Biomedical subjects

I Kodama

Publications and source records attributed to I Kodama.

At least 91 records · Page 5Linked to original sources

PubMed1996

Correlation between electrical activity and the size of rabbit sino-atrial node cells.

1. Single cells were isolated from rabbit sino-atrial (SA) node by enzymatic dissociation. Spontaneous action potentials and membrane currents were recorded using the whole-cell patch clamp technique to study the relationship between electrical activity and the size of the cells. 2. The size of SA node cells was estimated by measuring the cell capacitance. The cell capacitance of SA node cells ranged from 21.8 to 61.5 pF with a mean +/- S.E.M. of 38.2 +/- 1.3 pF (n = 61). 3. The action potential amplitude, maximum diastolic potential, take-off potential and action potential upstroke velocity were greater in larger cells. The rate of diastolic depolarization was greater and the intrinsic spontaneous activity was faster in larger cells. 4. The density of hyperpolarization-activated current (i(f)) was greater in larger cells, whereas the density of L-type calcium current was not correlated with the size of SA node cells. 5. TTX-sensitive sodium current (iNa) was absent in small cells with a capacitance of less than approximately 25 pF, and the density of iNa was greater in larger cells. 6. The greater density of iNa in larger cells may explain the higher upstroke velocity of the action potential in large cells, and the greater density of i(f) and iNa could be responsible for the faster intrinsic spontaneous activity of large cells. These results suggest that the SA node consists of electrophysiologically heterogeneous pacemaker cells with different electrical membrane properties.

Action Potentials↗

PubMed1996

Regional differences in the response of the isolated sino-atrial node of the rabbit to vagal stimulation.

1. The effects of brief postganglionic vagal nerve stimulation on electrical activity in different regions of the rabbit sino-atrial node and surrounding atrial muscle were recorded. 2. At the centre of the node (the leading pacemaker site), the brief stimulation resulted in a large hyperpolarization followed by a depolarization and a shortening of the action potential. All effects were short lasting (time to 90% recovery of membrane potential, 0.8 s). 3. At other sites within the node and in the surrounding atrial muscle, although there was still a substantial action potential shortening, the hyperpolarization was smaller and the depolarization was small or absent. All effects were longer lasting (time to 90% recovery in atrial muscle, 11.4s). 4. The depolarization in the centre of the node was abolished by block of the hyperpolarization-activated current (i(f)) by Cs+ or zatebradine (UL-FS 49). It could, therefore, result from the activation of i(f) during the preceding hyperpolarization. 5. Block of acetylcholinesterase by eserine greatly slowed recovery from vagal stimulation at all sites, demonstrating that recovery is dependent on acetylcholinesterase. The longer lasting effects of vagal stimulation in atrial muscle, therefore, result from lower acetylcholinesterase activity. 6. Vagal stimulation resulted in a short lasting initial slowing of spontaneous action potentials followed by a long-lasting secondary slowing. Whereas the initial slowing coincided with the effects of vagal stimulation on the centre of the node, the secondary slowing coincided with the slower effects of vagal stimulation on the surrounding atrial muscle. The secondary slowing was reduced by 68 +/- 11% (n = 5) by cutting the atrial muscle away from the node. 7. It is concluded that the short-lasting initial slowing of spontaneous action potentials is the direct effect of vagal stimulation on the centre of the sino atrial node, whereas the secondary slowing is the result of the longer lasting effects of vagal stimulation on the surrounding atrial muscle and the electrotonic suppression of the node by the muscle.

Action Potentials↗

PubMed1996

X-ray Holographic Microscopy of Biological Specimens with an Electronic Zooming Tube.

X-ray holographic microscopy of biological specimens has been performed using in-line holography with the following improvements: (i) an electronic zooming tube is utilized as a detector, and (ii) the object planes are restricted by a metal frame which is not transparent to X-rays at the wavelengths used in the present experiments. The latter modification is useful in computer reconstruction and serves as a reference area where there are no photons in the reconstructed images. This system can minimize the inclusion of errors when recording and reading out holograms compared with methods using an X-ray resist as a detector, or optical reconstruction methods. Two-dimensional images of human cells have been successfully obtained with the present system. Comparison of these images with optical images revealed a good coincidence in structure outlines but not in internal structure images. Holographic observation of HeLa cells at different wavelengths showed a wavelength dependence of the reconstructed images. Since the electronic zooming tube is applicable to a wide range of X-ray wavelengths and has a promising potential to improve its resolution, these results strongly suggest that the present system is a good candidate for the development and establishment of an X-ray holographic microscopy system.

Journal Article↗

PubMed1996

Evaluation of the cell kinetics of MNNG-treated rat gastric mucosa based on AgNOR and ODC activity.

To investigate the process of carcinogenesis in gastric cancer, we studied the histological features and cell kinetics in the gastric mucosa of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated rats. Samples of gastric mucosa from both MNNG-treated and control rats were histologically examined by staining with nucleolar argylophilic nonhistone (AgNOR) proteins, and their ornithine decarboxylase (ODC) activity was determined every 2 months for 10 months. In 40% of the MNNG-treated rats, atrophy of the gastric mucosa was observed after 2 months, followed by adenomatous proliferation. More AgNOR-positive granules were found in the pyloric glands than in the fundic glands, and the total number of positive granules increased over time. Cancerous and hyperplastic lesions preferentially developed in the pyloric glands and showed significantly more AgNOR-positive granules than the normal mucosa. After 6 months the ODC activity in the MNNG-treated rats was significantly higher than that in the control rats. These results thus suggest that the pyloric glands have a high growth activity, while in addition, adenomatous proliferation is a characteristic pathological feature of precancerous lesions in the stomach in MNNG-treated rats.

Adenocarcinoma↗

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

Discrepant effects of mexiletine on cycle length of ventricular tachycardia and on the effective refractory period in the area of slow conduction.

OBJECTIVE: Monomorphic sustained ventricular tachycardia (VT) can often be entrained and interrupted at a critical paced cycle length. The aim was to evaluate a possible determinant of this phenomenon by observing the action of mexiletine on the critical paced cycle length and other variables. METHODS: Nine consecutive patients with symptomatic VT were studied. After induction of VT, the area of slow conduction was mapped as the earliest site of the activation or the site with mid-diastolic potential during the tachycardia. Rapid pacing was performed at a site distant from the tachycardia circuit to entrain the tachycardia, starting at a cycle length 10-20 ms shorter than the VT cycle length, and repeated after a decrement of the cycle length in steps of 10 ms to obtain the longest paced cycle length that interrupted the tachycardia: the block cycle length. The effective refractory period (ERP) was measured at the pacing site at which the myocardium was presumed to be normal and also in the area of slow conduction. The effects of mexiletine on the cycle length of VT, the block cycle length, and the ERP at two sites were obtained before and after mexiletine administration. The relation between the cycle length of VT and block cycle length and their changes were also analysed. RESULTS: 11 VTs with the same morphology were induced before and after mexiletine administration. The VT cycle length was prolonged by mexiletine from 309 (SD 53) to 361 (47) ms, and it was interrupted at block cycle lengths of 247 (37) and 307 (41) ms, respectively, the changes being 18 (12)% and 23 (8)% (both P < 0.001). All VTs were entrained, and during pacing at the block cycle length there was abrupt loss of fusion and change in the presystolic electrogram, always associated with interruption of VT on cessation of rapid pacing. A good correlation was observed between the VT cycle length and the block cycle length (r = 0.77 to 0.80). The ERP at the pacing site (normal myocardium) and in the area of slow conduction showed no significant change: 241 (21) v 240 (22) ms and 262 (9) v 252 (9) ms, respectively. The block cycle length was longer than the ERP after mexiletine administration: 362 (55) v 252 (9) ms (P < 0.02). CONCLUSIONS: Mexiletine prolonged the cycle length of VT and the VT-interrupting critical cycle length but not the ERP. The prolongation of the VT cycle length and the block cycle length by mexiletine seemed to be unrelated to the action potential duration, but related to depressed intercellular conduction.

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

Remnant-stump early gastric cancer following partial gastrectomy.

Eight rare cases of remnant-stump early gastric cancer (RS-EGC) were investigated, retrospectively. The incidence of RS-EGC was 0.9% (8/845) of all resected early gastric cancers. The macroscopic cancer type was elevated in 75% and mucosal in 88%. All were the differentiated type with no lymph node metastasis. The initial reconstruction involved a Billroth II in 75% of the patients. The RS-EGC was usually found during a periodic endoscopic follow-up. All patients are still alive with no postoperative complications and no cancer recurrence.

Aged↗

PubMed1996

A clinicopathological study of distal advanced gastric carcinoma with duodenal invasion.

We studied retrospectively the clinicopathological features of gastric cancer with duodenal invasion and compared these with those with non-invasion, to investigate the prognostic significance of duodenal invasion. The patients were grouped into two groups of Group A (65 patients) with duodenal invasion and Group B (197 patients) without invasion who underwent gastrectomy for advanced distal gastric carcinoma according to histological findings. In Group A, many were at high age and with symptoms of pyloric stenosis. Group A (91%) had a significantly higher incidence of serosal invasion and infiltration into the pancreas head than did Group B (76%) (p < 0.01). In N3 metastasis, there was a significant difference between Group A (60%) and Group B (36%) (p < 0.01). The five-year-survival rate in Group A was 14.0% and in Group B was 43.3% (p < 0.001). In cases of duodenal invasion, patients with symptoms of pyloric stenosis demonstrated a poorer prognosis than those without. Those with longer than 20 mm invasion had a significantly higher incidence of N3 metastasis than those with less than 10 mm (p < 0.05). Lymphangitic type had longer invasive length to duodenum, and N3 metastasis of the lymphangitic type was frequent comparing to localized type (42%) and invasive type (47%) (p < 0.001) (95%) (p < 0.01). These results showed that duodenal invasion was a significant prognostic factor in cases of distal gastric carcinoma. In the therapeutic strategy for advanced gastric carcinoma with duodenal invasion, it is necessary to perform gastrectomy with regional lymph nodes dissection and with combined resection of adjacent organs.

Aged↗

PubMed1996

Remnant-stump gastric cancer following partial gastrectomy-clinicopathological studies.

Forty-five cases of remnant-stump (R-S) gastric cancer were investigated retrospectively, comparing those which were initially benign (Group 1: 31 cases) with those which were initially malignant (Group 2: 14 cases). The incidence of R-S gastric cancer over all gastrectomy cases from 1967 to 1994 was 1.4% (45/3,282). The mean period until development of the R-S gastric cancer following partial gastrectomy was 21.6 years in Group 1 and was 15.8 years in Group 2 (p < 0.05). Of those R-S cases that underwent resection, total gastrectomy was selected for 82% in Group 1 and for 85% in Group 2. The incidence of negative lymph nodes was only 25% in Group 1 and 62% in Group 2 (p < 0.05). The pathological stage I was 21% in Group 1 and 54% in Group 2 (p < 0.05). The 5-year-survival rate was 32% in Group 1 and was 62% in Group 2 (p < 0.05). To improve the prognosis for R-S gastric cancer, periodic endoscopic follow-up examinations to find any R-S cancer at the earliest stage is most important, especially in cases of a partial gastrectomy for an initially benign case.

Aged↗

PubMed1996

Mucinous adenocarcinoma of the stomach-clinicopathological studies.

The clinical and morphological features of 58 cases of the rare mucinous adenocarcinoma of the stomach (MUC) were investigated and compared to those of other pathological types. The incidence of MUC was only 2.9% of all cases of resected gastric cancer. Among the 58 cases of MUC, the incidence of early cases was only 19% (Group 1), while among other pathological types of cancer, it was 42% (Group 2) (p < 0.001). The incidence of early mucosal cancer was 0% in Group 1, and 54% in Group 2 of the resected early gastric cancer. The incidence of lymph node metastasis rate was 81% in Group 1, and was 46% in Group 2 (p < 0.001). The presence of peritoneal dissemination was 21% in Group 1, and was 8% in Group 2 (p < 0.001). The incidence of liver metastasis pre- and intraoperatively was 0% in Group 1, and was 3.5% in Group 2. The overall 5-year-survival rate was 45% in Group 1, and was 61% in Group 2 (p < 0.05). In stage III, the 5-year-survival rate was 30% in Group 1, and was 49% in Group 2 (p < 0.05). There was no statistical prognostic difference between the two groups in stage I, II and stage IV. Therefore, to improve the outcome for MUC, more effective radical gastrectomy and aggressive immunochemotherapy should be selected especially for stage III mucinous adenocarcinoma of the stomach.

Adenocarcinoma, Mucinous↗

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↗