The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 89, Issue 4
Displaying 1-15 of 15 articles from this issue
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Reviews
  • Nitric Oxide Synthase Gene Therapy for Cardiovascular Disease
    Alex F. Chen, Jun Ren, Chao-Yu Miao
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 327-336
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.327
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    Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
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  • Transcription Factors and Drugs in the Brain
    Noritaka Nakamichi, Yukio Yoneda
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 337-348
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.337
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    In mammalian cells, protein de novo synthesis is mainly regulated at the stage of gene transcription by RNA polymerase II in the nucleus. Transcription factors are proteins that bind to the specific nucleotide sequences at promoter or enhancer regions on target genes to control the transcription of mRNA from genomic DNA. In this article, we have outlined the signal responsiveness of different transcription factors to particular drugs in the brain. Nuclear transcription factors rapidly respond to a variety of extracellular signals carried by neurotransmitters, hormones and autacoids as a third messenger in frequent situations. Translated proteins are responsible for a number of physiological and pathological events for a long period in the brain. We have also discussed possible involvement of transcription factors in molecular mechanisms underlying development of tolerance and dependence to drugs following acute and chronic administration.
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Full Papers
  • 5-Hydroxytryptamine Receptors, Especially the 5-HT4 Receptor, in Guinea Pig Urinary Bladder
    Akira Yoshida, Yasuko S.-Yamashita, Muneshige Kaibara, Kohtaro Taniyam ...
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 349-355
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.349
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    The function of 5-hydroxytryptamine (5-HT) receptors, especially the 5-HT4 receptor, in the urinary bladder were examined in preparations isolated from the guinea pig by in vitro receptor autoradiography and determinations of mechanical activity and acetylcholine (ACh) release. Specific [125I]SB207710 binding sites were detected evenly throughout the urinary bladder. 5-HT (3 × 10−8 – 10−4 M) caused contractions of strips of the urinary bladder, in a concentration dependent manner. Ketanserin antagonized the 5-HT-induced contractions, while granisetron and SB204070 antagonized the contractions induced by high concentrations of 5-HT. Atropine inhibited the contractions induced by high concentrations of 5-HT. Ketanserin prevented the 5-HT-induced contractions in the presence of atropine, but granisetron and SB204070 did not affect the contractions under such a condition. 5-HT enhanced the electrically-stimulated (5 Hz, 0.5 ms) outflow of [3H]acetylcholine from strips preloaded with [3H]choline, and the enhancement was antagonized by granisetron and SB204070. Thus, the contractile response to 5-HT was mediated by activations of 5-HT2, 5-HT3 and 5-HT4 receptors. The 5-HT2 receptor may be a property of high affinity to 5-HT and located on the smooth muscle cells. The 5-HT4 as well as 5-HT3 receptor may be a property of low affinity to 5-HT and located on the cholinergic neurons.
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  • Possible Involvement of M5 Muscarinic Receptor in the Enhancing Actions of the Novel Gastroprokinetic Agent Z-338 on Nifedipine-Sensitive Voltage-Dependent Ca2+ Currents in Guinea Pig Stomach
    Hiromitsu Morita, Kihachiro Abe, Yushi Ito, Ryuji Inoue
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 356-365
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.356
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    We investigated the effects of the novel gastroprokinetic agent Z-338 (N-(N'-N'-diisopropylaminoethyl)-[2-(2-hydroxy-4,5-dimethoxybenzoylamino)-1,3-thiazole-4-yl] carboxyamide monohydrochloride trihydrate) on L-type voltage-dependent Ca2+ currents (ICa) in guinea pig gastric myocytes by using the whole-cell patch clamp technique. Bath-applied acetylcholine (ACh) produced biphasic effects on ICa, i.e., enhancement (1 – 100 nM) and inhibition (1 – 100 μM), both of which were abolished by pretreatment with atropine (10 μM) or intracellular perfusion of GDPβS (500 μM). Z-338 (≥1 nM, ED50: 120 nM) mimicked the enhancing effects of ACh, but did not inhibit ICa. The effects of Z-338 and ACh were non-additive and blocked by atropine and GDPβS, but not by pertussis toxin (PTX) pretreatment (500 ng/ml). ACh (≥1 μM) induced slow inward currents via activation of the muscarinic receptor/PTX-sensitive G-protein pathway, but Z-338 was devoid of these effects. Neither pirenzepine (1 μM), AF-DX116 (1 μM), nor oxybutynin (100 nM) could prevent Z-338 (1 μM) and ACh (10 nM) from enhancing ICa, whilst 4-DAMP (100 nM) blocked the effects of Z-338 and ACh. Bath-application of protein kinase C (PKC) activator PDBu (phorbol-12,13-dibutyrate) (250 nM) enhanced ICa, and conversely, pipette inclusion of PKC inhibitor peptide (150 μM) abolished the effects of ACh and Z-338 on ICa. These results collectively suggest that although contribution of the M3 receptor is not excluded, the major actions of Z-338 on gastric myocytes are potentiation of ICa through activation of M5-like receptor.
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  • A1 and A2 Adenosine Receptor Activation Inversely Modulates Potassium Currents and Membrane Potential in DDT1 MF-2 Smooth Muscle Cells
    Teréz Márián, Bálint Rubovszky, A. J&oacut ...
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 366-372
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.366
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    Adenosine receptors are widely distributed in mammalian tissues and have been possibly involved through transmembrane potential changes in cell function regulation. The effect of A1 and A2A adenosine receptor ligands on transmembrane potential measured with flow cytometry and potassium conductance measured by the patch-clamp technique was investigated in DDT1 MF-2 smooth muscle cells. The A1 adenosine-receptor agonist CPA (50 nM) and the A2A adenosine-receptor agonist CGS 21680 (50 nM) elicited a rapid and maintained increase and decrease in the potassium conductance, respectively, and a concomitant hyperpolarization and depolarization of the membrane, respectively. These effects were eliminated by subtype-selective adenosine receptor antagonists (DPCPX, CSC, ZM 241385, all 1 μM). The ligand induced membrane potential changes were reversible. Based on these detected membrane potential changes along with the published voltage dependence of the adenylyl cyclase, the regulation of cAMP production by A1- and A2A-receptor activation is suggested to be mediated through the induced early hyperpolarization and depolarization. The interaction between the effects of these receptor subtypes allows for a complex regulation mechanism.
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  • Induction of Cyclooxygenase-2 Expression in Glomeruli by Aggregated Protein
    Tadashi Nagamatsu, Hitomi Ishikami, Tsutomu Nishiyama, Yoshio Suzuki
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 373-379
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.373
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    Cyclooxygenase has two isozymes, a constitutive type (cyclooxygenase-1) and an inducible type (cyclooxygenase-2). The aim of the present study was to determine whether cyclooxygenase-2 is associated with the increased production in prostaglandin E2 in glomeruli by aggregated protein. Mice were injected with aggregated bovine serum albumin. Glomeruli were isolated using sieves and a magnet. Production of prostaglandin E2 was increased in glomeruli after injection of aggregated bovine serum albumin. RT-PCR analysis indicated enhanced expression of cyclooxygenase-2 mRNA in aggregated bovine serum albumin-loaded glomeruli. Western blotting analysis indicated an increase in cyclooxygenase-2 protein in glomeruli by aggregated bovine serum albumin. Glomeruli were incubated with indomethacin, NS-398 or niflumic acid in the presence of arachidonic acid. Indomethacin resulted in remarkable reduction of prostaglandin E2 levels in aggregated bovine serum albumin-loaded glomeruli. Niflumic acid also inhibited prostaglandin E2 production, and its inhibitory rate was more than that of NS-398. In conclusion, aggregated protein induces cyclooxygenase-2 in glomeruli, suggesting that cyclooxygenase-2 is involved in the process of disposal of aggregated protein in glomeuli.
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  • Vasorelaxing Effect of Mesaconitine, an Alkaloid From Aconitum japonicum, on Rat Small Gastric Artery: Possible Involvement of Endothelium-Derived Hyperpolarizing Factor
    Mana Mitamura, Koen Boussery, Syunji Horie, Toshihiko Murayama, Johan ...
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 380-387
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.380
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    Aconiti tuber, roots of aconite (Aconitum japonicum), has been used for centuries in Japan and China to increase peripheral body temperature. We previously reported that mesaconitine, an alkaloid from Aconitum japonicum, elicits endothelium-dependent and nitric oxide-mediated relaxation in isolated rat aorta. In the present study, we investigated the effect of mesaconitine on isolated rat small gastric arteries. Mesaconitine elicited a concentration-dependent (10, 30, 100 μM) vasorelaxation in isolated rat gastric artery precontracted with norepinephrine, which was resistant to Nω-nitro-L-arginine (L-NNA) (an inhibitor of nitric oxide synthase) and indomethacin (an inhibitor of cyclooxygenase). The L-NNA- and indomethacin-resistant relaxation by mesaconitine was mainly endothelium-dependent, inhibited by high K+ (30 mM), and inhibited by a combination of Ca2+-dependent K+ channel blockers, charybdotoxin and apamin. The relaxation by mesaconitine was proportional to the external Ca2+ concentration. These results suggest that mesaconitine elicits vasorelaxation of isolated rat small gastric artery mainly via release of endothelium-derived hyperpolarizing factor.
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  • Involvement of γ-Aminobutyric Acid (GABA) B Receptors in the Hypotensive Effect of Systemically Administered GABA in Spontaneously Hypertensive Rats
    Masayuki Kimura, Kazuhito Hayakawa, Hiroshi Sansawa
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 388-394
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.388
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    We investigated the effects of intraduodenally (i.d.) administered γ-aminobutyric acid (GABA) on blood pressure (BP) in anesthetized spontaneously hypertensive rats (SHR) and the mechanism underlying this effect, especially the type of GABA receptor involved in the depressive effect of this amino acid. GABA (0.3 to 300 mg/kg, i.d.) caused a dose-related decrease in the BP of 9.20 ± 3.96 to 35.0 ± 5.34 mmHg (mean ± S.E.M.) that lasted for 30 to 50 min. The minimum effective i.d. dose of GABA was 0.3 to 1.0 mg/kg. Results pertaining to the mechanism underlying the GABA-induced effects on BP were as follows: a) GABA did not alter the BP-related effects of exogenous noradrenaline and acetylcholine; b) pretreatment with hexamethonium decreased the GABA-induced fall in BP, and GABA tended to reduce the pressor response associated with injection of dimethyl phenylpiperazinium; and c) pretreatment with 2-hydroxysaclofen markedly reduced the GABA-induced drop in BP, whereas pretreatment with bicuculline did not. In conclusion, in SHR, low-dose (0.3 to 1.0 mg/kg, i.d.) GABA had a hypotensive effect, which may result from attenuation of sympathetic transmission through the activation of GABAB receptors at presynaptic or ganglionic sites.
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  • Rebound Contraction by Nitric Oxide in the Longitudinal Muscle of Porcine Gastric Fundus
    Junho La, Taewan Kim, Taesik Sung, Jeongwoo Kang, Hyunju Song, Hyunju ...
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 395-404
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.395
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    The rebound contraction induced by electrical field stimulation (EFS) and nitric oxide (NO) donor, S-nitroso-L-cysteine (cysNO), were investigated in the longitudinal muscle of porcine gastric fundus (LM-PGF). Under the presence of atropine and guanethidine, cysNO and EFS produced sequential relaxation-contraction in LM-PGF. Tetrodotoxin abolished the EFS-induced response, while leaving the cysNO-induced one unaffected. A soluble guanylate cyclase inhibitor, lH-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, inhibited both cysNO and EFS-induced biphasic response. A cGMP analogue only relaxed LM-PGF. A phosphodiesterase V inhibitor, zaprinast, prolonged the cysNO and the EFS-induced relaxation and inhibited the rebound contraction. The rebound contraction was inhibited by verapamil, an L-type Ca2+ channel blocker. The cysNO and the EFS-induced biphasic response were inhibited by ryanodine plus cyclopiazonic acid or by ruthenium red, a ryanodine-receptor blocker. LM-PGF was relaxed on exposure to caffeine and then produced a verapamil-sensitive rebound contraction during the washout period. CysNO and EFS did not induce the rebound contraction in the presence of caffeine. These results suggest that the NO-induced rebound contraction involves both Ca2+-release from the ryanodine-sensitive store and Ca2+-influx through L-type channels. Although the NO-induced biphasic response is dependent on cGMP, rapid removal of cGMP seems necessary for the rebound contraction.
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  • Effects of Sarpogrelate, a Novel 5-HT2 Antagonist, on 5-HT-Induced Endothelium-Dependent Relaxations in Porcine Coronary Artery
    Mamunur Rashid, Mikio Nakazawa, Takafumi Nagatomo
    Subject area: Infomation Science
    2002 Volume 89 Issue 4 Pages 405-412
    Published: 2002
    Released on J-STAGE: August 26, 2002
    DOIhttps://doi.org/10.1254/jjp.89.405
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    The aim of the present study was to examine the effects of sarpogrelate, a 5-HT2 antagonist, on 5-HT-induced endothelium-dependent relaxation in isolated porcine coronary artery preincubated with ketanserin (3 × 10−6 M) and precontracted by U 46619 (5 × 10−9 M) and compare its effects with other 5-HT2 antagonists such as ritanserin and cyproheptadine. The investigation showed that sarpogrelate (10−7 – 10−5 M) had a weak antagonistic effect on 5-HT-induced relaxation and its effect was weaker than that of ritanserin (10−9 – 10−7 M) and cyproheptadine (10−8 – 10−6 M). The rank order of the antagonistic effects was: ritanserin > cyproheptadine > sarpogrelate. The study also showed that both sarpogrelate and ritanserin had no inhibitory effect on bradykinin-induced relaxation. In our previous study, we investigated the binding affinity of sarpogrelate, ritanserin and cyproheptadine to the 5-HT2A-receptor in rabbit cerebral cortex membranes and the pKi values found were 7.22, 8.98 and 7.54, respectively (M. Rashid et al., Jpn J Pharmacol 87, 189 – 194, 2001). Rank order of the calculated ratio of concentration of pA2 or pD′2 vs Ki was: sarpogrelate > ritanserin > cyproheptadine. Thus, these findings suggest that sarpogrelate has the lowest antagonistic effect on 5-HT-induced endothelium-dependent relaxation and the highest selectivity towards 5-HT2A receptor and might also be the safest drug with respect to its clinical implications in comparison with ritanserin and cyproheptadine.
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