Biomedical subjects

K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 19 recordsLinked to original sources

PubMed1996

Relative selectivity for negative chronotropic and inotropic effects of a novel dihydropyridine derivative CD-832.

The effects of CD-832 [(4R)-(-)-2-(nicotinoyl-amino) ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate], a novel dihydropyridine derivative, on various guinea-pig myocardial preparations were compared with those of nifedipine, verapamil and diltiazem. CD-832 decreased the action potential duration of isolated papillary muscles without substantially affecting other parameters. In voltage-clamped single ventricular myocytes, CD-832 decreased the L-type Ca2+ current amplitude while having little effect on outward currents. CD-832 and other Ca2+ channel antagonists produced negative chronotropic effects in isolated right atrial preparations and negative inotropic effects in right ventricular papillary muscles, respectively, in a concentration-dependent manner. The potency order for the negative chronotropic effect was CD-832 > nifedipine > verapamil > diltiazem, while that for the negative inotropic effect was nifedipine > verapamil > or = CD-832 > diltiazem. The ratio, EC20 for negative inotropic effect divided by EC20 for negative chronotropic effect, which was considered to be an index of selectivity for negative chronotropic effect was highest for CD-832, the ratio for CD-832, nifedipine, verapamil and diltiazem being 5.4, 0.11, 0.25 and 0.37, respectively. These results indicate that CD-832 is an L-type Ca2+ channel antagonist with relative selectivity for a negative chronotropic effect rather than for a negative inotropic effect. This 'chrono-selective' cardiosuppressive effect of CD-832 could be of value in the treatment of cardiovascular diseases such as angina pectoris.

Action Potentials↗

PubMed1996

Developmental changes in action potential and membrane currents in fetal, neonatal and adult guinea-pig ventricular myocytes.

Developmental changes in electrophysiological properties were investigated in enzymatically isolated ventricular cardiomyocytes from fetal (45-55 days after conception), neonatal (1-5 days after birth) and adult (45-60 days after birth) guinea-pigs. Action potentials were elicited at 1 Hz in current-clamp mode, and membrane currents were measured using whole cell voltage clamp method. Action potential durations at 50% and 90% repolarization decreased between fetal and neonatal periods and increased between neonatal and adult periods, while there was no substantial age-related change in resting membrane potential and action potential overshoot. Because cell membrane capacitance increased with age, indicating a developmental increase in cell size, current density was normalized to membrane capacitance for each cell. The L-type calcium current (lCaL) density at 0 and + 10 mV was significantly smaller in fetal and neonatal cells than in adult ones, although the voltage dependence and inactivation kinetics were similar among the three age groups. The delayed rectifier K+ current (lK) density at 0 and + 30 mV was significantly smaller in fetal cells than in neonatal and adult ones. No significant difference in the inward rectifier K+ current (lK1) density was observed among the three age groups. Thus, the electrophysiological properties of the guinea-pig ventricular myocytes were demonstrated to change during pre- and postnatal development. The observed changes in action potential duration could be explained by changes in the balance between lK and lCaL.

Animals↗

PubMed1996

Effects of 8-(N-N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) on skinned myocardial fibres of the rat: reversible inhibition of calcium release from the sarcoplasmic reticulum.

The effects of 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-3), which is reported to inhibit the release of intracellularly stored Ca2+ in skeletal and smooth muscles, were examined in ventricular myocardia of the adult rat. In skinned papillary muscle fibres with functional sarcoplasmic reticulum (SR) preserved, application of 100 or 300 microM TMB-8 during the Ca2+ loading period had no significant effect on the peak tension of subsequent caffeine-induced contraction, but when applied during exposure to caffeine, concentration-dependent reduction of the peak tension was observed. At 1000 microM, TMB-8 reduced the peak tension of caffeine-induced contraction when applied either during Ca2+ loading or during exposure to caffeine. TMB-8 had no substantial influence on the Ca(2+)-tension of skinned fibres without functional SR. In isolated papillary muscle preparations, TMB-8 prolonged the action potential duration and decreased the maximum rate of rise of potential, leading to abolition of contraction at 100 microM. In conclusion, TMB-8 may be a useful pharmacological tool for inhibiting Ca2+ release from SR, but only in skinned myocardial preparations.

Action Potentials↗

PubMed1996

Positive inotropic and chronotropic effects of beraprost sodium, a stable analogue of prostacyclin, in isolated guinea pig myocardium.

1. Inotropic and chronotropic effects of beraprost sodium (beraprost), a chemically stable prostacyclin analogue, were examined in isolated myocardial preparations of guinea pigs. 2. In the left atria, 10(-9) - 10(-7) M beraprost had no significant effect on the contractile force, but 10(-6) and 10(-5) M produced a concentration-dependent positive inotropic response. This effect was antagonized by S-145, a potent and selective thromboxane A2 (TXA2) receptor antagonist, but not by propranolol. 3. Beraprost, from 10(-9) to 10(-5) M, had no significant inotropic effect in the right ventricular papillary muscles. 4. In the right atria, 10(-9) and 10(-8) M beraprost had no significant effect, but 10(-7) - 10(-5) M caused an increase in beating rate; this effect was not affected by S-145. 5. The present study demonstrates that beraprost has positive inotropic and chronotropic effects at high doses on isolated guinea pig atria. The inotropic effect may be mediated by the TXA2 receptor, but some mechanism other than the TXA2 receptor is responsible for the chronotropic effect.

Adrenergic beta-Antagonists↗

PubMed1996

Inhibitory effects of terfenadine on the rising phase of action potentials and sinus rates in isolated guinea-pig myocardium.

1. Effects of terfenadine on the ventricular action potential and sinus rate of isolated guinea-pig myocardial preparations were examined to elucidate whether the drug has any cardioinhibitory effect. 2. Terfenadine significantly and concentration dependently decreased the maximum rate of rise (Vmax) of action potentials, the decrease of which was 60% of the control value at 2 x 10(-5) M. 3. Terfenadine decreased the sinus rate concentration dependently at 10(-6) M and higher concentrations; in some preparations, spontaneous beating was abolished at 2 x 10(-5) M (sinus arrest). 4. On the other hand, KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6-11-dihydrodibenz[b, e]oxepin- 2-acetic acid hydrochloride), a new antiallergic drug having higher antiallergic potency than terfenadine, exerted a weaker inhibitory effect on the Vmax without affecting the sinus rate. 5. In conclusion, the antiallergic drug terfenadine has inhibitory effects on isolated myocardia. The cardioinhibitory effects of antiallergic drugs seem to be independent of their antiallergic potency.

Action Potentials↗

PubMed1996

Myocardial and vascular effects of efonidipine in vitro as compared with nifedipine, verapamil and diltiazem.

1. Effects of efonidipine on isolated myocardial and aortic preparations were compared with those of nifedipine, verapamil and diltiazem. 2. All drugs produced concentration-dependent negative chronotropic effects on isolated guinea-pig atrial preparations. The potency order was efonidipine > or = nifedipine > diltiazem > or = verapamil, EC30 values being 3.08 x 10(-8)M, 3.48 x 10(-8)M, 1.27 x 10(-7)M and 1.47 x 10(-7)M, respectively. 3. Nifedipine, verapamil and diltiazem produced concentration-dependent negative inotropic effects on isolated guinea-pig left atrial preparations. The potency order was nifedipine > verapamil > diltiazem, EC30 values being 4.94 x 10(-8)M, 1.49 x 10(-7)M and 8.03 x 10(-7)M, respectively. Efonidipine, even at 1 microM produced no inotropic effect: 10 microM efonidipine decreased the contractile force by about 20%. 4. All drugs concentration-dependently attenuated the KCl-induced contraction of isolated rat aortic ring preparation. The potency order was nifedipine > efonidipine > verapamil > diltiazem, EC30 values being 2.98 x 10(-9)M, 1.24 x 10(-8)M, 3.96 x 10(-8)M and 2.13 x 10(-7)M, respectively. 5. Thus, efonidipine was demonstrated to be a potent vasodilator with negative chronotropic but minimal negative inotropic activity, which may be of benefit in the treatment of cardiovascular disorders.

Animals↗

PubMed1996

Cardioprotective effects of NIP-121, a novel ATP-sensitive potassium channel opener, during ischemia and reperfusion in coronary perfused guinea pig myocardium.

We investigated the effect of NIP-121, a novel ATP-sensitive K+ channel opener, on myocardial damage during ischemia/reperfusion. The action potential and contractile force of coronary-perfused guinea pig right ventricular walls were recorded. The preparations were subjected to 30-min no-flow ischemia with or without NIP-121 or glibenclamide, followed by 60-min reperfusion. In untreated tissues, decreases in action potential duration (APD) and contractile force and an increase in resting tension were observed during the no-flow period. On reperfusion, transient arrhythmias were observed and resting or contractile force returned to <50% of preischemic values. NIP-121, at 0.3 microM, a concentration showing only a slight negative inotropic effect, caused a faster decrease in APD and contractile force but abolished the increase in resting tension (RT) during the no-flow period. On reperfusion, no arrhythmia was observed in NIP-121-treated preparations, and contractile force recovered to approximately 80% of the preischemic value. Glibenclamide 1 microM attenuated the decrease in APD but affected neither the decrease in contractile force nor the increase in RT during the no-flow period. On reperfusion, the incidence of arrhythmia was increased in glibenclamide-treated preparations, and the recovery of basal tension and contractile force was inhibited: Contractile force recovered to only approximately 15% of the preischemic value. NIP-121 was also shown to attenuate the decrease in tissue ATP during ischemia and reperfusion. We demonstrated that NIP-121 may have protective effects against myocardial injury during ischemia and reperfusion. Activation of ATP-sensitive K+ current may be an adaptive mechanism for cardioprotection under compromised blood flow.

Action Potentials↗

PubMed1996

Intracellular free Ca2+ movements in cultured cardiac myocytes as shown by rapid scanning confocal microscopy.

Two-dimensional images of intracellular free Ca2+ movements in cultured cardiac myocytes were obtained at 33-ms intervals with a Ca(2+)-sensitive fluorescence probe, fluo-3, and a rapid scanning confocal laser microscope, a prototype of Nikon RCM8000. The cells used were isolated from the ventricular myocardium of neonatal mice, cultured for approximately 72 h and loaded with fluo-3. One type of cytoplasmic Ca2+ movement observed was a simultaneous increase in [Ca2+] throughout the cytoplasm, termed a "spike"; another type was a local increase in [Ca2+] propagating in the cytoplasm, termed a "wave." Cells with either spike or wave or both types of movements were observed. Tetrodotoxin (TTX) 10(-5) M, nicardipine 10(-6) M, and increased extracellular potassium concentration (40 mM) selectively inhibited spike, and ryanodine 10(-6) M and cyclopiazonic acid (CPA) 3 x 10(-6) M selectively inhibited wave. These results indicate that spike was triggered by depolarization-induced Ca2+ influx across the sarcolemma, whereas wave was a propagating local increase in Ca2+ due to Ca2+ release from the sarcoplasmic reticulum (SR). On spike, nuclear [Ca2+] was shown to increase and decrease synchronously with cytoplasmic [Ca2+], with a delay and slower time course.

Aniline Compounds↗

PubMed1996

Bone SPET of symptomatic lumbar spondylolysis.

The aim of this study was to clarify the clinical role of bone single photon emission tomography (SPET) of the lumbar spine in young persons with persistent lumbar pain which might be due to spondylolysis. Thirty-one bone SPET studies were performed on 25 patients (19 males, 6 females) aged 7-26 years (average 15.6 years) who had suffered lumbar pain associated with physical activity, and who were suspected of having spondylolysis. Planar and SPET images of the lumbar spine were obtained 2-3 h following the injection of 99Tc(m)-methylene diphosphonate using a single-head rotating gamma camera. The findings on the bone scintigram were compared with those on the radiograph. Bone scintigraphy at presentation was positive in only 7 of 15 sites of the pars interarticularis defects demonstrated on plain radiographs. On the other hand, seven sites of the pars interarticularis which were normal on the radiograph were positive on bone SPET. As clinical symptoms improved after immobilization using a lumbar corset, bone SPET tended to revert towards normal. The planar image was abnormal in only 8 (42%) of the 19 abnormal sites on the SPET image. A bone SPET study is indicated in patients who are negative on radiological tests and who are still suspected of having spondylolysis. If SPET is positive in these patients, the increased bone uptake is most likely suggestive of a state of 'stress reaction', and may be a good indicator for patient management. If negative, further radiological examinations will be required for proper assessment of the origin of lumbar pain.

Adolescent↗

PubMed1996

[Developmental aspects of electrophysiology in cardiac muscle].

Electrical properties of the cardiac muscles drastically change with development. The changes in the current density of ionic currents of cardiomyocytes are inconsistent among species. In cultured embryonic chick ventricular myocytes, the developmental changes in the fast Na+ channel properties (3- to 17-day-old) are reviewed. The sensitivity to TTX, with a KD as high as 2 nM, remains unchanged. The limiting conductance (GNa) increased by 8-10-fold. The activation kinetics such as the steady-state activation (m infinity) and time constant of activation (tau m) remain unchanged. The voltage-dependence of inactivation kinetics such as the steady state inactivation (h infinity) and time constant (tau h) shift in the hyperpolarizing direction. The window conductance tends to be reduced. On the other hand, the L-type Ca2+ channel is important during the development of rat heart, and also the fe-type current (dihydropyridine-resistant) is important in the fetal stage. In chick embryo cardiomyocytes, the L-type channel exhibits long-lasting opening behavior. The behavior is gradually abolished during development, cAMP-dependent protein kinase enhances the Ca2+ channel current on and after the late fetal/embryonic stage. cGMP-dependent protein kinase markedly inhibits the Ca2+ channel current in the fetal/embryonic stage, compared with adult heart. These changes would play an important role for cardiac functions during development.

Animals↗

PubMed1996

[Developmental changes in the pacemaker current and membrane currents of the guinea pig myocardium].

The pacemaker current (I(f)) in embryonic chick ventricular myocytes is present, but decreases during development. beta-Adrenergic agonists stimulate I(f), whereas muscarinic cholinergic agonists inhibit I(f) and reverse beta-adrenoceptor stimulation. G-proteins directly and indirectly couple autonomic receptors to I(f) channels in embryonic ventricular cells. The I(f) may contribute partly to the electrogenesis of the pacemaker potential. On the other hand, Ito current, voltage-dependent and 4-AP-sensitive, exists even in young embryonic cardiomyocytes, but not in all cells. The Ito increases during development, resulting in modulation of the action potential configuration. The action potential duration of guinea pig ventricular myocardium decreases during the late fetal period and increases postnatally. Single cell voltage clamp analyses revealed that the decrease and increase in action potential duration are due to developmental increases in the current densities of the calcium current and delayed rectifier potassium current, respectively. The role of the sarcoplasmic reticulum in contraction and relaxation of the guinea pig myocardium increases during fetal development.

Action Potentials↗

PubMed1996

Restricted propagation of cytoplasmic Ca2+ oscillation into the nucleus in guinea pig cardiac myocytes as revealed by rapid scanning confocal microscopy and indo-1.

Two-dimensional images of cytoplasmic and nuclear free Ca2+ movements in cardiac myocytes were obtained at 67-msec intervals using a Ca(2+)-sensitive fluorescence probe, indo-1, and a rapid scanning confocal laser microscope, Nikon RCM8000. Isolated guinea pig ventricular cells were loaded with indo-1 and stimulated at 0.5 Hz through patch pipettes. On stimulation, nuclear Ca2+ concentration ([Ca2+]) was observed to rise and fall following cytoplasmic [Ca2+] with an obvious delay. Application of isoproterenol significantly increased the peak [Ca2+] on stimulation in both the cytoplasm and nucleus with no substantial change in the basal [Ca2+]; the increase in peak [Ca2+] produced by application of isoproterenol was larger in the cytoplasm than in the nucleus. Under a low [Na+] condition, the basal [Ca2+] was increased from the control values in both the cytoplasm and nucleus; no difference in basal [Ca2+] was observed between the two regions. The increase in peak [Ca2+] by low [Na+] in the cytoplasm was significantly larger than that in the nucleus. When the cells were voltage clamped at 0 mV for 3 sec, no difference in the steady state [Ca2+] was observed between the cytoplasm and nucleus. Nuclear [Ca2+] was also observed to increase following a Ca2+ wave, a local increase in [Ca2+] propagating within the cytoplasm, with a delay. Thus, we demonstrated in isolated myocardial cells that cytoplasmic Ca2+ movements, although hampered by the nuclear envelope, are propagated into the nucleus, a mechanism through which factors affecting cytoplasmic Ca2+ may influence intranuclear events.

Animals↗

PubMed1996

Use of chloride blockers: a novel approach for cardioprotection against ischemia-reperfusion damage.

We examined whether the chloride channel blockers anthracene-9-carboxylic acid (9-AC) and 4-acetamide-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) exert protective effects against myocardial ischemia-reperfusion damage. In isolated guinea pig ventricular cells, 9-AC (200 microM), but not SITS (100 microM), inhibited the chloride current induced by isoproterenol. Electrical and mechanical activities and intracellular pH of arterially perfused guinea pig right ventricular preparations were recorded with an intracellular microelectrode, a force transducer and a pH-sensitive fluorescent probe, respectively. The preparations were subjected to 30 min of no-flow ischemia, with or without 9-AC (100 microM) or SITS (10 microM), followed by reperfusion. No-flow ischemia produced decreases in action potential amplitude and duration, and the contractile force was completely abolished. Although the changes in electrical parameters were reversed upon reperfusion, the contractile force recovered only to about 50% of preischemic values. 9-AC and SITS had no inhibitory effect on contractile force under normal conditions and during ischemia but significantly improved the recovery of contractile force upon reperfusion to about 80% of preischemic values. Both 9-AC and SITS showed significant inhibition of the ischemia-induced abbreviation of action potential duration. Other parameters were not affected by 9-AC or SITS. During ischemia, intracellular pH showed a transient small increase followed by a sustained decrease, which was completely recovered upon reperfusion. The decrease in pH during ischemia was attenuated by 80% in SITS- but not 9-AC-treated preparations. Thus, we demonstrated that the chloride channel blockers 9-AC and SITS, which have no cardiosuppressive effects, exert protective effects against myocardial ischemia-reperfusion damage.

Action Potentials↗

PubMed1996

[Confocal laser scanning microscopy for the study of membrane transporter proteins].

Confocal laser scanning microscopy, in combination with fluorescent probes including fluorescence labelled antibodies, enables us to obtain optical sectioning images of fixed and living biological samples. It is a powerful method for studies of membrane transporter proteins in that it provides information on the spatial distribution of not only the transporter proteins themselves, but also the molecules and ions they transport. In the near future, it may also provide information on molecular interaction between and conformation changes of various proteins with the aid of new type of fluorescent probes which utilize the fluorescence resonance energy transfer phenomenon.

Animals↗

PubMed1995

Chronotropic and inotropic effects of histamine in developing chick heart: differential mechanisms before and after hatching.

Chronotropic and inotropic effects of histamine were examined in isolated atrial and ventricular preparations from embryonic and hatched chicken hearts. Histamine produced positive chronotropic and inotropic responses both in embryonic and hatched hearts. The responses to histamine in middle embryonic myocardia, which were observed in the micromolar range, were antagonized by H2 antagonists but not by H1, H3 antagonists and propranolol. Isobutyl-methylxantine, an inhibitor of phosphodiesterase, produced a leftward shift of the concentration-response curve for the chronotropic effect of histamine in the embryo. The responses to histamine in myocardia from hatched chicks, which were observed in the milimolar range, appeared concurrently with the responses to tyramine during development and were antagonized by beta adrenoceptor antagonists but not by any of the histamine antagonists. The positive inotropic response to histamine in hatched ventricular preparations were greatly attenuated by reserpine pretreatment or in the presence of desipramine. Thus, we demonstrated that exogenously applied histamine produces positive chronotropic and inotropic responses in developing chicken hearts and that the mechanisms are different between embryonic and hatched chicks: direct action on H2 receptors in the embryonic heart and release of norepinephrine from sympathetic nerve terminals in hatched hearts.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Difference in excitation-contraction mechanisms between atrial and ventricular myocardia of hatched chicks.

1. Effects of inotropic interventions on contractile force were examined in isolated atrial and ventricular preparations from hatched chicks. 2. The duration of twitch contractions were briefer in the atria than in the ventricle. 3. No difference in the extracellular Ca(2+)-contractile force curve was observed between atrial and ventricular preparations. 4. The sensitivity to nicardipine was higher in the ventricular preparations than in atrial preparations while that to ryanodine was higher in atrial preparations. 5. The magnitude of post-rest contraction was larger than the basal contractile force in atrial preparations, while it was smaller than the basal contractile force in ventricular preparations. 6. These results suggested that the atrial myocardium of hatched chick was more dependent on sarcoplasmic reticulum function than its ventricular myocardium, which is similar to the case with mammalian species.

Animals↗

PubMed1995

Myocardial action potential prolongation by calcium channel activation under calcium free-EGTA condition in rats: developmental and regional variations.

1. Prolongation of action potentials upon the addition of isoproterenol, forskolin, isobutylmethyl-xanthine (IBMX) and dibutyril cAMP (dbcAMP) under Ca-free EGTA condition was examined in isolated myocardial preparations from neonatal and adult rats, whose action potential configuration greatly differ. 2. The prolongation of the action potential was previously suggested to be produced by persistent sodium influx through calcium channel due to the lack of calcium-mediated inactivation of calcium channels under such experimental condition. 3. Preparations used were papillary muscles and free walls of the right and left ventricles from neonatal and adult rats. 4. In adult preparations, the prolongation produced by isoproterenol, forskolin and IBMX in the right free wall was smaller than those in the other three regions, while no regional difference was observed with dbcAMP. 5. The degree of prolongation by all of the four drugs were smaller in the neonate than in the adult. No regional difference was observed with any of the drugs in the neonate. 6. Our present results suggest that contribution of calcium-mediated inactivation of calcium channels to the repolarization of rat myocardium may increase postnatally to produce the developmental shortening of its action potential. Also, regional difference in the cAMP related mechanisms may appear postnatally.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Cardiovascular selectivity of 1,4-dihydropyridine derivatives, efonidipine (NZ-105), nicardipine and structure related compounds in isolated guinea-pig tissues.

1. The cardiovascular selectivities of 1,4-dihydropyridine derivatives, efonidipine (NZ-105), nicardipine, 3NZ5NIC (the drug with NZ-105-type side-chain at C3 position and nicardipine-type at C5) and 3NIC5NZ (the drug with nicardipine-type side chain at C3 and NZ-105-type at C5) were studied in vitro. 2. All four compounds caused relaxation of guinea-pig aortae precontracted with a high K+. The pEC50 values were 7.5, 8.3, 8.1 and 5.6, for NZ-105, nicardipine, 3NIC5NZ and 3NZ5NIC, respectively. The relaxation produced by NZ-105 was slower in onset than those produced by the other compounds. The rate constant K(hr-1) of the relaxations were 0.59, 1.31, 1.02 and 1.24, for NZ-105, nicardipine, 3NIC5NZ and 3NZ5NIC, respectively. 3. In the electrically paced guinea-pig papillary muscles, NZ-105, 3NIC5NZ and 3NZ5NIC, even at concentrations as high as 10(-6) M, slightly decreased the contractile force (by 44.9 +/- 7.1%, 58.6 +/- 5.4% and 52.2 +/- 3.9%, respectively), whereas 10(-6) M nicardipine decreased the force by 84.9 +/- 3.3%. The negative inotropic effect of NZ-105 and 3NIC5NZ, but not that of 3NZ5NIC or nicardipine, was over 10 times weaker than their vasorelaxant effect. 4. In the guinea-pig right atria, NZ-105 and nicardipine at 10(-8) M decreased the spontaneous contraction rate by 67.9 +/- 15.0% and 39.7 +/- 15.4%, respectively. 3NIC5NZ at 3 x 10(-9) M and 3NZ5NIC at 3 x 10(-8) M had little effect on the rate, whereas 10(-8) M 3NIC5NZ and 10(-7) M 3NZ5NIC arrested the beating within 3 hr after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗