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H Nakaya

Publications and source records attributed to H Nakaya.

At least 19 recordsLinked to original sources
PubMed1995

Anticholinergic effects of class III antiarrhythmic drugs in guinea pig atrial cells. Different molecular mechanisms.

BACKGROUND: It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor-mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined. METHODS AND RESULTS: Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, IK.ACh was activated by extracellular application of carbachol (1 mumol/L) or adenosine (10 mumol/L) or by intracellular loading of GTP gamma S (100 mumol/L). Sotalol (3 to 1000 mumol/L), E-4031 (1 to 100 mumol/L), and MS-551 (1 to 100 mumol/L) inhibited the carbachol-induced IK.ACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 mumol/L, respectively. However, the GTP gamma S-induced and adenosine-induced IK.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol. CONCLUSIONS: Sotalol may inhibit IK.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K+ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on IK.ACh.

Acetylcholine↗
PubMed1995

Carbonic anhydrase is required for statoconia homeostasis in organ cultures of statocysts from Aplysia californica.

A novel organ culture system has been developed to study the regulation of statoconia production in the gravity sensing organ in Aplysia californica. Statocysts were cultured in Leibovitz (L15) medium supplemented with salts and Aplysia haemolymph for four days at 17 degrees C. The viability of the system was evaluated by examining four parameters: statocyst morphology, the activity of the mechanosensory cilia in the statocyst, production of new statoconia during culture and change in statoconia volume after culture. There were no morphological differences in statocysts before and after culture when ciliary beating was maintained. There was a 29% increase in the number of statoconia after four days in culture. Mean statocyst, statolith and statoconia volumes were not affected by culture conditions. The presence of carbonic anhydrase in the statocysts was shown using immunohistochemistry. When statocysts were cultured in the presence of 4.0 x 10(-4) M acetazolamide to inhibit the enzyme activity, there was a decrease in statoconia production and statoconia volume, indicating a role for this enzyme in statoconia homeostasis, potentially via pH regulation. These studies are the first to report a novel system for the culture of statocysts and show that carbonic anhydrase is involved in the regulation of statoconia volume and production.

Animals↗
PubMed1995

Cyclic GMP-mediated inhibition of L-type Ca2+ channel activity by human natriuretic peptide in rabbit heart cells.

1. Effects of atrial natriuretic peptide (ANP) on the L-type Ca2+ channels were examined in rabbit isolated ventricular cells by use of whole-cell and cell-attached configurations of the patch clamp methods. ANP produced a concentration-dependent decrease (10-100 nM) in amplitude of a basal Ca2+ channel current. 2. The inactive ANP (methionine-oxidized ANP, 30 nM) failed to decrease the current. 3. 8-Bromo-cyclic GMP (300 microM), a potent activator of cyclic GMP-dependent protein kinase (PKG), produced the same effects on the basal Ca2+ channel current as those produced by ANP. The cyclic GMP-induced inhibition of the Ca2+ channel current was still evoked in the presence of 1-isobutyl-3-methyl-xanthine, an inhibitor of phosphodiesterase. ANP failed to produce inhibition of the Ca2+ channel current in the presence of 8-bromo-cyclic GMP. 4. In the single channel recording, ANP and 8-bromo-cyclic GMP also inhibited the activities of the L-type Ca2+ channels. Both agents decreased the open probability (NPo) without affecting the unit amplitude. 5. The present results suggest that ANP inhibits the cardiac L-type Ca2+ channel activity through the intracellular production of cyclic GMP and then activation of PKG.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias. Beneficial effect of angiotensin II blockade.

To evaluate the preventive effect of regression of left ventricular hypertrophy (LVH) on sudden cardiac death (SCD), the incidence of ventricular tachycardia or ventricular fibrillation (VT/Vf) after left coronary artery occlusion in Langendorff preparations was studied in the following five groups: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR treated with captopril (SHR-C), (3) SHR treated with the angiotensin II receptor antagonist TCV-116 (SHR-A), (4) SHR treated with hydralazine (SHR-H), and (5) Wistar-Kyoto (WKY) rats. Although blood pressure was equally lowered in all treated groups, SHR-C and SHR-A but not SHR-H showed regression of LVH. The incidence of VT/Vf was 5% in WKY rats, 63% in SHR-N (P < .005 versus WKY rats), 0% in SHR-C, 10% in SHR-A, and 45% in SHR-H (P < .05 versus WKY rats). Further evaluation of the effect of TCV-116 revealed that SHR treated with a low dose of TCV-116 (1 mg/kg per day) showed a decrease in left ventricular mass with only a little decrease in blood pressure and that the incidence of VT/Vf was reduced in association with the degree of regression of LVH. Electrophysiological study using microelectrode techniques revealed that in the LVH groups (SHR-N and SHR-H), the action potential duration (APD) of the left ventricular papillary muscle was more prolonged than in WKY rats, whereas APD shortened to a greater extent during superfusion with a hypoxia/no-glucose solution. APD showed no difference in the regression groups (SHR-C and SHR-A) compared with the WKY group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1995

Vasopressin V1-receptor stimulation produces a positive inotropic response without affecting pHi in guinea pig papillary muscles.

Effects of arginine-vasopressin (AVP) on the contractile force, action potential (AP) and intracellular pH (pHi) were studied in isolated guinea pig papillary muscles using conventional and ion-selective microelectrode techniques. AVP increased the developed tension and the resting tension, and these responses were attenuated by the V1-receptor antagonist OPC-21268 (1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2 (1H)- quinolinone). However, AVP failed to affect AP configuration or pHi. These results suggest that AVP produces a positive inotropy by mechanism(s) other than intracellular alkalinization.

Animals↗
PubMed1993

Effects of MS-551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes.

1. Electrophysiological effects of MS-551, a new class III antiarrhythmic drug, were examined and compared with those of (+)-sotalol in rabbit ventricular cells. 2. In rabbit ventricular muscles stimulated at 1.0 Hz, MS-551 (0.1-10 microM) and (+)-sotalol (3-100 microM) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization (Vmax). The class III effect of MS-551 was approximately 30 times more potent than that of (+)-sotalol. 3. Class III effects of MS-551 and (+)-sotalol showed reverse use-dependence, i.e., a greater prolongation of APD at a longer cycle length. 4. In rabbit isolated ventricular cells, 3 microM MS-551 and 100 microM sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than -50 mV and saturated around +20 mV. 5. MS-551 at a higher concentration of 10 microM decreased the transient outward current (Ito) and the inward rectifier potassium current (IK1) although 100 microM sotalol failed to inhibit these currents. 6. MS-551 is a non-specific class III drug which can inhibit three voltage-gated K+ channels in rabbit ventricular cells.

Action Potentials↗
PubMed1993

A dual-component positive inotropic effect of endothelin-1 in guinea pig left atria: a role of protein kinase C.

This study was designed to analyze the mechanism(s) underlying the positive inotropic effect (PIE) of endothelin-1 (ET-1) in the guinea pig left atrium. ET-1 exhibited a greater PIE at lower frequencies of pacing and potentiated significantly the postrest contraction similar to isoproterenol. However, ET-1 prolonged the duration of a single contraction, whereas isoproterenol shortened it. ET-1 was similar to methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate in the prolonged duration of a single contraction but different from this drug in the force-frequency relationship. ET-1 at concentrations of 10 nM and higher caused a dual-component PIE composed of an initial increasing phase (early component) and a second greater positive inotropic phase (late component). The early component was correlated to the ET-1-induced prolongation of the duration of the action potential in the time course. Both nifedipine and ryanodine suppressed the late component much more than the early component. ET-1 (> or = 3 nM) produced significant stimulation of phosphoinositide hydrolysis as measured by [3H]inositol monophosphate accumulation. ET-1 was found to activate protein kinase C (PKC) instantaneously but transiently (evaluated by the translocation of PKC activity to the particulate fraction). Pretreatment with 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine and staurosporine, PKC inhibitors, markedly inhibited the late component of the PIE of ET-1 without affecting the early component. These data indicate that the two components of the PIE induced by ET-1 in the guinea pig left atrium may be mediated by different mechanisms. The early component may be attributed to the increased Ca++ influx as a result of the prolongation of the duration of the action potential, whereas the late component may be linked to stimulation of phosphoinositide hydrolysis and subsequent PKC activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Effects of Cl- channel blockers on beta-adrenoceptor-mediated decreases in resting potential and intracellular Cl- activity in guinea-pig heart.

In order to find a more specific blocker of the cardiac Cl- channel, we examined the effects of anthracene-9-carboxylic acid (9AC) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) on the beta-adrenoceptor-mediated decreases in resting potential and intracellular chloride ion activity (aiCl) in guinea-pig papillary muscles by using Cl- ion selective microelectrodes. 9AC (1 mM) significantly inhibited the isoproterenol (1 microM)-induced decreases in resting potential and aiCl in quiescent preparations. However, 1 mM DIDS did not significantly affect the changes in aiCl and resting potential during beta-adrenergic stimulation. Thus, in cardiac cells, 9AC is a more potent blocker of the Cl- channels activated by beta-adrenergic stimulation than DIDS.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Electrophysiologic and anticholinergic effects of pirmenol enantiomers in guinea-pig myocardium.

Since it has been reported that several class I drugs stereoselectively block sodium channels, potassium channels and muscarinic receptors in cardiac tissues, electrophysiologic and anticholinergic effects of enantiomers of pirmenol, a class I antiarrhythmic drug, were examined. Both (+) and (-) pirmenol depressed the maximum upstroke velocity (Vmax) of the action potential in a concentration-dependent manner in guinea-pig papillary muscles driven at 1.0 Hz, and there was no significant difference in the potency of the class I effect between the enantiomers. The onset rates of use-dependent block (UDB) of Vmax at 2.0 Hz for 10 mumol/l (+) and (-) pirmenol were 0.30 +/- 0.03 and 0.29 +/- 0.01 per action potential, and the recovery time constants from UDB for (+) and (-) pirmenol were 27.0 +/- 2.7 and 27.7 +/- 1.9 s, respectively, indicating no difference in the binding and unbinding kinetics to the sodium channel between the enantiomers. Both (+) pirmenol and (-) pirmenol prolonged action potential duration (APD) at low concentrations (1-10 mumol/l) and shortened it at high concentrations (30-100 mumol/l). Again, there was little difference with respect to the effects on APD between the enantiomers. However, in the isolated guinea-pig left atria (-) pirmenol more potently antagonized the negative inotropic effect of carbachol than (+) pirmenol, and the pA2 values for (+) and (-) pirmenol were 6.41 and 6.71, respectively. The functional study was supported by the radioligand binding experiments using [3H]N-methylscopolamine ([3H]NMS) in guinea-pig left atrial membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1992

Mechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cells.

Mechanism of the membrane depolarization induced by oxidative stress was examined using ion-selective microelectrode and patch clamp techniques. In guinea-pig papillary muscles stimulated at 0.5 Hz, cumene hydroperoxide (CH) at a concentration of 300 microM decreased the resting membrane potential and shortened the action potential, concomitantly with muscle contracture. The membrane depolarization was not associated with a significant decrease in intracellular potassium ion activity, indicating that the depolarization is not due to a decrease in potassium equilibrium potential resulting from leak of intracellular K+. In isolated guinea-pig ventricular cells. CH (10-30 microM) consistently decreased the inward rectifier potassium current and slightly decreased the calcium current. In cell-attached patches CH inhibited the opening of the inward rectifier K+ channel without affecting the unit amplitude of the single channel current. Thus, the depolarization of the resting membrane induced by oxidative stress is, at least in part, due to the inhibition of the inward rectifier K+ channel activity, and may play an important role in the genesis of reperfusion-induced arrhythmias.

Animals↗
PubMed1992

Voltage-dependent modification of Vmax recovery from use-dependent block by pirmenol in guinea pig papillary muscles: comparison with other class I drugs.

Voltage-dependent modification of Vmax (the maximum upstroke velocity of the action potential) recovery from use-dependent block (UDB) by pirmenol was examined and compared with those observed with other Class I drugs using standard microelectrode techniques. A partial depolarization of the resting membrane by increasing extracellular potassium concentration ([K+]o) from 4 to 8 mM potentiated UDB at 2 Hz stimulation by any of the following drugs: pirmenol (10 microM), disopyramide (20 microM), pentisomide (50 microM), quinidine (20 microM), mexiletine (30 microM), and flecainide (5 microM). The recovery time constants from UDB of quinidine and mexiletine were prolonged and that of flecainide was unchanged in 8 mM [K+]o. However, the recovery time constant from UDB of pirmenol was shortened in high K+ solution, as observed with disopyramide and pentisomide. Thus, disopyramide and its analogues, including pirmenol, show a voltage dependency of recovery process, which is different from those of other class Ia, Ib, and Ic drugs. The main unblocking pathway of disopyramide and its analogues from sodium channels during diastolic interval may be different from that of other Class I drugs.

Action Potentials↗
PubMed1992

Alpha 1-adrenoceptor stimulation enhances the delayed rectifier K+ current of guinea pig ventricular cells through the activation of protein kinase C.

The effect of alpha 1-adrenoceptor stimulation on the delayed rectifier K+ current (IK) was examined in isolated guinea pig ventricular cells by use of the patch-clamp method. IK was evoked by a 3-second depolarizing pulse from a holding potential of -30 mV in a Na(+)- and K(+)-free solution containing 3 microM nifedipine. Phenylephrine (30 microM) in the presence of propranolol (1 microM) produced an increase in IK. In five cells, phenylephrine increased the tail current of IK by 23 +/- 5%. This effect of phenylephrine was blocked by prazosin (0.3 microM), a selective alpha 1-blocker. Phenylephrine produced only a small effect on the voltage and time dependence of IK. Pretreatment with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7, 10 microM) abolished the phenylephrine-induced increase in IK. In addition, pretreatment with a maximally effective concentration of 12-O-tetradecanoylphorbol 13-acetate (100 nM) abolished the phenylephrine-induced increase in IK. In conclusion, alpha 1-adrenoceptor stimulation increases IK in guinea pig cardiomyocytes. This alpha 1-adrenoceptor-mediated response may be related to an activation of protein kinase C. The increase in IK may explain a shortening of action potential duration observed after alpha 1-adrenoceptor stimulation in guinea pig cells.

Action Potentials↗
PubMed1992

Electrophysiologic mechanisms responsible for inotropic responses to ketamine in guinea pig and rat myocardium.

Inotropic and electrophysiologic effects of ketamine were investigated in cardiac preparations isolated from guinea pigs and rats. Ketamine produced a concentration-dependent negative inotropic effect in electrically driven guinea pig papillary muscles, an effect that was accompanied by a decrease in action potential duration at the 0-mV level (APD0). In contrast, ketamine produced a concentration-dependent positive inotropic effect in rat left atria in the presence of 10(-6) M propranolol. The increase in force of contraction was accompanied by an increase in APD0. Experiments using patch clamp techniques revealed that ketamine reduced the transsarcolemmal Ca2+ current (ICa) as well as the inward rectifier K+ current and delayed outward K+ current in guinea pig single ventricular cells. These results indicate that the shortening of APD0 observed in guinea pig papillary muscles might result from the suppression of ICa. In rat single ventricular cells ketamine reduced the Ca(2+)-insensitive transient outward current (Ito) and did not enhance ICa, suggesting that the ketamine-induced prolongation of APD0 observed in rat left atria is due to a decrease in Ito rather than an increase in ICa. Treatment of rat left atria with the specific Ca(2+)-insensitive Ito inhibitor 4-aminopyridine (2 mM) produced a positive inotropic effect and prolongation of APD0, and these effects were equivalent to those caused by the highest concentration of ketamine. In the presence of 4-aminopyridine, ketamine failed to induce a positive inotropic effect and instead caused a negative inotropic one. In conclusion, the negative and positive inotropic effects of ketamine may result from the suppression of ICa and Ito, respectively. The inhibitory action on these membrane currents may at least in part explain the species and tissue differences in inotropic responses to ketamine.

Action Potentials↗
PubMed1991

Pharmacological analysis of the positive inotropic effect of endothelin-1 in guinea pig left atria.

Endothelin-1 (ET-1) increased the force of contraction and stimulated phosphoinositide hydrolysis in guinea pig left atria. ET-1 at 20 nM produced a dual-component positive inotropic effect composed of an initial increasing phase (early component) and a second and late developing, greater positive inotropic phase (late component). The late component was preferentially and markedly inhibited by nifedipine and the protein kinase C inhibitors H-7 and staurosporine. In guinea pig left atria, the activation of protein kinase C might contribute to the establishment of the positive inotropic effect of ET-1 mediated by modulation of voltage-dependent Ca2+ channels.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Effects of ATP-sensitive K+ channel blockers on the action potential shortening in hypoxic and ischaemic myocardium.

1. In order to determine whether activation of adenosine triphosphate (ATP)-sensitive K+ channels exclusively explains the hypoxia- and ischaemia-induced action potential shortening, effects of tolbutamide and glibenclamide on changes in action potential duration (APD) during hypoxia, metabolic blockade or experimental ischaemia were examined in guinea-pig and canine isolated myocardium by standard microelectrode techniques. 2. With use of patch clamp techniques, activity of ATP-sensitive K+ channels was recorded from open cell-attached patches of guinea-pig isolated ventricular myocytes. The probability of opening of the K+ channels was decreased by 2 mM tolbutamide and 20 microM glibenclamide to almost the same extent, whereas it was increased by 100 microM pinacidil. 3. In guinea-pig papillary muscles a marked shortening of the action potential produced by 100 microM pinacidil was completely antagonized by 2 mM tolbutamide or 20 microM glibenclamide. 4. In guinea-pig papillary muscles exposed to hypoxic, glucose-free solution or dinitrophenol (10 microM)-containing, glucose-free solution, APD declined gradually and twitch tension decreased. Pretreatment with glibenclamide partially but significantly inhibited the action potential shortening, whereas tolbutamide failed to improve it during hypoxia or metabolic blockade. 5. When in canine isolated myocardium, experimental ischaemia was produced by the cessation of coronary perfusion, APD was gradually shortened. The action potential shortening was partially but not completely inhibited by pretreatment with 20 microM glibenclamide. 6. These results suggest that changes in membrane current(s) other than the outward current through ATP-sensitive K+ channels also contribute to the action potential shortening in hypoxic or ischaemic myocardium.

Action Potentials↗
PubMed1991

[Establishment and characterization of endometrial undifferentiated carcinoma cell line (TMCC-2.U)].

We established new cell line designed TMCC-2.U, which suggested transformation to undifferentiated carcinoma, derived from endometrial clear cell carcinoma cell line (TMCC-2). The monolayer culture cell showed a pavement arrangement and spindle like shape. A rough-endoplasmic reticulum, mitochondria etc. are well developed. But cytoplasmic endocrine granulosa were so poorly, it suggests functional developments are poor. The TMCC-2.U cells were transplanted to nude mice which showed no typical pattern suggested undifferentiated carcinoma. Their chromosome number varied and the mode is 78. Marker chromosome were found frequency. Growth pattern and production of tumor marker are clearly differentiate from TMCC-2. As mensioned above, TMCC-2.U cell line will be very valuable in basic research on mechanism of transformation and effects of patient's serum on hystogenesity.

Adenocarcinoma↗
PubMed1990

Effects of N-acetylprocainamide and sotalol on ion currents in isolated guinea-pig ventricular myocytes.

The effects of N-acetylprocainamide (NAPA) and sotalol on membrane current systems of guinea-pig ventricular myocytes were examined and compared with those of quinidine using patch-clamp techniques. All of the drugs prolonged the action potential duration (i.e. Class III effect) in isolated guinea-pig papillary muscles. In isolated ventricular cells. NAPA (300 microM) and sotalol (100 microM) produced a decrease in the delayed outward potassium current (IK) concomitantly with a slight decrease in the calcium current (ICa), which was similar to quinidine (10 microM). NAPA also slightly depressed the inward rectifier potassium current (IKrect). Thus, NAPA and sotalol both inhibited IK, and this action appears to be mainly responsible for their Class III effect.

Acecainide↗