in the central region. Tissue from the central area was the least sensitive to acetylcholine in five out of six hearts. Pacemaker shift can occur within the sinus node in response to various interventions, and differences in electrical activity as observed in this study may underlie such changes.

Acetylcholine↗
PubMed1985

Anisotropic conduction properties of canine ventricular muscles. Influence of high extracellular K+ concentration and stimulation frequency.

The effects of fiber direction on the conduction of excitation and the characteristics of both extracellular and intracellular action potentials were examined in isolated dog ventricular muscle preparations. Conduction velocity and amplitude of extracellular potentials during propagation in the direction parallel to the long axis of fibers (longitudinal propagation) were significantly greater than those during propagation in the direction perpendicular to it (transverse propagation). However, the maximum rate of rise and amplitude of intracellular action potential were significantly greater during transverse propagation than during longitudinal propagation. Compared with the transverse propagation, the longitudinal propagation was more susceptible to conduction failure under high extracellular K+ concentration, suggesting a lower safety factor of the latter mode of propagation in depolarized cardiac tissue. In contrast, high frequency stimulation caused a greater decrease in the conduction velocity during transverse than longitudinal propagation resulting in augmentation of anisotropic conduction properties. These results suggest that the anisotropic conduction properties of cardiac tissue may play important roles in conduction disturbances leading to arrhythmias under various pathological conditions.

Action Potentials↗
PubMed1985

Effects of dimethylpropranolol (UM-272) on the electrophysiological properties of guinea-pig ventricular muscles.

The effects of dimethylpropranolol (UM-272) on transmembrane action potentials were examined in isolated right ventricular papillary muscles of the guinea pig. UM-272 (10(-5) to 3 X 10(-4) M) caused a dose-dependent decrease in the Vmax of the action potential. At 3 X 10(-4) M, a slight decrease in the amplitude of action potential was also observed. The resting potential and the action potential duration were not affected by the drug. In the presence of UM-272, trains of stimuli at rates higher than 0.1 Hz led to an exponential decline in Vmax (onset rate, 0.13-0.28 per action potential) to a new plateau level. This use-dependent block was augmented at the higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block (offset) was 7.1 to 7.3 sec. In depolarized papillary muscles with 8 or 10 Mm [K+]0, the inhibitory action of UM-272 on Vmax of the first action potential 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 under 5 mM [K+]0. The curves relating membrane potential and Vmax in preparations stimulated infrequently were shifted by 7.2 mV with UM-272 at 10(-4) M in the direction of more negative potentials. These findings suggest that UM-272 has kinetically similar use-dependent inhibitory action of the fast sodium channels of cardiac muscles as other Class Ia antiarrhythmic drugs like quinidine or procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1984

Combined effects of hypoxia, hyperkalemia and acidosis on membrane action potential and excitability of guinea-pig ventricular muscle.

The effects of hypoxia (with and without acidosis) on membrane action potentials and recovery kinetics of their upstroke velocity (Vmax) were studied in isolated guinea-pig papillary muscles at various extracellular K+ concentrations. At 5 mM [K+]0, hypoxia (hypoxic and glucose-free perfusate) at pH 7.4 caused a progressive shortening of action potential duration and a slight decrease in Vmax and resting potential. The recovery kinetics of Vmax assessed by premature stimuli were not affected by hypoxia. At high [K+]0 of 10 or 12 mM, hypoxia caused a marked decrease in Vmax, while the shortening of the action potential and the decrease in resting potential were similar to those at 5 mM [K+]0. However, the recovery kinetics of Vmax were markedly slowed by hypoxia. When hypoxia was added in the presence of mild acidosis (pH 6.8), the shortening of the action potential due to hypoxia was appreciably less. However, other hypoxia-induced changes in action potential and in recovery kinetics of Vmax under normal and high [K+]0 were not influenced by the concomitant acidosis. These results show that the depressant effect of hypoxia on the action potential upstroke and on the recovery of excitability of ventricular myocardium is increased when the muscles are partly depolarized at high K+. Slight differences in extracellular K+ in the presence of hypoxia have a marked effect on the time course of recovery of excitability. This inhomogeneity in refractoriness could be important for the occurrence of re-entrant arrhythmias in ischemic myocardium.

Acidosis↗
PubMed1984

Electromechanical effects of bepridil on rabbit isolated hearts.

Electromechanical effects of a new antianginal agent, bepridil, on Langendorff-perfused rabbit hearts were compared with those of verapamil and lidocaine. Bepridil at concentrations above 2 X 10(-7)M caused a dose-related decrease in heart rate (HR), a prolongation of the atrio-His bundle conduction time (A-H interval) and a prolongation of the functional refractory period (FRP) of the atrioventricular (A-V) node. Similar changes in HR, A-H interval and the FRP of the A-V node were observed with verapamil at concentrations above 2 X 10(-8)M. Lidocaine at above 4 X 10(-5)M prolonged slightly the A-H interval and the FRP of the A-V node but did not decrease the HR. Bepridil at concentrations above 10(-6)M prolonged both the His bundle-ventricular conduction time (H-V interval) and the effective refractory period (ERP) of ventricular muscles. Similar changes in the H-V interval and in the ERP of ventricular muscles were observed with lidocaine at above 10(-5)M. Verapamil ranging between 5 X 10(-8)M and 8 X 10(-7)M had no effect on the H-V interval and appreciably shortened the ERP of ventricular muscles. Bepridil at concentrations above 2 X 10(-6)M reduced the developed tension as did verapamil at above 10(-7)M. On a molar basis, the depressant effect of bepridil on HR and the A-V nodal conduction, which may reflect inhibitory action on the slow channels, was less than one tenth that of verapamil. Bepridil was more potent than lidocaine in prolonging the H-V interval and the ERP of ventricular muscles indicating a possible inhibition of the fast sodium channels. Both of these electrophysiological effects of bepridil may afford significant bases for the antiarrhythmic action of the drug.

Animals↗
PubMed1984

Effects of bepridil on the electrophysiological properties of guinea-pig ventricular muscles.

Effects of bepridil, a new antianginal and potential antiarrhythmic agent, on transmembrane action potentials of ventricular muscles were examined in isolated right ventricular papillary muscles of guinea-pig. Bepridil at concentrations above 5 X 10(-6)M caused a dose-dependent decrease in both the maximum upstroke velocity (Vmax) and the action potential duration from the upstroke to 30% repolarization ( APD30 ). On the other hand, the resting potential (RP), the amplitude of action potential (AMP), and the action potential duration from the upstroke to 90% repolarization ( APD90 ) were not affected even at the highest concentration applied (10(-5)M). The curves relating membrane potential and Vmax were shifted by bepridil at 5 X 10(-6)M along the voltage axis in the direction of more negative potentials. The recovery kinetics of Vmax assessed by premature stimuli were definitely slowed by bepridil at above 10(-6)M. This effect was more pronounced with higher [K+]o (10 mM) than normal [K+]o (5 mM). Bepridil at 5 X 10(-6)M caused a rate-dependent decrease of Vmax (use-dependent block) with rapid onset and offset, as did lidocaine. Slow responses, which had been induced by isoprenaline (5 X 10(-6)M) in K+-depolarized preparations, were suppressed significantly by additional application of bepridil at 10(-5)M. These findings suggest that bepridil has electrophysiological characteristics similar to those both of Class Ib and Class IV antiarrhythmic drugs.

Action Potentials↗
PubMed1983

Effects of amrinone on the transmembrane action potential of rabbit sinus node pacemaker cells.

Effects of amrinone on the membrane action potential and spontaneous activity were investigated in sinus node pacemaker cells of rabbit heart by use of microelectrode techniques. Amrinone (1 X 10(-4) M to 6 X 10(-6) M) caused a shortening of cycle length of spontaneous firing (SPCL) accompanied by an increase in the maximum upstroke velocity at phase O (Vmax) and amplitude of action potential (AAP), while it did not affect the maximum diastolic potential (MDP). All the effects of amrinone on sinus node pacemaker cells were markedly attenuated or abolished in a low calcium medium (Ca+ 0.1 mM or 0.3 mM) or in the presence of the slow channel blocking agent, verapamil (5 X 10(-7) M, 2 X 10(-6) M). The effects of amrinone were not antagonized by the beta-adrenoceptor blocking agent, pindolol (2 X 10(-7) M). These results indicate that amrinone has an intrinsic effect on sinus node pacemaker cells, increasing their spontaneous firing activity. It is also assumed that the effects of amrinone on sinus node cells are probably mediated by an augmentation of the slow calcium and/or sodium inward current through the cell membrane.

Action Potentials↗
PubMed1983

Epicardial activation patterns and dispersion of refractoriness initiating ventricular tachycardia in the canine left ventricle during acute ischemia.

We examined the activation patterns in the left ventricular epicardial surface of dog hearts using multielectrode grid during the beats initiating ventricular tachycardia 5 to 120 min after coronary artery occlusion. The grid was placed on the ischemic border zone (the area was confirmed by ST-isopotential mapping) to record simultaneously 36 unipolar epicardial potentials. Under the control conditions almost radial spread of activation from the central stimulating electrode of the grid was observed. Activation during acute ischemia showed crowded isochrone lines in the ischemic area, especially during the premature beats with shorter coupling intervals. In 8 out of 15 episodes, where ventricular tachycardia was induced by a single premature stimulus, the conduction delay during premature beats culminated in the local conduction block accompanied by circus movement of activation. Subsequent initial beats of ventricular tachycardia also showed similar activation patterns indicating reentry of excitation. In the remaining 7 episodes, however, we could not obtain such circus movement of activation under the grid. We also measured the effective refractory period at 5 sites under the grid. The results showed greater dispersion of the effective refractory period in the ischemic border zone throughout 5 to 120 min after coronary occlusion in the cases where ventricular tachycardia developed. These findings suggest that reentry of excitation, which is most probably caused by inhomogeneity of refractoriness in the ischemic border zone, may play an important role in the genesis of ventricular tachyarrhythmias during acute ischemia.

Animals↗