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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

Effects of nicorandil on the recovery of reflex potentials after spinal cord ischaemia in cats.

1. The pathophysiological significance of ATP-sensitive K+ (KATP) channels in the central nervous system is not fully understood. In this study the effects of nicorandil (a hybrid vasodilator having a dual mechanism of action as a K+ channel opener and a nitrate) on the recovery of the spinal cord reflex potentials after spinal cord ischaemia were examined and compared with those of pinacidil and nitroprusside in anaesthetized spinal cats. 2. Spinal cord ischaemia was produced by occlusion of the thoracic aorta and the bilateral internal mammary arteries for 10 min. Regional blood flow in the spinal cord was continuously measured with a laser-Doppler flow meter. The monosynaptic (MSR) and polysynaptic reflex (PSR) potentials, elicited by electrical stimulation of the tibial nerve, were recorded from the lumbo-sacral ventral root. The recovery process of spinal reflex potentials was reproducible when the occlusion was repeated twice at an interval of 120 min. 3. Pretreatment with nicorandil (30-100 micrograms kg-1) accelerated the recovery of PSR potentials after spinal cord ischaemia. Such an accelerating effect on the recovery of PSR potentials was also shared by pinacidil (100 micrograms kg-1), another K+ channel opener. In addition, the accelerating effect of nicorandil (100 micrograms kg-1) on the recovery of PSR potentials was abolished by co-administration of glibenclamide (3 mg kg-1), a sulphonylurea KATP channel blocker. Nitroprusside (8 micrograms kg-1min-1) retarded rather than improved the recovery of PSR potentials after spinal cord ischaemia. All of these drugs failed to improve the spinal cord blood flow during ischaemia and reperfusion. 4 These results suggest that nicorandil promotes the recovery of polysynaptic reflex potentials after spinal cord ischaemia by opening the KATP channels of neurones rather than by increasing local bloodflow. K+ channel openers may exert a salutary effect on the functional recovery of the ischaemic spinal cord.

Animals↗
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↗
PubMed1995

Effects of GABAergic drugs on the recovery of reflex potentials after spinal cord ischemia in cats.

Effects of GABAergic drugs on the recovery of reflex potentials after spinal cord ischemia were examined in anesthethized spinal cats. Monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials, elicited by electrical stimulation of the tibial nerve in spinal cats, were recorded from the lumbo-sacral ventral root. The spinal reflex potentials were immediately depressed by occlusion of the thoracic aorta and the bilateral mammary arteries for 10 min. The potentials recovered gradually to the control level within 90 min after reperfusion. Pretreatment with bicuculline (0.3 mg/kg, i.v.), a GABA antagonist, or semicarbazide (200 mg/kg, i.v.), an inhibitor of GABA synthesis, accelerated the recovery of PSR potentials after the removal of the arterial occlusion. In contrast, pretreatment with aminooxyacetic acid (10 mg/kg, i.v.), an inhibitor of GABA degradation, retarded the recovery of PSR potentials, and this effect was overcome by the addition of the opioid antagonist naloxone (10 mg/kg, i.v.). These results suggest that the GABAergic system retards the recovery of PSR potentials after a brief spinal cord ischemia, which can be antagonized by naloxone.

Animals↗
PubMed1994

Depressed responsiveness to angiotensin II in ventricular myocytes of hypertrophic cardiomyopathic Syrian hamster.

Electromechanical responsiveness to angiotensin II (Ang II) receptor stimulation in ventricular myocardium and myocytes of hypertrophic cardiomyopathic Syrian hamsters (BIO 14.6) was examined and compared with that in preparations of normal hamsters (F1B) using conventional microelectrode and patch clamp techniques. Action potential duration (APD) and developed tension (DT) corrected for the cross-sectional area of the papillary muscles of 14-20 week-old BIO 14.6 hamsters were significantly smaller than those in preparations of age-matched normal hamsters. An Ang II (1 microM)-induced increase in DT in BIO 14.6 papillary muscles (24.7 +/- 11.0%) was significantly smaller than that in F1B papillary muscles (53.8 +/- 8.5%), which was associated with a smaller increase in APD in BIO 14.6 papillary muscles. In ventricular myocytes of both BIO 14.6 and F1B hamsters. Ang II increased the calcium current (ICa) following a transient decrease in ICa. However, the magnitude of the Ang II-induced increase in ICa in BIO 14.6 myocytes (35.5 +/- 7.5%) was significantly smaller than that in F1B myocytes (86.0 +/- 19.7%), suggesting a causal relationship between ICa and mechanical response to Ang II in these hamsters. The depressed responsiveness to Ang II receptor stimulation in hypertrophic cardiomyopathic hamster is in a marked contrast with the enhanced responsiveness to alpha 1-adrenergic stimulation, which was demonstrated by previous studies, and may be one of adaptational changes to the activated renin-angiotensin system in the cardiomyopathy.

Action Potentials↗
PubMed1994

Enhancement of the positive inotropic effect mediated by alpha 1-adrenoceptors in pertussis toxin-treated rabbit papillary muscles.

1. In rabbit papillary muscles, pretreatment with pertussis toxin (PTX) significantly increased the positive inotropic response to isoprenaline and abolished the inhibitory action of carbachol on the isoprenaline response. 2. Phenylephrine in the presence of propranolol produced a positive inotropic effect and prolonged action potential duration through activation of alpha 1-adrenoceptors. Both of the effects of phenylephrine were significantly enhanced by PTX pretreatment. 3. Accumulation of [3H]inositol monophosphate (IP1) in papillary muscles prelabeled with myo-[3H]inositol was increased by phenylephrine in a concentration-dependent manner, which was antagonized by prazosin. Although PTX pretreatment significantly elevated the basal level of [3H]IP1 formation, the phenylephrine-induced increase in [3H]IP1 formation was unaffected. 4. It is concluded that the cardiac responses to alpha 1-adrenoceptor stimulation studied in these experiments are not transduced by a PTX sensitive G protein (Gi). However, the positive inotropic effect and prolongation of action potential duration mediated by alpha 1-adrenoceptor may be negatively regulated by Gi.

Action Potentials↗
PubMed1994

Beta 1 adrenoceptor mediated decrease in pHi in quiescent ventricular myocardium.

OBJECTIVE: The aims were to examine the effect of beta adrenergic stimulation on the intracellular pH (pHi) and to compare it with that of alpha adrenergic stimulation in ventricular myocardium. METHODS: Using conventional and ion selective electrodes membrane potential and pHi were measured simultaneously in quiescent papillary muscles of guinea pigs in HEPES or bicarbonate buffered solution. Isoprenaline and propranolol (1 microM) plus phenylephrine (30 microM) were used to stimulate beta and alpha adrenoceptors, respectively. In order to evaluate underlying mechanism(s) of beta adrenoceptor mediated pHi change, effects of Na(+)-H+ exchange, Cl(-)-HCO3- exchange, Na(+)-HCO3- symport, and glycolysis blockers on the pHi change were examined. RESULTS: Isoprenaline (1 microM) produced a decrease in pHi of 0.08(SEM 0.01) pH units and a transient depolarisation of the resting membrane. The isoprenaline induced intracellular acidosis was blocked by the beta 1 blocker atenolol (10 microM) but not by the beta 2 blocker ICI 118,551 (0.1 microM). Forskolin also produced a decrease in pHi of 0.06(0.03) pH units. In contrast, alpha adrenergic stimulation produced an increase in pHi, which was abolished by 1 mM amiloride, an Na(+)-H+ exchange blocker. In the presence of amiloride, the isoprenaline induced decrease in pHi was rather enhanced. 4,4'-Diisothiocyanostilbene-2,2'-disulphonic acid (DIDS, 1 mM), a blocker of Cl(-)-HCO3- exchange and the Na(+)-HCO3- symport system, failed to affect the isoprenaline induced pHi decrease in bicarbonate buffered solution. However, pretreatment with 2-deoxyglucose or iodoacetic acid abolished the isoprenaline induced pHi decrease. CONCLUSIONS: beta 1 Adrenoceptor stimulation causes intracellular acidosis via the enhanced glycolysis, and the Na(+)-H+ exchange system appears to play a compensatory role. The beta 1 adrenoceptor mediated intracellular acidosis may modulate inotropic response to adrenergic stimulation in ventricular myocardium.

Adrenergic beta-Antagonists↗
PubMed1994

The effects of ketamine on conduction velocity and maximum rate of rise of action potential upstroke in guinea pig papillary muscles: comparison with quinidine.

Using standard microelectrode techniques, the effects of ketamine on the maximum rate of rise of action potential upstroke (Vmax) and the conduction velocity were examined and compared with the effects of quinidine, a sodium channel blocker, in isolated guinea pig papillary muscles. Both ketamine and quinidine decreased Vmax and the square of the conduction velocity in a concentration-dependent manner. The conduction slowing paralleled the decreases in Vmax, suggesting that the sodium current inhibition produced by these drugs is responsible for the conduction slowing. In the presence of quinidine, a train of stimulation after a quiescent period produced an exponential decline in Vmax, and the decrease in Vmax was enhanced by increasing stimulation frequency (i.e., use-dependent block). Ketamine significantly depressed Vmax of the first action potential after a long quiescent period (tonic block), and failed to produce a further decrease in Vmax during the subsequent train of stimulation. The decrease in Vmax was enhanced by simultaneous administration of ketamine and quinidine. Thus, ketamine decreases conduction velocity by inhibiting the sodium current. The mode of action on cardiac conduction is similar to that of quinidine, but different from that of volatile anesthetics which produce conduction slowing by impairing cell-to-cell coupling. However, ketamine produces a tonic block of the sodium channel while quinidine produces a use-dependent block. We conclude that ketamine should be administered with caution to patients receiving Class I antiarrhythmic drugs.

Action Potentials↗
PubMed1993

Membrane currents of porcine granulosa cells in primary culture: characterization and effects of luteinizing hormone.

In ovarian granulosa cells, LH depolarizes the membrane potential and induces steroid production. The membrane currents of porcine granulosa cells in primary culture were studied by means of the whole cell configuration of the patch-clamp technique to investigate whether the ionic channels are involved in the effects of LH. We identified and characterized two types of K+ currents--a transient outward current (Ito) and a delayed rectifier K+ current (IK)--and one Ca2+ current (ICa). Ito and IK were voltage- and calcium-dependent. Both currents were blocked by 4-aminopyridine, a K+ channel blocker, but only IK was sensitive to tetraethylammonium, another K+ channel blocker. ICa was inactivated within 50 ms of the test pulse. Nifedipine and verapamil, L-type CA2+ channel blockers, did not suppress ICa even at a concentration of 10 microM. Tetramethrin (1 microM), a T-type Ca2+ channel blocker, decreased ICa by 38.4 +/- 5.6% (n = 3). These findings suggest that the current may be a T-type Ca2+ current. LH and dibutyryl cAMP, potent stimulants of steroid production, attenuated Ito only by 13.9 +/- 1.8% (n = 7) and 21.0 +/- 1.5% (n = 4), respectively. However, they did not affect IK and ICa. These results indicated that LH does not modulate CA2+ current directly, but it slightly decreased Ito through cAMP elevation. The LH-induced inhibition of Ito may be involved in the depolarizing effect of LH and may play some role in steroid secretion or other functions in granulosa cells.

4-Aminopyridine↗
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

Induction by endogenous noradrenaline of an alpha 1-adrenoceptor-mediated positive inotropic effect in rabbit papillary muscles.

1. The possible involvement of alpha 1-adrenoceptors in the inotropic and electrophysiological responses to endogenous noradrenaline released by tyramine was examined in rabbit papillary muscles. 2. A concentration-dependent positive inotropic effect was produced by tyramine. This effect of tyramine was not observed in muscles from rabbits pretreated with reserpine. 3. The positive inotropic effect of tyramine was greatly inhibited by propranolol, but not altered by prazosin. However, when beta-adrenoceptors were blocked by pretreatment with propranolol, tyramine still produced a positive inotropic effect, an effect which was antagonized by prazosin. 4. Tyramine caused a decrease in action potential duration (APD) and an increase in action potential amplitude in a concentration-dependent manner. Isoprenaline also produced the same electrophysiological effects. These electrophysiological effects of both agents were inhibited by propranolol. 5. When beta-adrenoceptors were blocked by propranolol, the observed prazosin-sensitive positive inotropic effect of tyramine was not accompanied by any change in APD. In contrast, APD was markedly prolonged by alpha 1-adrenoceptor stimulation with phenylephrine in the presence of propranolol, in association with the positive inotropic effect. 6. It is concluded that in rabbit papillary muscles, endogenous noradrenaline causes a positive inotropic effect predominantly mediated by beta-adrenoceptors, but can still evoke a positive inotropic effect through alpha 1-adrenoceptors when beta-adrenoceptor stimulation is eliminated. This suggests that the alpha 1-adrenoceptor-mediated positive intropic mechanism(s) may be masked by simultaneous activation of beta-adrenoceptors. In addition, this study indicates that APD prolongation is not involved in the alpha 1-adrenoceptor-mediated inotropic responses to endogenous noradrenaline.

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↗