Biomedical subjects

Norio Hashimoto

Publications and source records attributed to Norio Hashimoto.

6 recordsLinked to original sources

PubMed2006

Blockade by NIP-142, an antiarrhythmic agent, of carbachol-induced atrial action potential shortening and GIRK1/4 channel.

Mechanisms for the atria-specific action potential-prolonging action of NIP-142 ((3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol), a benzopyran compound that terminates experimental atrial arrhythmia, was examined. In isolated guinea-pig atrial tissue, NIP-142 reversed the shortening of action potential duration induced by either carbachol or adenosine. These effects were mimicked by tertiapin, but not by E-4031. NIP-142 concentration-dependently blocked the human G protein-coupled inwardly rectifying potassium channel current (GIRK1/4 channel current) expressed in HEK-293 cells with an EC50 value of 0.64 microM. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC50 value of 44 microM. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under beta-adrenergic stimulation, indicating lack of effect on the muscarinic receptor and Gi protein. These results suggest that NIP-142 directly inhibits the acetylcholine-activated potassium current.

Action Potentials↗

PubMed2006

Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation.

It is well known that vagal nerve tone plays a crucial role in atrial fibrillation (AF). Acetylcholine-activated potassium current (IKACh) mediates much of the cardiac response to vagal nerve stimulation (VNS), but the contribution of IKACh to AF remains unknown. We investigated the role of the IKACh channel in canine AF models using tertiapin, a selective IKACh blocker. Tertiapin (4-41 nmol kg(-1), i.v.) terminated AF in the canine VNS-induced and aconitine-induced AF models. The muscarinic M-receptor antagonist AF-DX-116 terminated AF in these models, but the adenosine receptor antagonist DPCPX had no effect. Thus it is likely that IKACh activation via the M-receptor has a crucial role in both models. Tertiapin (12 nmol kg(-1), i.v.) preferentially prolonged the atrial effective refractory period (ERP) but not the ventricular ERP under the VNS condition. This peptide (4-41 nmol kg(-1), i.v.) did not affect PQ, QRS and corrected QT intervals in isoflurane-anaesthetised dogs. These results suggest that a selective IKACh blocker is effective in canine AF models without affecting ventricular repolarisation, and might be useful for the treatment of patients with AF.

Animals↗

PubMed2003

Increased expression of 3 beta-hydroxysteroid dehydrogenase mRNA in dorsal root ganglion neurons of adult rats following peripheral nerve injury.

3beta-hydroxysteroid dehydrogenase (3beta-HSD) is an enzyme that converts pregnenolone to progesterone. It has been believed that 3beta-HSD is simply a converting enzyme of female steroid hormone. Recently, 3beta-HSD expressing cells were identified in the spinal cord. Steroid synthesis in the nervous system may indicate that steroid plays a role in the nervous system. We report here the increased expression of 3beta-HSD mRNA in the dorsal root ganglion (DRG) after peripheral nerve injury using reverse transcription-polymerase chain reaction and in situ hybridization histochemistry techniques. We detected only a few 3beta-HSD signals in the naïve DRG, and found that 3beta-HSD mRNA expression increased 3 days after injury and this increase was still observed at 14 days. Our results suggest that progesterone may have a role in the process against neuronal injury or in regeneration in the peripheral nervous system.

Animals↗

PubMed2003

Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats.

Neuropathic pain models, such as the chronic constriction injury (CCI) model, are partial nerve injury models where there exist both intact and injured peripheral axons. Recent studies suggested that dorsal root ganglion (DRG) neurons with intact axons also show the alteration of excitability and gene expression and might have some role in the pathophysiological mechanisms of neuropathic pain. The incidence of pain-related behavior after the CCI is unstable and variable. In the present study, we used activating transcription factor 3 (ATF3) expression as a neuronal injury marker, and analyzed a relationship between the number of axotomized neurons and the incidence of pain-related behavior. We divided all rats into three groups according to the percentage of ATF3-immunoreactive (IR) neurons, group 1 (<12.5%), group 2 (12.5-25%), and group 3 (>25%). We found that rats in groups 2 and 3 showed thermal hyperalgesia, whereas only the rats in group 2 developed tactile allodynia from the third day to the fourteenth day after surgery. Rats in group 1 did not show thermal hyperalgesia or tactile allodynia. The DRG neurons in group 2 contained ATF3-IR neurons mainly in medium- and large-sized neurons. In order to investigate brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid(A)-receptor (GABA(A)-R) regulation in both intact and injured primary afferent neurons after the CCI, we used a double-labeling method with immunohistochemistry and in situ hybridization, as well as double immunofluorescent staining. The CCI induced an increased number of BDNF-labeled neurons in the ipsilateral DRG and the increase in BDNF expression was observed mainly in small- and medium-sized neurons that were mainly ATF3-negative. On the other hand, the number of GABA(A)-Rgamma2 subunit mRNA-positive neurons decreased in the ipsilateral DRG and GABA(A)-R- and ATF3-labeled neurons rarely overlapped. These changes in molecular phenotype in intact and injured primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by partial nerve injury.

Activating Transcription Factor 3↗

PubMed2002

Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation.

A variety of molecules released by inflammatory reactions in the dorsal root and dorsal root ganglion (DRG) may play important roles in the pathology of neuronal abnormalities in lumbar disc herniation. In order to elucidate the pathophysiological mechanisms of painful radiculopathy, secondary to lumbar disc herniation, we evaluated pain-related behavior and the change of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG and dorsal root using a rat model of lumbar disc herniation. In the nucleus pulposus (NP) group, the left L4/5 nerve roots were exposed after hemilaminectomies and autologous intervertebral discs, which were obtained from coccygeal intervertebral discs, were implanted on each of the exposed nerve roots without mechanical compression. Rats in the NP group, but not the sham-operated rats, developed mechanical allodynia on the ipsilateral hind paw for 1 day after surgery and showed a significant increase in the number of NGF-immunoreactive (IR) cells in the nerve root and DRG. NGF-IR cells in the nerve root and DRG included macrophages and Schwann cells, because these cells were labeled for NGF and ED-1 or glial fibrillary acid protein by dual immunostaining. A significant increase in the percentage of BDNF-IR neurons in the DRG was observed in the NP group at 3 days after surgery and the increase in BDNF mRNA expression was confirmed using in situ hybridization histochemistry and reverse transcription-polymerase chain reaction. We also injected NGF into the endoneurial space of the normal rat spinal nerve root and found that the NGF injection produced dose-dependent mechanical allodynia on the ipsilateral hind paw at 1 day after surgery and an increase in the percentage of BDNF-IR neurons in the DRG at 3 days after surgery compared to the group receiving saline injection. These findings suggest that in the lumbar disc herniation model, i.e. neuritis of the nerve root, increased NGF produced by the inflammatory responses in the dorsal root and DRG tissues may affect the production of BDNF in the DRG and may play important roles in the modulation of the dorsal horn neurons. These changes in neurotrophic factors in the primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by lumbar disc herniation.

Animals↗

PubMed2002

Expression of Apc2 during mouse development.

APC2 (previously known as APCL), a molecule closely related to the adenomatous polyposis coli (APC) tumor suppressor, can deplete cytoplasmic beta-catenin, like APC itself. Recently, it has been shown that APC2 may regulate the localization of p53 and the microtubule stability and/or extension. Although it has been reported that APC2 mRNA is expressed in human brain, the anatomical and ontogenic expression patterns remain unclear. The purpose of this study was to investigate the distribution of mouse Apc2 during mouse development. In the adult brain, Apc2 is expressed predominantly in neurons and throughout the brain. Northern blot analysis demonstrated a high level of Apc2 expression in embryonic and early postnatal brain. Ontogenic analysis has indicated that Apc2 is expressed in neural tissue, including the peripheral nervous system. During development of cortex, retina and cerebellum, Apc2 is expressed in post-mitotic cells. These findings suggest that Apc2 may contribute to the development of neuronal cells.

Animals↗