Noritsugu Tohse

Sapporo Medical University, Sapporo, Hokkaido, Japan

Are you Noritsugu Tohse?

Claim your profile

Publications (92)284.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: There were several reports suggesting α-adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of α-adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved. Method: We used 130 male Sprague-Dawley rats. After root constriction, rats received three local injections of α-adrenoceptor antagonists around DRG. We administered the non-selective α-adrenoceptor antagonist phentolamine for 3 consecutive days from day 0, 4 or 11 after the surgery, and the α1 -adrenoceptor antagonist prazosin, the α1 -adrenoceptor antagonist silodosin, the more preferred α1 -adrenoceptor than prazosin and the α2 -adrenoceptor antagonist yohimbine for 3 consecutive days from day 0 after the surgery. Results: Phentolamine and yohimbine continually attenuated pain behaviour. Prazosin at high dose attenuated pain behaviour, however, prazosin at low dose did not attenuate pain behaviour every experimental day. Silodosin had no analgesic effect. Phentolamine injections from day 4 after surgery attenuated pain behaviour that had been established on the 3rd experimental day until the 28th post-operative day, although effect of phentolamine wore off. Phentolamine injections from day 11 after surgery temporarily attenuated pain behaviour that had been established on the 3rd, 7th and 10th experimental days. Conclusions: This study showed α-adrenoceptor antagonists could suppress pain behaviour via α2 -adrenoceptor in acute phase and temporary attenuate pain behaviour in chronic phase. These findings presented potentials sympathetic nerve blockade contributed to treat neuropathic pain.
    No preview · Article · Oct 2015 · European journal of pain (London, England)
  • [Show abstract] [Hide abstract]
    ABSTRACT: Study Design. Animal experimental study with interventionObjective. We investigated whether sympathectomy and pharmacological sympathetic blockade reduced pain behavior and reversed adrenoceptor mRNA expression of the dorsal root ganglion (DRG) in a lumbar radiculopathy model. The abnormal sympathetic-somatosensory interaction may underlie some forms of neuropathic pain. There are several reports sympathectomy and pharmacological sympathetic blockade are often effective to treat neuropathic pain. However its pathophysiological mechanisms remain obscure. We used 91 male Sprague-Dawley rats. Just after root constriction (RC), the rats underwent sympathectomy or received three local injections of subtype-specific α-adrenergic receptor antagonists around the DRG. We evaluated the analgesic effects of sympathectomy and sympathetic blockade using behaviors indicative mechanical allodynia and thermal hyperalgesia. We estimated the mRNA expression levels of the DRG adrenoceptor subtypes using real time reverse transcription polymerase chain reaction (RT-PCR). Sympathectomy and α2-antagonist significantly reduced the mechanical allodynia and thermal hyperalgesia following RC. Real time RT-PCR analysis indicated that sympathectomy possibly reversed α2A- and α2B-adrenoceptors mRNA overexpression in the DRG following RC. We considered that pain behavior of neuropathic pain are due, at least in part, to enhanced sympathetic noradrenergic transmission within the DRG. Suppression of sympathetic activity by reducing adrenergic release, α2-adrenoceptor stimulation, and/or α2-adrenoceptor upregulation in the DRG may relieve neuropathic pain.
    No preview · Article · Jul 2015 · Spine
  • Source

    Preview · Article · Jan 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Lumbar radicular pain is categorized as a type of neuropathic pain, but its pathophysiological mechanisms are not fully understood. The substantia gelatinosa (SG) in the spinal cord dorsal horn receives primary afferent inputs and is considered to be a therapeutic target for treating neuropathic pain. In vivo patch-clamp recording is a useful procedure for analyzing the functional properties of synaptic transmission in SG neurons. Transient receptor potential ankyrin 1 (TRPA1) has been widely identified in the central and peripheral nervous systems, such as in the peripheral nociceptor, dorsal root ganglion, and spinal cord dorsal horn and is involved in synaptic transmission of pain. However, its functional role and mechanism of pain transmission in the spinal cord dorsal horn are not well understood. The purpose of this study was to use in vivo patch-clamp analysis to examine changes in the excitatory synaptic transmission of SG neurons treated with TRPA1 antagonist and to clarify the potential role of TRPA1 in the rat spinal cord dorsal horn. Results The rats with root constriction (RC) showed mechanical hypersensitivity, hyperalgesia, and thermal hyperalgesia. In addition, pin pricks elicited pain-related behavior even in the sham and naïve rats. These pain-related behaviors were significantly attenuated by intrathecal injection of a TRPA1 antagonist. The degrees of intrathecal injection efficacy were equivalent among the 3 groups (RC, sham, and naïve groups). In an electrophysiological study, the frequencies and amplitudes of excitatory postsynaptic currents (EPSCs) were significantly increased in the RC rats compared with those in the sham and naïve rats. Spontaneous EPSCs and evoked-EPSCs by non-noxious and noxious stimuli were significantly decreased by TRPA1 antagonist. As in the behavioral study, there were no statistically significant differences among the 3 groups. Conclusion These data showed that the TRPA1 antagonist had an inhibitory effect on mechanical hypersensitivity and hyperalgesia as well as on physiological pain transmission in the spinal cord dorsal horn. This suggests that TRPA1 is consistently involved in excitatory synaptic transmission even in the physiological state and has a role in coordinating pain transmission.
    Full-text · Article · Sep 2014 · Molecular Pain
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims: We examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Methods: Subendocardial myocytes (END) and subepicardial myocytes (EPI) were isolated from left ventricles of OLETF, a rat model of T2DM, and LETO, non-diabetic control. END and EPI were used for whole-cell patch-clamp recordings and for protein and mRNA analyses. Results: Action potential durations (APDs) in END and EPI were longer in OLETF than in LETO, and the difference was larger in END. Steady-state transient outward K(+) current (Ito) density was reduced in END, but not in EPI, of OLETF compared with those in LETO, though contribution of the fast component of Ito current recovery from inactivation was smaller in both END and EPI of OLETF than in those of LETO. Kv4.2 protein was reduced only in END in OLETF, though KChIP2 protein levels in both END and EPI were lower in OLETF than in LETO. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO. The mRNA level of iroquois homeobox 5 (Irx5) in END was 53% higher in OLETF than in LETO. Densities of inward rectifier K(+) current and L-type Ca(2+) current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO. Conclusion: T2DM induces subendocardium-predominant prolongation of APD via reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Irx5 expression may underlie Kv4.2 downregulation in T2DM.
    Full-text · Article · Jan 2014 · AJP Heart and Circulatory Physiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to elucidate the influence of sympathetic nerves on lumbar radiculopathy, we investigated whether sympathectomy attenuated pain behaviour and altered the electrical properties of the dorsal root ganglion (DRG) neurons in a rat model of lumbar root constriction. Sprague-Dawley rats were divided into three experimental groups. In the root constriction group, the left L5 spinal nerve root was ligated proximal to the DRG as a lumbar radiculopathy model. In the root constriction + sympathectomy group, sympathectomy was performed after the root constriction procedure. In the control group, no procedures were performed. In order to evaluate the pain relief effect of sympathectomy, behavioural analysis using mechanical and thermal stimulation was performed. In order to evaluate the excitability of the DRG neurons, we recorded action potentials of the isolated single DRG neuron by the whole-cell patch-clamp method. In behavioural analysis, sympathectomy attenuated the mechanical allodynia and thermal hyperalgesia caused by lumbar root constriction. In electrophysiological analysis, single isolated DRG neurons with root constriction exhibited lower threshold current, more depolarised resting membrane potential, prolonged action potential duration, and more depolarisation frequency. These hyperexcitable alterations caused by root constriction were significantly attenuated in rats treated with surgical sympathectomy. The present results suggest that sympathectomy attenuates lumbar radicular pain resulting from root constriction by altering the electrical property of the DRG neuron itself. Thus, the sympathetic nervous system was closely associated with lumbar radicular pain, and suppressing the activity of the sympathetic nervous system may therefore lead to pain relief.
    Full-text · Article · Sep 2012
  • Source

    Preview · Article · Jan 2012 · Biophysical Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although many researchers have tried to observe the beginning of the heartbeat, no study has shown the beginning of the calcium transient. Here, we evaluate the beginning of the calcium transient in the Wistar rat heart. We first tried to reveal when the heart of the Wistar rat begins to contract because no previous study has evaluated the beginning of the heartbeat in Wistar rats. Observation of embryos transferred to a small incubator mounted on a microscope revealed that the heart primordium, the so-called cardiac crescent, began to contract at embryonic day 9.99-10.13. Observation of embryos loaded with fluo-3 AM revealed that the beginning of the calcium transient precedes the initiation of contraction which precedes the appearance of the linear heart tube. Nifedipine (1 μM), but not ryanodine (1 μM), abolished the calcium transients. These results indicate that calcium transients in the early embryonic period involve exclusively calcium entry through L-type calcium channels in contrast to the situation in mature hearts. This study provides the first demonstration of the relationship between morphological changes in the heart primordium and the beginning of the calcium transient and contraction.
    No preview · Article · Mar 2011 · The Journal of Physiological Sciences
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Postganglionic neurons in the sympathetic nervous system reportedly are involved in lumbar radicular pain and release norepinephrine (NE), a neurotransmitter. Increased numbers of sympathetic nerve fibers have been found in dorsal root ganglion (DRG) neurons in a root constriction model. Whether this is a reasonable model for pain, however, is unclear We asked whether: (1) painful behaviors occurred in the root constriction model; (2) NE enhanced the excitability of DRG neurons in the root constriction model; and (3) which adrenoceptors were related to the mediation of the NE effects. The L5 root was sutured proximal to the DRG as the root constriction model. Behavioral tests were performed until 28 days after surgery. At 10 to 14 days after the root constriction, DRG neurons were quickly excised and digested with collagenase for electrophysiologic studies. Action potentials were recorded from single DRG neurons using a whole-cell patch clamp technique. NE (10 μmol/L) was directly applied to the DRG neurons. The adrenergic sensitivity was examined in combination with antagonists. The rats with root constriction exhibited painful behavior. NE increased the excitability of DRG neurons in the root constriction model. The effects of NE were inhibited by pretreatment with an α-antagonist and α(2)-antagonist but not an α(1)-antagonist. Our observations suggest NE plays an important role in generating lumbar radicular pain mainly via α(2)-adrenoceptors. An α(2)-antagonist may be an appropriate agent for trials to treat lumbar radicular pain.
    Full-text · Article · Feb 2011 · Clinical Orthopaedics and Related Research
  • Tatsuya Sato · Takeshi Kobayashi · Tetsuji Miura · Noritsugu Tohse
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Although cardiac ion channel remodeling has been reported in type 1 diabetes mellitus (T1DM), modification of the channels by type 2 DM (T2DM) is poorly understood. Here we characterized ion channel properties in cardiomyocytes of OLETF, a rat model of obese T2DM. Methods and Results: We isolated myocytes from subepicardial (EPI) and subendocardial (END) regions of the left ventricle for whole-cell patch clamp experiments. Action potential duration at 50% repolarization (APD50) at 1 Hz was significantly longer in OLETF than in non-diabetic control (LETO) (EPI; 8.89±1.04 vs. 5.20±0.75 ms, END; 22.01±3.64 vs. 9.89±1.74 ms). In both EPI and END, L-type Ca2+ current and inward rectifier K+ current were similar between OLETF and LETO. In EPI, transient outward K+ current (Ito) density at 0.1 Hz was similar. However, the fast recovering component from inactivation of Ito was significantly decreased in OLETF. In END, Ito density at 0.1 Hz was significantly reduced in OLETF (8.77±0.78 vs. 14.50±1.31 pA/pF at +60 mV), in addition to slower recovery of Ito. Membrane capacitances were similar in all groups. Conclusions: T2DM slowed Ito recovery form inactivation and decreased END-Ito density without cardiomyocyte hypertrophy. This regional difference in the effect on Ito has not been reported for T1DM and appears characteristic to T2DM.
    No preview · Article · Jan 2011 · Journal of Arrhythmia
  • Sachiko Maeda · Takeshi Kobayashi · Noritsugu Tohse
    [Show abstract] [Hide abstract]
    ABSTRACT: We recently reported that the heart-beat in rat embryo initiated between E9.99 and E10.13 using CCD camera system, and also L-type Ca2+ channel (Cav1.2, Cavβ2), Na+/Ca2+ exchanger (NCX1), and voltage-gated K+ channels (ERG1, MiRP1) contribute to action potential (AP) configuration in the period of heart-beat initiation in the early rat embryo. Furthermore, we found that the Ca2+ transient firstly began a part of cardiac crescent, then the contraction starts about several minutes late (Kobayashi, et al. J Physiol Sci 2011). In the present study, we studied mRNA expression of L-type Ca2+ channel Cav1.3 that is important for the generation of spontaneous AP in SA node cells by participating to diastolic depolarization. To investigate delay of contraction after initiation of excitation, we also examined mRNA expression of sarcomeric-related proteins; cardiac α-actin (Actc1) and cardiac troponin C (TnnC1). Whole mount in situ hybridization and RT-PCR showed that Actc1 and TnnC1 mRNA expressed at day E9.8. Interestingly, expression of Cav1.3 mRNA was not observed at day E9.8, and was up-regulated at day E10.0. These results suggest that mRNA expression of Cav1.3 contribute to the initiation of excitation, and also mRNA expression of Actc1 and TnnC1 are necessary to the initiation of contraction in the early rat embryo.
    No preview · Article · Jan 2011 · Journal of Arrhythmia

  • No preview · Article · Aug 2009 · Hokkaido Journal of Orthopaedics and Traumatology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although there is evidence that the volatile anaesthetic desflurane directly relaxes preconstricted airway smooth muscle in vitro, the anaesthetic increases the lung resistance in vivo. The constrictive mechanisms of desflurane are, however, still unknown. This study was conducted to clarify the increasing mechanisms of desflurane on lung resistance by examining the vagal nerve reflexes in guinea pigs. The effects of desflurane and sevoflurane on total lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were investigated in animals that were either untreated, pretreated with atropine or vagotomy, pretreated with the tachykinin receptor antagonists sendide or MEN-10376, or given chronic pretreatment with capsaicin. Desflurane biphasically and dose-dependently increased R(L) (by 180% and 230% at the first and second peaks, respectively, at 2 minimum alveolar concentration) concomitant with a decrease in C(Dyn). However, sevoflurane had little effect on either R(L) or C(Dyn). Although vagotomy partially inhibited the first peak of R(L) by 30%, neither atropine nor vagotomy had any effect on the other respiratory responses to desflurane. Antagonization of tachykinin receptors of airway smooth muscles completely diminished the increase in R(L) induced by desflurane. Desflurane also had little effect on respiratory parameters after the capsaicin pretreatment, in which tachykinin containing afferent C-fibres was desensitized. Desflurane but not sevoflurane increased R(L) concomitant with a decrease in C(Dyn) in guinea pigs. The increase in lung resistance by desflurane might be due to antidromic tachykinin release from afferent C-fibres but not acetylcholine release from parasympathetic efferent nerves.
    Preview · Article · Apr 2009 · BJA British Journal of Anaesthesia
  • [Show abstract] [Hide abstract]
    ABSTRACT: A rat model of lumbar root constriction with an additional sympathectomy in some animals was used to assess whether the sympathetic nerves influenced radicular pain. Behavioural tests were undertaken before and after the operation. On the 28th post-operative day, both dorsal root ganglia and the spinal roots of L4 and L5 were removed, frozen and sectioned on a cryostat (8 microm to 10 microm). Immunostaining was then performed with antibodies to tyrosine hydroxylase (TH) according to the Avidin Biotin Complex method. In order to quantify the presence of sympathetic nerve fibres, we counted TH-immunoreactive fibres in the dorsal root ganglia using a light microscope equipped with a micrometer graticule (10 x 10 squares, 500 mm x 500 mm). We counted the squares of the graticule which contained TH-immunoreactive fibres for each of five randomly-selected sections of the dorsal root ganglia. The root constriction group showed mechanical allodynia and thermal hyperalgesia. In this group, TH-immunoreactive fibres were abundant in the ipsilateral dorsal root ganglia at L5 and L4 compared with the opposite side. In the sympathectomy group, mechanical hypersensitivity was attenuated significantly. We consider that the sympathetic nervous system plays an important role in the generation of radicular pain.
    No preview · Article · Jan 2008 · The Bone & Joint Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: The beta subunits of voltage-dependent calcium channels bind the pore-forming alpha(1) subunit and play an important role in the regulation of calcium channel function. Recently, we have identified a new splice variant of the beta(4) subunit, which we have termed the beta(4d) subunit. The beta(4d) subunit is a truncated splice variant of the beta(4b) subunit and lacks parts of the guanylate kinase (GK) domain and the C-terminus. The calcium current in BHK cells expressing alpha(1C) and alpha(2)delta with the beta(4d) subunit was as small as that without the beta(4d) subunit. Western blot analysis revealed that beta(4d) protein was expressed to a lesser extent that the beta(4b) protein. In addition, a GST pull down assay showed that the beta(4d) subunit could not interact with the alpha(1) subunit of the calcium channel. Collectively, our results suggest that the GK domain of the beta subunit is essential for the expression of the functional calcium channel.
    No preview · Article · Sep 2007 · Biochemical and Biophysical Research Communications
  • [Show abstract] [Hide abstract]
    ABSTRACT: In our previous report, we showed that L-arginine induced depolarization of smooth muscle cells of the rat portal vein with an increased contraction. To clarify the ionic mechanism of the membrane depolarization, the effect of L-arginine on the holding current was studied in freshly isolated smooth muscle cells of the rat portal vein. The whole-cell patch-clamp technique was used, with the membrane potential held at -60 mV. In the presence of Na+ in the perfusate, L-arginine 10 mM induced an inward current in about 50% of the cells. In Na+-deficient perfusate, L-arginine 10 mM increased the amplitude of the inward current in a Na+ concentration-dependent manner. BCH, an inhibitor of the Na+-dependent amino acid transporter, ceased the L-arginine-induced current. These results indicate that L-arginine induces an inward current via Na+-dependent mechanisms in rat portal venous smooth muscle cells.
    No preview · Article · Jul 2007 · Journal of Smooth Muscle Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ca(V)1.2 (alpha(1c)) is a pore-forming subunit of the voltage-dependent L-type calcium channel and is expressed in many tissues. The beta and alpha(2)/delta subunits are auxiliary subunits that affect the kinetics and the expression of Ca(V)1.2. In addition to the beta and alpha(2)/delta subunits, several molecules have been reported to be involved in the regulation of Ca(V)1.2 current. Calmodulin, CaBP1 (calcium-binding protein-1), CaMKII (calcium/calmodulin-dependent protein kinase II), AKAPs (A-kinase anchoring proteins), phosphatases, Caveolin-3, beta(2)-adrenergic receptor, PDZ domain proteins, sorcin, SNARE proteins, synaptotagmin, CSN5, RGK family, and AHNAK1 have all been reported to interact with Ca(V)1.2 and the beta subunit. This review focuses on the effect of these molecules on Ca(V)1.2 current.
    No preview · Article · May 2007 · Journal of Pharmacological Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: The DRG neuron was electrophysiologically investigated using a rat model with constriction of the proximal site of the DRG. To investigate the pathomechanisms of lumbar radiculopathy, we established a rat model with constriction of the proximal site of the DRG. And to characterize the DRG neurons in the rat model of lumbar radiculopathy, the physiologic properties regarding action potential, Na, and K current of the DRG neurons were analyzed through the use of patch clamp recordings. In lumbar root constriction models, properties of secondary afferent neurons in the dorsal horn have been investigated. However, the electrical properties of DRG neuron have not been well investigated. To compare the excitability of DRG neurons between root constriction models and sham, we examined the threshold current, action potential (AP) threshold, resting membrane potential (RMP), afterhyperpolarization (AHP), action potential duration 50 (APD50), action potential amplitude, maximum rise time of AP, and pattern of discharges evoked by depolarizing current. We also examined the peak Na current and steady-state Na and K currents with the voltage clamp technique. The rats in the root constriction group demonstrated mechanical allodynia and thermal hyperalgesia. In measurement of the action potential, lower threshold current, more depolarized RMP, larger AHP, and prolonged APD50 were measured in the root constriction neurons compared with the sham group. The incidence of sustained burst was significantly higher in root constriction neurons. The Na current in root constriction neurons was markedly larger. There were no significant differences in K current density and voltage dependency. The constriction of lumbar root increased excitability and Na current amplitude of DRG neurons. These findings indicate that lumbar radicular pain may be associated with increased excitability of involved DRG neurons.
    No preview · Article · Feb 2007 · Spine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using isolated perfused lungs of normal or monocrotaline (MCT: 50 mg/kg)-induced pulmonary hypertensive rats, we tested the hypothesis that the pulmonary vascular effects of propofol depend on activation of the alpha-adrenoreceptor. Changes in pulmonary perfusion pressure induced by propofol (10(-5) to 10(-4) M) were measured with or without phenylephrine (10(-6) M) pretreatment. Before phenylephrine administration, we assessed the effects of inhibitors of nitric oxide synthase (N(omega)-nitro-l-arginine methylester: 10(-4) M), cyclooxygenase (indomethacin: 10(-5) M), and protein kinase C inhibitor, bisindolylmaleimide I (10(-6) M) or calphostin C (10(-6) M). Changes in pulmonary perfusion pressure by phenylephrine after pretreatment of nitric oxide synthase inhibitor and indomethacin in normal rats were significant (5 +/- 3 and 7 +/- 2 mm Hg), whereas that after pretreatment of bisindolylmaleimide I were small in MCT-rats (2 +/- 1 mm Hg). Propofol caused pulmonary vasoconstriction after phenylephrine pretreatment both in normal and MCT-treated rats. In normal rats, the propofol-induced increase in pulmonary perfusion pressure after indomethacin pretreatment was slightly smaller than that in the non-pretreated lungs (P < 0.05). In MCT-treated rats, the propofol-induced increases in pulmonary perfusion pressure after both protein kinase C inhibitors were smaller than that in the non-pretreated lungs (P < 0.05). Propofol may increase pulmonary vascular resistance during alpha-adrenoreceptor activation.
    Full-text · Article · Jan 2007 · Anesthesia and analgesia
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: During early apoptosis, adult cardiomyocytes show unusual beating, suggesting possible participation of abnormal Ca(2+) transients in initiation of apoptotic processes in this cell type. Simultaneously with the beating, these cells show dynamic structural alteration resulting from cytoskeletal disintegration that is quite rapid. Because of the specialized structure and extensive cytoskeleton of cardiomyocytes, we hypothesized that its degradation in so short a time would require a particularly efficient mechanism. To better understand this mechanism, we used serial video microscopy to observe beta-adrenergic stimulation-induced apoptosis in isolated adult rat cardiomyocytes while simultaneously recording intracellular Ca(2+) concentration and cell length. Trains of Ca(2+) transients and corresponding rhythmic contractions and relaxations (beating) were observed in apoptotic cells. Frequencies of Ca(2+) transients and beating gradually increased with time and were accompanied by cellular shrinkage. As the cells shrank, amplitudes of Ca(2+) transients declined and diastolic intracellular Ca(2+) concentration increased until the transients were lost. Beating and progression of apoptosis were significantly inhibited by antagonists against the L-type Ca(2+) channel (nifedipine), ryanodine receptor (ryanodine), inositol 1,4,5-trisphosphate receptor (heparin), sarco(endo)plasmic Ca(2+)-ATPase (thapsigargin), and Na(+)/Ca(2+) exchanger (KB-R7943). Electron-microscopic examination of beating cardiomyocytes revealed progressive breakdown of Z disks. Immunohistochemical analysis and Western blot confirmed that disappearance of Z disk constituent proteins (alpha-actinin, desmin, and tropomyosin) preceded degradation of other cytoskeletal proteins. It thus appears that, in adult cardiomyocyte apoptosis, Ca(2+) transients mediate apoptotic beating and efficient sarcomere destruction initiated by Z disk breakdown.
    Full-text · Article · May 2006 · AJP Heart and Circulatory Physiology

Publication Stats

2k Citations
284.96 Total Impact Points


  • 1995-2015
    • Sapporo Medical University
      • • Division of Orthopaedic Surgery
      • • School of Medicine
      • • Department of Anesthesiology
      • • Department of Physiology
      Sapporo, Hokkaido, Japan
  • 1987-1998
    • Hokkaido University Hospital
      • Division of Cardiovascular Medicine
      Sapporo-shi, Hokkaido, Japan
  • 1986-1997
    • Hokkaido University
      • • Department of Cardiovascular Medicine
      • • Laboratory of Pharmacology
      Sapporo, Hokkaidō, Japan
  • 1990-1994
    • University of Cincinnati
      • College of Medicine
      Cincinnati, OH, United States
  • 1993
    • Chiba University
      • Department of Pharmacology
      Tiba, Chiba, Japan