The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 86, Issue 4
Displaying 1-12 of 12 articles from this issue
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Reviews
  • Identifying Endothelium-Derived Hyperpolarizing Factor: Recent Approaches to Assay the Role of Epoxyeicosatrienoic Acids
    Meetha Medhora, Jayashree Narayanan, David Harder, Kristopher G. Maier
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 369-375
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.369
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    Investigation of endothelial regulation of vascular reactivity and tone has led to the discovery of chemical mediators such as nitric oxide (NO) and prostacyclin (PGI2). Evidence has emerged indicating another as yet unidentified hyperpolarizing agent (endothelium-derived hyperpolarizing factor or EDHF) that is different from NO and PGI2 and exerts it effects through calcium-activated potassium channels (KCa). Previous studies to identify EDHF have been carried out using inhibitors that block NOS and COX before application of KCa channel and/or muscarinic receptor antagonists. Such pharmacological manipulation has complicated interpretation of results, clearly pointing to the need for altered approaches to verify previous studies. Evidence has emerged that potential EDHF candidates vary with vessel size, species and tissue beds, indicating that there may be more than one EDHF. To date, the most commonly described and best characterized of them all are a set of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs). These compounds are synthesized both intra- and extravascularly. Until recently, methodology to detect EETs in the microvasculature has been tedious and expensive, limiting the experimentation that is necessary to confirm EETs as an EDHF. This review describes state-of-the-art methods for assaying EETs in biological samples, after summarizing evidence for EETs as an EDHF and introducing emerging concepts of the role of extravascular EETs in linking neuronal activity to localized blood flow during functional hyperemia.
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  • Strategy for Modulation of Central Dopamine Transmission Based on the Partial Agonist Concept in Schizophrenia Therapy
    Atsuko Inoue, Yoshihiro Nakata
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 376-380
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.376
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    The dopamine system is known to be closely involved in brain neuronal dysfunction and in diseases such as Parkinson's disease, Tourette's syndrome, attention deficit hyperactive disorder, generation of pituitary tumors and schizophrenia. According to the classical dopamine hypothesis on the pathology of schizophrenia, conventional antipsychotics has D2 dopamine receptor antagonistic profiles. However, the use of typical antipsychotics has several limitations; that is, some patients do not respond to them, they can even worsen negative symptoms, and they can provoke unacceptable extrapyramidal and endocrine side effects. To produce effective antipsychotics with reduced side effects, partial agonists to D2 dopamine receptors (D2 receptors) have been developed. Despite the effectiveness of partial agonists for pre- and post-synaptic D2 receptors, administration of such drugs results in inconsistent clinical effects to ameliorate the symptoms of schizophrenia. Thus, strategies for obtaining ideal effective antipsychotics with reduced side effects are considered in this short review with respect to the intrinsic efficacies and affinities of the partial agonists, based on the partial agonist concept.
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Full Papers
  • Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia
    Ryoko Tokunaga, Kazushi Kushiku, Katsuhiro Yamada, Hiromi Yamada, Tats ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 381-389
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.381
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    We investigated the ganglionic effects of angiotensin II (Ang II) and the signal transduction involved in the cardiac sympathetic ganglia by the direct administration of agents to the ganglia through the right subclavian artery and monitoring the heart rate as an indicator of the ganglionic function in pithed dogs. Ang II given i.a. caused increases in the heart rate, which was inhibited by the treatment with the AT1-receptor antagonist forasartan, but not by the AT2-receptor antagonist PD-123319. The stimulation by Ang II, but not by acetylcholine, was inhibited after treatment with an inhibitor of phospholipase C, U-73122; a cell-permeant modulator of the Ins(1,4,5)P3 receptors, 2-aminoethoxydiphenyl borate; an intracellular calcium and calcium-associated protein kinase inhibitor, HA-1077; calmodulin (CaM) inhibitor, W-7; Ca2+/CaM-dependent protein kinase II inhibitor, KN-93; a selective protein kinase C inhibitor, calphostin C; and Na+-H+ exchange inhibitor, dimethylamiloride. These results suggest that Ang II stimulates the ganglionic transmission at postsynaptic sites via the activation of AT1 receptor coupled to either activation of phospholipase C, phosphoinositide hydrolysis and subsequent increase in intracellular Ca2+ and activation of protein kinase C and Ca2+/CaM kinase II, although this ganglionic stimulation seems to involve, at least in part, the protein kinases-dependent increase of amiloride-sensitive Na+ inflow.
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  • Mechanism of a Nitric Oxide Donor NOR 1-Induced Relaxation in Longitudinal Muscle of Rat Proximal Colon
    Tadayoshi Takeuchi, Keisuke Sugimoto, Hajime Morimoto, Akikazu Fujita, ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 390-398
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.390
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    We previously suggested that nitric oxide (NO)-mediated relaxation of the rat proximal colon is not associated with change in cyclic GMP content. We further studied the intracellular mechanism of NO-induced relaxation by measuring changes in tension and intracellular Ca2+ concentration ([Ca2+]i), simultaneously. NOR 1, NO donor, relaxed the longitudinal muscle of the rat proximal colon, which was precontracted by carbachol, with a concomitant decrease in [Ca2+]i. ODQ, an inhibitor of soluble guanylate cyclase, partially inhibited the relaxant effect of only higher concentrations of NOR 1, but Rp-8-Br-cGMPS, an inhibitor of cyclic GMP-dependent protein kinase (PKG), did not have any effects on the relaxant effect of NOR 1. When the preparations were transferred to normal solution after the treatment with thapsigargin, an inhibitor of sarcoplasmic reticulum (SR) Ca2+-ATPase, in the absence of Ca2+, contraction with a concomitant increase in [Ca2+]i occurred. NOR 1 did not show significant effects on the tension and [Ca2+]i in thapsigargin-treated preparations. In high K+-precontracted preparations, NOR 1 relaxed the preparations with a slight change in [Ca2+]i. The relaxant effect was significantly inhibited by ODQ and Rp-8-Br-cGMPS. These results suggest that NO induces the relaxation preferentially by acting thapsigargin-sensitive function of SR and in turn decreasing [Ca2+]i, although a cyclic GMP-PKG pathway is suggested under the experimental conditions of a high K+ concentration.
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  • Changes of Tissue Factor-Dependent Coagulant Activity Mediated by Adhesion Between Polymorphonuclear Leukocytes and Endothelial Cells
    Tohru Watanabe, Shogo Tokuyama, Masako Yasuda, Tadanori Sasaki, Toshin ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 399-404
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.399
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    The purpose of this study was to examine whether polymorphonuclear leukocytes (PMNs) facilitate a tissue factor, a physiologic initiator of coagulation in endothelial cells, -dependent coagulant activity (TF activity). The TF activity in bovine endothelial cells (BAECs) was significantly increased in a concentration-dependent manner by PMNs (1 × 105 - 1 × 107 cells/ml) without affecting the treatment of N-formyl-methionyl-leucyl-phenylalanine, a selective activator of PMNs, and the addition of PMNs finally resulted in cell damage as evaluated by the lactate dehydrogenase leakage method. In the same conditions, an increase of adhesion between PMNs and BAECs was also observed in a time-dependent manner. However, since direct adhesion of PMNs to BAECs was impossible by using the transwell, PMNs failed to induce any changes in the TF activity. Hence, the change of TF activity found here might be closely related to the PMNs adhesion to BAECs. Indeed, anti-intercellular adhesion molecule-1 (anti-ICAM-1) antibody blocked the increase of TF activity in BAECs. These findings suggest that PMNs could increase TF activity in endothelial cells, which is triggered by adhesion to endothelial cells through ICAM-1.
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  • Transactivation of Core Binding Factor α1 as a Basic Mechanism to Trigger Parathyroid Hormone-Induced Osteogenesis
    Takashi Fujita, Ryo Fukuyama, Nobuo Izumo, Takao Hirai, Toru Meguro, H ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 405-416
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.405
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    During 28-day culture of bone marrow- and calvaria-derived osteoblasts, the constant presence of parathyroid hormone (PTH)(1 - 34) retarded differentiation and nodule formation (NF) in a dose-dependent fashion (C-phase). In contrast, addition of PTH(1 - 34) in late stage cultures (from day 10 to 21) accelerated NF (A-phase). The stable production of such an A-phase allowed us to study the mechanism of bone anabolic action of PTH(1 - 34). Subcellular localization studies of core binding factor α1 (Cbfa1) and reporter assays provided the results indicating that in the A-phase, PTH(1 - 34) triggers its bone anabolic action via enhancement of Cbfa1 transactivation. RT-PCR and Northern blot analyses revealed that alkaline phosphatase, osteocalcin and bone sialoprotein expression decreased in the C-phase and increased in the A-phase; however, expression of other bone proteins (Cbfa1, PTH/PTH-related peptide-receptor, osteopontin, collagen I α1, collagen I α2, vitamin K-dependent γ-glutamyl carboxylase) did not change in a phase transition-related manner. Ovariectomized osteopenic mice, treated with PTH(1 - 34) (4 and 40 μg/kg, s.c., every other day, 4 or 6 weeks), recovered lost bone, displayed elevated nuclear localization of Cbfa1 in tibiae without alteration of its cytosolic level and exhibited upregulation of expressions of the same set of proteins (alkaline phosphatase, osteocalcin and bone sialoprotein) in femora. These results obtained by a concerted study in vitro and in vivo suggest that PTH triggers its osteogenic action via promotion of the transactivation of Cbfa1.
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  • Effect of 1DMe, a Neuropeptide FF Analog, on Acetylcholine Release From Myenteric Plexus of Guinea Pig Ileum
    Tadayoshi Takeuchi, Akikazu Fujita, Michel Roumy, Jean-Marie Zajac, Fu ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 417-422
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.417
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    Since neuropeptide FF (NPFF) is a putative neurotransmitter to exert anti-opioid activity, we examined the effects of [D-Tyr1, (NMe)Phe3]neuropeptide FF (1DMe), a stable NPFF analog, on acetylcholine (ACh) release from a longitudinal muscle-myenteric plexus (LMMP) preparation of guinea pig ileum in which opioids were known to inhibit ACh release when muscarinic autoinhibition was not fully activated. In the presence of atropine, 1DMe increased spontaneous and electrical field stimulation (EFS)-evoked ACh release in a concentration-dependent manner. Naloxone also increased ACh release. The stimulatory effects of 1DMe and naloxone were not additive. In the absence of atropine, 1DMe did not affect ACh release. Morphine decreased spontaneous and EFS-evoked ACh release in the presence of 1 μM atropine. 1DMe as well as naloxone counteracted the inhibitory effects of morphine on EFS-evoked ACh release. The combination of 1DMe and naloxone was not more inhibitory than either drug alone. 1DMe had no appreciable effect on norepinephrine-induced inhibition of spontaneous and EFS-evoked ACh release. These results first demonstrated the effects of a NPFF analog on neurotransmitter release: 1DMe had a stimulatory effect on spontaneous and EFS-induced ACh release from the LMMP preparation of guinea pig ileum, probably by counteracting the inhibitory effect of endogenous opioids on ACh release.
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  • Involvement of β2-Adrenergic and μ-Opioid Receptors in Antinociception Produced by Intracerebroventricular Administration of α,β-Methylene-ATP
    Masato Fukui, Takayuki Nakagawa, Masabumi Minami, Masamichi Satoh
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 423-428
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.423
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    The present study examined what kind of receptors are involved in the antinociception produced by intracerebroventricular (i.c.v.) administration of α,β-methylene-ATP using antagonists at adrenergic, serotonin or opioid receptors. Antinociceptive effect of α,β-methylene-ATP (10 nmol/rat) was significantly attenuated by subcutaneous pretreatment with propranolol and naloxone, but not phentolamine or methysergide, at a dose of 10 mg/kg. I.c.v. pretreatment with propranolol (100 nmol/rat), butoxamine (100 nmol/rat), ICI-118,551 (100 nmol/rat) and naloxone (30 nmol/rat) significantly attenuated the antinociceptive effect of α,β-methylene-ATP. However, i.c.v. pretreatment with atenolol (100 nmol/rat), naltrindole (30 nmol/rat) or nor-binaltorphimine (30 nmol/rat) did not show any significant effects. These results suggest that supraspinal β2-adrenergic and μ-opioid receptors are involved in the antinociceptive effect of i.c.v. administered α,β-methylene-ATP.
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  • Excitation of Rat Striatal Large Neurons by Dopamine and/or Glutamate Released From Nerve Terminals via Presynaptic Nicotinic Receptor (α4β2 Type) Stimulation
    Hiroaki Matsubayashi, Taku Amano, Hiroko Amano, Masashi Sasa
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 429-436
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.429
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    Previous in vivo experiments using rats anesthetized with chloral hydrate have revealed that nicotine applied iontophoretically increased firing of striatal neurons receiving excitatory dopaminergic input from the substantia nigra, and nicotine-induced firing was inhibited by domperidone, a dopamine D2 antagonist. The results suggest that nicotine increases release of dopamine from the terminals of dopaminergic neurons. Therefore, we performed the present patch clamp study using slice and acutely dissociated preparations of the rat striatum to elucidate the mechanisms underlying the nicotine-induced excitation of striatal neurons. Application of nicotine (100 μM) to large striatal neurons in slice preparations did not produce any effect on the resting membrane potential, but did increase the frequency of miniature postsynaptic potentials (mpps) and action potentials in all 15 neurons tested. The nicotine-induced increase in mpps and action potentials were inhibited during simultaneous application of domperidone; L-glutamic acid diethyl ester hydrochloride, a non-selective glutamate receptor antagonist; and/or dihydro-β-erythroidine, a central nicotinic acetylcholine receptor (α4 β2 type) antagonist. Postsynaptic current was not induced by nicotine applied by U-tube in 96% of acutely dissociated striatal neurons. The present findings suggest that nicotine mainly acts on the presynaptic nicotinic receptors in the nerve terminals to release neurotransmitters such as dopamine and/or glutamate, thereby activating the striatal large neurons.
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  • Effects of Dehydroepiandrosterone on Oleic Acid Formation in the Liver of Rats, Mice and Guinea Pigs
    Koichi Imai, Naomi Kudo, Matajirou Koyama, Akira Shirahata, Yoichi Kaw ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 4 Pages 437-447
    Published: 2001
    Released on J-STAGE: September 18, 2001
    DOIhttps://doi.org/10.1254/jjp.86.437
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    The purpose of the present study is to answer the question of whether there is a species difference in the effects of a pharmacological dose of dehydroepiandrosterone (DHEA) on the enzymes that participate in oleic acid (18:1) formation in the liver. Feeding a diet containing 0.5% (w/w) DHEA for 14 days markedly increased the activities of acyl-coenzyme A (CoA) synthetase, palmitoyl-CoA chain elongase and stearoyl-CoA desaturase in the liver of rats and mice. These enzyme activities, however, were not changed by DHEA in guinea pigs. The treatments of rats and mice with DHEA markedly increased proportions of 18:1 in hepatic lipids, especially phosphatidylcholine (selectively at C-2 position), triacylglycerol and cholesterol ester. DHEA caused no significant changes in acyl compositions of hepatic lipids of guinea pigs. The levels of DHEA or dehydroepiandrosterone sulfate (DHEAS) were markedly increased in serum and livers by DHEA administration to rats, mice and guinea pigs. High correlations were observed between hepatic levels of DHEA or DHEAS and stearoyl-CoA desaturase activities in rats. These results indicate that there are species differences in the inducing effects of DHEA or DHEAS on hepatic formation of 18:1 and that guinea pigs lack the machinery to induce the enzymes.
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