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Biomedical subjects

T Shirayama

Publications and source records attributed to T Shirayama.

At least 19 recordsLinked to original sources
PubMed1996

Biphasic effects of intrapipette cyclic guanosine monophosphate on L-type calcium current and contraction of guinea pig ventricular myocytes.

The effects of intracellular cyclic guanosine monophosphate (cGMP) on L-type calcium current (lCa) and contraction of ventricular myocytes enzymatically isolated from guinea pig hearts were investigated to test the hypothesis that cGMP increases contractions along with ICa in these cells. ICa and contractions, elicited every 15 sec, were recorded simultaneously with a whole-cell voltage-clamp method and a video edge-detector, respectively. Cells were superfused with Tyrode's solution (22 degrees C); the pipette solution contained 120 mM potassium aspartate, 30 mM KCl, 4 mM ATP, 5 mM N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid), 0.01 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and various concentrations of cGMP, which entered the cell interior through the patch electrode. In the presence of 3 nM isoproterenol (ISO) in the bath, ICa was increased 3.2-fold. ICa was further increased by 20% with 30 microM cGMP; cell contractions were also increased by 32%. When ICa was maximal in the presence of 30 nM ISO, cGMP no longer increased ICa or contractions, an indication that the effects of cGMP and ISO were additive. When ICa was increased maximally (4.3-fold) by 100 microM isobutylmethylxanthine, a nonselective phosphodiesterase inhibitor, application of 100 microM cGMP in the pipette decreased ICa by 53% and cell shortening by 64%. Cyclic GMP changed contraction in parallel with ICa in the presence of either ISO or isobutylmethylxanthine. 5'-GMP had no significant effect on ICa or contraction in the presence of ISO or isobutyl-methylxanthine. Cyclic GMP alone, at 30 microM, increased ICa by 25%; this effect on basal ICa was reversed by removal of cGMP from the pipette solution. We conclude that intracellular cGMP had two effects on ICa and contraction, namely, 1) an increase caused by an action on cGMP-inhibited phosphodiesterase and 2) a decrease attributed to activation of cGMP-dependent protein kinase.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Effects of disopyramide on the atrial fibrillation threshold in the human atrium.

The effects of disopyramide on the atrial fibrillation threshold (AFT) in the human atrium were investigated. To evaluate atrial vulnerability, the following electrophysiologic parameters were measured before and after the administration of disopyramide (2 mg/kg) in 12 patients with paroxysmal atrial fibrillation: The right atrial effective refractory period (ERP) and percentage maximum atrial fragmentation (%MAF) were measured by atrial premature stimulation based on a cycle length of 500 ms. The inter-atrial conduction time (ACT) was measured by burst pacing (120/min) for 30 s. AFT was measured by applying a high-frequency (50 Hz) stimulation for 1 s given at the right atrial appendage. AFT was defined as the lowest intensity of electrical current that could induce atrial fibrillation lasting for more than 30 s. Disopyramide significantly reduced %MAF, and prolonged ERP and ACT. AFT was measured in all patients and the mean AFT was 3.1 +/- 1.7 mA. After the administration of disopyramide, AFT significantly increased to 6.1 +/- 3.6 mA. There was a positive correlation between ERP and AFT, and a negative correlation between %MAF and AFT. No correlation was detected between ACT and AFT. In conclusion, disopyramide increased AFT in the human atrium.

Adult↗
PubMed1995

Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.

We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.

Anti-Arrhythmia Agents↗
PubMed1994

Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7-23 in normal individuals. In patients one allele was expanded to between 49-75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.

Alleles↗
PubMed1994

Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA).

Dentatorubral and pallidoluysian atrophy is associated with expansion of an unstable CAG repeat on chromosome 12p. We have determined the nucleotide sequences of overlapping cDNA clones and deduced the gene structure. The gene is ubiquitously expressed to form a single 4.5 kb transcript and encoded by an open reading frame of 1184 amino acids (aa), in which a polyglutamine track with variable length starts at aa 484. Although the predicted amino acid sequence does not reveal any function, it does contain several interesting motifs consisting of a simple repeated amino acid sequence, a homo-proline track, two stretches of arginine-glutamic acid dipeptides and a stretch of alternative histidine residues. These results provide clues toward understanding neurodegenerative diseases associated with triplet repeat expansion.

Atrophy↗
PubMed1994

Effects of E-4031 on atrial fibrillation threshold in guinea pig atria: comparative study with class I antiarrhythmic drugs.

The effects of E-4031, a new class III antiarrhythmic agent, on atrial fibrillation threshold (AFT), atrial effective refractory period (ERP), and interatrial conduction time (ACT) were investigated in Langendorff-perfused guinea pig hearts; the results were then compared with those of the class I agents disopyramide, procainamide, lidocaine, and flecainide. Whole guinea pig hearts were perfused with Tyrode's solution containing acetylcholine (ACh 3 x 10(-7) M). The three indexes were measured before and after administration of the test drugs, using right atrial extrastimulus and 50-Hz continuous stimulation. Disopyramide, procainamide, and flecainide (> or = 10(-6) M) significantly increased AFT. Although E-4031 (> or = 3 x 10(-6) M) also increased AFT, this effect was less potent than that observed with the other drugs. E-4031 (> or = 10(-6) M) significantly prolonged ERP, and this prolongation was less pronounced than that observed with disopyramide but similar to that observed with procainamide or flecainide. E-4031 did not affect ACT, and the greatest prolongation of ACT was observed with flecainide. Lidocaine had no effect on any of the indexes. These findings suggest that in guinea pig hearts E-4031 exerts an antifibrillatory effect by prolonging atrial ERP alone, but this effect is less pronounced than that observed with class I drugs, because AFT measured by 50-Hz continuous stimulation is influenced by both ERP and ACT.

Acetylcholine↗
PubMed1993

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers.

The electrophysiological effects of flecainide acetate (3 x 10(-6) M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD50) were slightly but significantly decreased by 2 +/- 1 mV and 2 +/- 1 msec, respectively. The effective refractory period (ERP) was increased by 3 +/- 1 msec. The reduction of Vmax was 20.6 +/- 1.2%. The half-maximum potential (Vh) of the relationship between Vmax and the resting potential was shifted to become more negative by flecainide (from -60.6 +/- 2.1 mV to -63.2 +/- 1.7 mV). After 90-120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the Vmax by 16.9 +/- 3.1%, along with a slight but significant increase in ERP (3 +/- 1 msec) and shifted Vh to become more negative (from -60.6 +/- 2.1 to -63.1 +/- 1.8 mV). In the presence of flecainide, Vmax further decreased by 20.2 +/- 2.6%, and Vh shifted from -63.1 +/- 1.8 to -65.0 +/- 1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased Vmax by 34.0 +/- 2.7%, reduced the resting membrane potential by 3 +/- 1 mV, decreased Eov by 4 +/- 1 mV, and shifted Vh from -60.6 +/- 2.1 to -65.0 +/- 1.5 mV, while the APD50 and ERP did not change. In conclusion, the reduction of Vmax in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the Vmax-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.

Animals↗
PubMed1993

Effects of PDE inhibitors and carbachol on the L-type Ca current in guinea pig ventricular myocytes.

The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produced by IBMX or papaverine. However, ICa could not be restored to its original magnitude on washout of CCh in the presence of phosphodiesterase inhibitors. In pertussis toxin-treated cells or in the presence of Ly-83583 (1-100 microM), IBMX retained its effect but CCh was unable to reduce ICa. Dialysis with guanosine 3',5'-cyclic monophosphate (cGMP; 0.1-100 microM) or 8-bromoguanosine 3',5'-cyclic monophosphate (30 microM) suppressed the increase of ICa by IBMX; the inhibition by cGMP was additive with that produced by CCh. We suggest that the major part of IBMX and papaverine effect is mediated by phosphodiesterase inhibition and involves an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. CCh reversal of phosphodiesterase inhibitor action probably involves an elevation of cGMP levels and activation of cGMP-dependent protein kinase.

1-Methyl-3-isobutylxanthine↗
PubMed1993

[Effect of pilsicainide hydrochloride on atrial fibrillation threshold].

To inventigate the electrophysiologic effects of pilsicainide hydrochloride on atrial fibrillation, we compared atrial fibrillation threshold (AFT), right atrial effective refractory period (RAERP), and inter-atrial conduction time (Inter-ACT) before and after the administration of pilsicainide in 12 patients with lone paroxysmal atrial fibrillation. The following electrophysiologic study was performed before and after the administration of the drug as the paced cycle length of 500msec. First, RAERP was measured. Secondly, Inter-ACT from the stimulating artifact to the initial deflection in the elecrocardiograms of the coronary sinus was measured. Thirdly, high-frequency (50Hz) stimulation was given at right atrial appendage continuously for one second just after the eighth basic paced beat. The stimulation current was increased by 1mA in a stepwise fashion from 2mA until atrial fibrillation ensued. AFT was defined as the lowest intensity of the current that induced atrial fibrillation or flutter of more than 30 seconds. Pilsicanide significantly increased AFT and Inter-ACT, but did not change RAERP. In conclusion, it is suggested that pilsicainide might decrease atrial vulnerability mainly by its effect on inter-atrial conduction delay and by the resulting increase in AFT.

Adult↗
PubMed1993

Carbachol-induced sodium current in guinea pig ventricular myocytes is not regulated by guanine nucleotides.

Muscarinic (M2) receptor occupancy by carbachol induces a tetrodotoxin- and pertussis toxin-resistant Na+ current which underlies its positive inotropic effect in guinea pig ventricular cells. We tested the effect of activating [GTP gamma S, Gpp(NH)p] and inactivating (GDP beta S) guanine nucleotides on this carbachol-induced current because guanine nucleotide binding proteins are reported to transduce the effect of muscarinic agonist. A whole-cell voltage clamp method was used. The carbachol (300 microM)-induced current was not significantly changed at any membrane voltage in the absence and the presence of 10 microM GTP gamma S, 100 microM Gpp(NH)p or 500 microM GDP beta S in the patch pipette (inward current amplitude at -80 mV: -21 +/- 1.5 pA, control; -22 +/- 1.3 pA, GTP gamma S; -20, -16 pA, Gpp(NH)p; -20 +/- 2.3 pA, GDP beta S; n = 31, 11, 2 and 14, respectively). The current amplitude was not affected by prolonged dialysis (120 min) of the cell with Gpp(NH)p and/or by the presence of greater concentrations of guanine nucleotides. On the other hand, 10 microM GTP gamma S directly activated the muscarinic K+ channel current within 60 sec after patch rupture in atrial myocytes; either GTP gamma S or GDP beta S (500 microM) occluded activation of this current by carbachol. When isoproterenol had increased L-type Ca++ current in ventricular myocytes, carbachol-induced inhibition of this current was suppressed when GTP gamma S (10 microM) was present in the pipette solution. Therefore, myocytes were dialyzed with effective concentrations of guanine nucleotides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Slow kinetic property of mexiletine in guinea pig atrium.

We studied the onset and offset of use-dependent block (UDB) of maximum rate of rise of action potential (Vmax) with 3 x 10(-5)M mexilietine in guinea pig left atrium. A large decrease of Vmax was observed between the first and the second excitation when the preparations were stimulated at 4Hz after two minutes of rest period. UDB after the second excitation developed slowly to reach steady state within 30 sec. These two onset rates were 1.016 +/- 0.055 and 0.070 +/- 0.009/action potential. Recovery process was also fitted with two exponential equations. The time constant of the fast recovery was 528 +/- 23 msec. and the slow one was 3099 +/- 435 msec. The relative contribution of the slow component was 38.3 +/- 2.6% in the onset and 29.7 +/- 3.1% in the recovery. In spite of elevated maximum diastolic potential at 4 Hz stimulation, the relationship between resting membrane potential and Vmax disclosed voltage-dependent block of Vmax was no more than 5%. It is concluded that mexiletine has a slow kinetic component as well as a fast one. When atrial muscle is depolarized, Vmax decreases further. Therefore, mexiletine may be more effective against the atrial arrhythmias than predicted previously.

Action Potentials↗
PubMed1992

[Electrophysiologic effects of flecainide on guinea pig atrium].

We investigated the effects of flecainide on guinea pig atrial muscle. Using Langendorff's method, the whole heart of a guinea pig was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Then, with right atrial extrastimulus and high frequency pacing method, the following values were measured before and after administration of flecainide (10(-7)-10(-5) M). A) Effective refractory period (ERP); the longest coupling interval which failed to produce right atrial activity at premature stimulus. B) Interatrial conduction time (ACT); After right atrial stimuli by trains at PCL 200 ms for 5 min the interval from the stimulation to the first deflection of the left atrial activity. C) Atrial fibrillation threshold (AFT); the minimal amount of current required to induce atrial fibrillation lasting for more than 30 sec by 50 Hz high frequency stimulation. Flecainide lengthened ERP (> or = 3 x 10(-5) M) and ACT (> or = 10(-7) M). Flecainide (10(-5) M) significantly increased AFT which correlated well with ERP (r = 0.81, p < 0.002) and ACT (r = 0.84, p < 0.002). In conclusion these effects of flecainide on guinea pig atrium might explain in part the clinical effectiveness of the drug on paroxysmal atrial fibrillation.

Animals↗
PubMed1991

Prolonged atrial activity due to delayed conduction in the atrium of patients with paroxysmal atrial fibrillation.

We investigated the relationship between the duration of electrical atrial activity and intra-atrial conduction time to determine whether the prolonged atrial activity was due to delayed conduction in the human atrium. The study included 15 patients with paroxysmal atrial fibrillation (PAF) and 15 control patients. The duration of atrial electrical activity was measured by selecting a minimum electrographic amplitude of 50 microV. In patients with PAF, the duration of atrial activity was prolonged in proportion to the delay of interatrial conduction time from the high right atrium to the coronary sinus as the coupling interval of premature extrastimuli was decreased. Both the fragmented atrial activity zone and the interatrial conduction delay zone were wider in patients with PAF than in control patients. It is concluded that assessment of the duration of atrial activity with a minimum amplitude of 50 microV is useful in evaluating human atrial vulnerability since it reflects the atrial conduction delay in patients with PAF.

Adolescent↗
PubMed1991

Inositol trisphosphate promotes Na-Ca exchange current by releasing calcium from sarcoplasmic reticulum in cardiac myocytes.

An early inward tail current evoked by membrane depolarization (from -80 to -40 mV) sufficient to activate sodium but not calcium current was studied in single voltage-clamped ventricular myocytes isolated from guinea pig hearts. Like forward-mode Na-Ca exchange, this early inward tail current required [Na+]o and [Ca2+]i and is thought to follow earlier reverse-mode Na-Ca exchange that triggers Ca2+ release from sarcoplasmic reticulum. The dependence of the early inward tail current on [Ca2+]i was supported by the ability of small (+10 mV) and large (+80 mV) voltage jumps from -40 mV to decrease and increase, respectively, the size of early inward tail currents evoked by subsequent voltage steps from -80 to -40 mV. As expected, tetrodotoxin selectively inhibited the early inward tail current but not the late inward tail current that followed voltage jumps to +40 mV test potentials. Although tetrodotoxin also blocked the fast Na+ current, replacement of extracellular Na+ by Li+ sustained the fast Na+ current. However, Li+, which does not support Na-Ca exchange, reversibly suppressed both the early and late inward tail currents. Inhibitors (ryanodine and caffeine) and promoters (intracellularly dialyzed inositol 1,4,5-trisphosphate) of sarcoplasmic reticulum Ca2+ release decreased and increased, respectively, the magnitude of the early inward tail current. The results substantiate the hypothesis that Ca2+ release from the sarcoplasmic reticulum participates in early Na-Ca exchange current and demonstrate that inositol 1,4,5-trisphosphate, by releasing Ca2+ from the sarcoplasmic reticulum, can promote Na-Ca exchange across the plasma membrane.

Animals↗
PubMed1991

Electrophysiological effects of sodium channel blockers on guinea pig left atrium.

The electrophysiological effects of five sodium channel blockers (mexiletine, lidocaine, disopyramide, aprindine and flecainide) on the guinea pig left atrium were investigated by recording the action potential and its maximum rate of rise (Vmax). The onset and offset kinetics of use-dependent block of Vmax were analyzed. Lidocaine, aprindine and flecainide were classified clearly as fast, intermediate and slow, respectively. Mexiletine and disopyramide had two components in onset and offset of use-dependent block. Mexiletine showed fast and intermediate kinetics, whereas disopyramide showed intermediate and slow kinetics. Action potential duration at 90% repolarization (APD) was prolonged by disopyramide and mexiletine. The other drugs did not change the action potential duration. Effective refractory period was prolonged by all drugs with relative potency in the following order: disopyramide greater than mexiletine greater than lidocaine greater than aprindine = flecainide. In conclusion, the modes of actions of sodium channel blockers on the atrium were disclosed to be different from those on the ventricle. The pharmacological therapy for atrial arrhythmias should be based on the electrophysiological effects of the drugs on the atrium, not on the ventricle.

Action Potentials↗
PubMed1991

[Electrophysiological effect of verapamil on human atrium].

To investigate the effect of verapamil on atrial vulnerability, the following measurements were performed before and after the intravenous administration of verapamil (0.15 mg/kg) in 10 subjects with paroxysmal atrial fibrillation (Paf), and 10 subjects without Paf (non-Paf). During the sinus rhythm, 1) intra-/interatrial conduction time (Intra-/Inter- ACT); the initial deflection of high right atrium (HRA) to that of His bundel/coronary sinus were measured. After 8 consecutive HRA stimuli (A1), premature stimulus (A2) was introduced by shortening the coupling interval (A1A2) and we measured 2) conduction delay zone (CDZ); the zone of A1A2 with the prolongation of Inter-ACT, 3) % maximum atrial fragmentation (%MAF); % maximum value of the ratio of HRA activity width at A2 (Awt) against that at A1 (Awc), 4) fragmented atrial activity zone (FAZ); the zone of A1A2 with % value of Awt/Awc more than 150%,5) repetitive atrial response (RAR); more than 2 atrial activities which occur in response to A2. (6) right atrial effective refractory period (RAERP). Verapamil significantly shortened CDZ and %MFA, slightly lengthened RAERP, and had RAR disappear in Paf, while it did not effect any indices significantly in non-Paf. We concluded that verapamil could reduce atrial vulnerability in Paf due to blocking of atrial conduction delay mediated by slow response fibers.

Adolescent↗