The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 63, Issue 4
Displaying 1-16 of 16 articles from this issue
  • Hiroichi Nagai, Toshimi Sakurai, Takehisa Iwama, Shuji Yamaguchi, Kuni ...
    1993 Volume 63 Issue 4 Pages 405-413
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Effects of R[+]-8-{[1-[3, 4-dimethoxyphenyl]-2-hydroxyethyl]amino}-3, 7-dihydro-7-[2-methoxyethyl]-1, 3-dimethyl-1H-purine-2, 6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 1) MKS-492 inhibited antigen-induced bronchoconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-induced bronchoconstriction and inhibited the increase in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle invitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen and phospholipase A2-induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced O21 generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF- or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.
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  • Koichi Nagata, Hiroshi Saito, Norio Matsuki
    1993 Volume 63 Issue 4 Pages 415-421
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Purinoceptor-mediated responses were characterized in the ileum of Suncus murinus. Adenosine as well as adenosine 5''-triphosphate (ATP) contracted the ileum in a concentration-dependent manner. Contractile responses to transmural electrical stimulation were attenuated by adenosine only at high concentrations. Theophylline competitively blocked the adenosine-induced contraction. Atropine also inhibited the adenosine-induced contraction but in a non-competitive manner. The ATP-induced contraction was not affected by theophylline, atropine or α, β-methylene ATP. Indomethacin shifted the concentration-response curves for adenosine and ATP to the right. These results suggest that adenosine elicited contractions via direct stimulation of postsynaptic P1-purinoceptors and postsynaptic potentiation of the acetylcholine response. Suncus ileum will be a unique model for the analyses of purinoceptor-mediated responses.
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  • Kiyofumi Yamada, Tomomi Teraoka, Seiji Morita, Takaaki Hasegawa, Toshi ...
    1993 Volume 63 Issue 4 Pages 423-432
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    We attemped to characterize the functional roles of subtypes of voltage-sensitive calcium channels in the brain. The maximal number of [125I]ω-conotoxin GVIA (ω-CTX) binding sites in rat brain associated with N-type calcium channels (N-channels) was approximately 10 times more than that of [3H]-PN200-110 associated with L-type calcium channels (L-channels). [125I]ω-CTX binding was inhibited by aminoglycoside antibiotics, neomycin and dynorphin A(1-13), but not by various classes of L-channel antagonists. A 6-hydroxydopamine-induced lesion of the striatum resulted in a marked reduction of both [125I]-ω-CTX and [3H]PN200-110 binding. Kainic acid-induced lesion of the striatum reduced [3H]PN200-110 binding by 57%, but did not reduce [125I]ω-CTX binding. ω-CTX produced a small (18%) but significant reduction of potassium-stimulated Ca2+ influx into rat brain synaptosomes, although it produced a concentration-dependent inhibition in chick brain synaptosomes. Neomycin inhibited Ca2+ influx in both preparations in a concentration-dependent manner. Both ω-CTX and neomycin inhibited potassium-stimulated [3H]dopamine (DA) release from rat striatal slices. The L-channel antagonists had no effect on either Ca2+ influx or [3H]DA release. These results suggest that DA release in the striatum is regulated by Ca2+ influx through N-channels located in presynaptic nerve terminals, and that the most of the Ca2+ influx in rat brain appears to be governed by neomycin-sensitive, ω-CTX and DHP-resistant calcium channels.
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  • Michiyo Kawakage, Hideaki Mizumoto, Etsuko Nukui, Soichiro Sato, Akira ...
    1993 Volume 63 Issue 4 Pages 433-438
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    ABSTRACT-We examined the effect of KW-3635, a specific thromboxane A2 (TXA2)-receptor antagonist, on the development of lupus nephritis in NZB × NZW Fl mice. KW-3635 was orally given once a day for 33 weeks beginning at eight weeks of age. In the control group, the mice began to die at 39 weeks of age, showing severe proteinuria and histopathologic abnormality in the renal glomeruli. Administration of KW-3635 (30 mg/kg/day) significantly reduced urinary protein excretion (1.7±0.9 vs. 8.5±2.4 mg/6 hr/mouse, P<0.01), mortality (1/18 vs. 6/19, P<0.05) and the histopathologic score of the kidney examined at 41 weeks of age. Thus, chronic administration of KW-3635 markedly attenuated the renal disease in NZB x NZW F1 mice, suggesting that TXA2 is an important mediator of the pathogenesis in this murine model of lupus nephritis.
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  • Yosuke Tojyo, Akihiko Tanimura, Satoko Matsui, Yoshito Matsumoto
    1993 Volume 63 Issue 4 Pages 439-446
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Carbachol (CCh) stimulated K+ release from rat parotid acini. Treatment with the intracellular Ca2+ antagonist 8-(N, N-diethylamino)octyl-3, 4, 5-trimethoxybenzoate (TMB-8) or the intracellular Ca2+ chelator 1, 2-bis(O-aminophenoxy)ethane-N, N, N'', N''-tetraacetic acid (BAPTA) strongly suppressed the CCh-induced K+ release. Combined addition of the Ca2+ ionophore ionomycin and the microsomal Ca2+-ATPase inhibitor thapsigargin caused a rapid increase in cytosolic Ca2+ concentration ([Ca2+]i) and resulted in a marked release of K+. In the absence of extracellular Ca2+, CCh or a combination of ionomycin and thapsigargin caused a transient release of K+ which correlated well with the transient change in [Ca2+]i. On the other hand, phorbol 12-myristate 13-acetate (PMA) did not potentiate the CCh-induced K+ release, although the CCh-induced amylase release was significantly enhanced in the presence of PMA. Staurosporine, a protein kinase C-inhibitor, did not inhibit the CCh-induced K+ release, which was in contrast with its inhibitory effect on amylase release. These results suggest that the K+ release from rat parotid acini induced by CCh stimulation is mediated by a rapid increase in [Ca2+]i but is not associated with activation of protein kinase C. This signal pathway is different from that for amylase release where activation of protein kinase C plays an important role.
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  • Shigeru Nakamura, Hiromu Kawasaki, Koichiro Takasaki
    1993 Volume 63 Issue 4 Pages 447-453
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    The effect of intracerebroventricular (i.c.v.) treatment with a vasopressin (AVP) V1-receptor antagonist on the pressor response to i.c.v. injection of clonidine was investigated in conscious rats with chronic i.c.v. guide cannulas and an arterial catheter. In conscious rats, i.c.v.-injected clonidine (5 and 10 μg) dose-dependently produced a pressor response with a decrease in heart rate. No significant depressor response was induced by clonidine. The i.c.v. pretreatment with an AVP V1-receptor antagonist ([d(CH2)5-Tyr(Me)]-AVP) at 0.5-2.5 μg dose-dependently inhibited the pressor response to 10 μg of i.c.v.-injected clonidine, while systemic (i.v.) pretreatment with the antagonist (2.5 μg) had no effect. In pentobarbital anesthetized rats, 10 μg of i.c.v.-injected clonidine caused a marked depressor response associated with bradycardia. However, i.c.v. pretreatment with the antagonist (2.5 μg) did not affect cardiovascular responses to i.c.v.-injected clonidine. These results suggest that endogenous AVP in the brain is involved in the mechanisms underlying the pressor response to i.c.v.-injected clonidine in conscious rats.
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  • Wataru Asakura, Kinzo Matsumoto, Hiroyuki Ohta, Hiroshi Watanabe
    1993 Volume 63 Issue 4 Pages 455-460
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Effects of REM sleep (REMs) deprivation on the basal swimming activity and the tricyclic antidepressants-induced increase in swimming activity in the forced swimming test were investigated. Immediately after a 48-hr period of REMs deprivation, the basal swimming activity in REMs-deprived mice was significantly higher than those in group-housed and socially isolated animals used as the control groups. The REMs deprivation-induced increase in the swimming activity was not changed by adrenoceptor antagonists and it returned to the control levels 3 hr after the REMs deprivation treatment. Moreover, imipramine and desipramine but not clomipramine further increased the swimming activity enhanced by REMs deprivation at doses that did not affect the activity in the control groups. The enhancing effect of REMs deprivation on the sensitivity to imipramine and desipramine remained unchanged even at 3 hr after the REMs deprivation treatment, and it was blocked by the α2-adrenoceptor antagonist yohimbine. These results suggest that the REMs deprivation-induced increase in basal swimming activity in the forced swimming test is not mediated by adrenoceptor mechanisms, whereas the enhancing effect of REMs deprivation on the sensitivity to imipramine and desipramine may be mediated by the functional changes in α2-adrenoceptors in the brain.
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  • Hiromi Tsushima, Mayumi Mori, Tomohiro Matsuda
    1993 Volume 63 Issue 4 Pages 461-468
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    The mechanisms for the antidiuretic effects of dynorphin (DYN), an endogenous κ-agonist, microinjected into the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei were investigated. DYN decreased the urine outflow rate dose-dependently from 5 to 20 nmol in the SON and PVN, and it increased vasopressin release. Microinjection of des-Tyr-DYN (a non-opioid peptide) into the SON produced antidiuretic effects with similar potency to that of the DYN-induced effects. However, in the PVN, the effects of des-Tyr-DYN were very markedly weaker than those of DYN. The DYN-induced antidiureses in the SON were partially inhibited by phenoxybenzamine, timolol and atropine, but not by naloxone. Those in the PVN were partially inhibited by naloxone, timolol and atropine, but not by phenoxybenzamine. Synthetic specific κ-agonists, U50, 488H and Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Arg-Leu-Arg-Gly 5-aminopentylamide (DAKLI), microinjected into the PVN also produced antidiuretic effects in a dose-dependent manner. The order of antidiuretic potency was DAKLI > DYN > U50, 488H, which was the same as that of κ-receptor binding affinity. The DAKLI-induced antidiureses in the PVN were not inhibited by naloxone. These results suggested that DYN caused antidiureses by vasopressin release, through adrenergic and cholinergic mechanisms in the SON and PVN. Only the DYN-induced effects in the PVN were mediated, at least partially, through opioid receptors, perhaps the κ-subtype.
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  • Manabu Amano, Masaya Hasegawa, Takaaki Hasegawa, Toshitaka Nabeshima
    1993 Volume 63 Issue 4 Pages 469-477
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    We examined the characteristics of 5-min cerebral ischemia-induced behavioral deficits in spontaneous locomotor activity and their effects on the performance of habituation (HAB), passive avoidance (PA) and 8-arm radial maze (RM) tasks in Mongolian gerbils. Performances in HAB, PA and RM were impaired within 2 days after occlusion, and gerbils showed hyperlocomotion during this period. Ten days after ischemia, the hyperlocomotion disappeared and performance in the HAB and PA was the same as that in the sham-operated group. Retention in the RM was impaired at that period, but this impairment was overcome, and retention recovered easily to the sham-operated level with a few additional trials. When the acquisition trial in the RM began at 11 days after occlusion, severe learning impairment was found. Destruction of hippocampal CA1 neurons appears from 2-3 days after ischemic insult, with most CA1 neurons having disappeared by day 7. These findings suggest that the impairment of performance in the HAB and PA within 2 days after occlusion may be related to an early phase of CA1 neuronal death and to hyperlocomotion, although the impairment of spatial learning and memory was clearly associated with CA1 injury 10 days after ischemia.
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  • Koji Takeuchi, Tomohisa Ohuchi, Mitsuhiro Narita, Susumu Okabe
    1993 Volume 63 Issue 4 Pages 479-485
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    We compared the recovery process of gastric mucosal integrity after damage by 20 mM sodium taurocholate (TC) in control, sensory deafferented and indomethacin-treated rats. Under anesthetized conditions, the stomach was mounted on a chamber and perfused with saline or 50 mM HCl. Application of TC (30 min) to the saline-perfused stomach produced a marked reduction in the potential difference (PD) (surface epithelial damage), followed by increases of gastric mucosal blood flow (GMBF) and luminal pH (alkalinization), but there was a rapid recovery of PD without development of gross lesions. Chemical ablation of capsaicin-sensitive sensory nerves had no influence on the PD reduction and luminal alkalinization, but significantly inhibited the rise in GMBF and the PD recovery. Indomethacin pretreatment (5 mg/kg, s.c.) significantly inhibited these changes seen after exposure to TC, except for PD reduction. In contrast, TC caused a sizable amount of H+ back-diffusion and a more pronounced and persistent rise in GMBF in the stomach perfused with 50 mM HCl, yet only minimal damage was observed in the control animals. Under these conditions, both sensory deafferentation and indomethacin inhibited such GMBF responses, leading to hemorrhagic damage without affecting the degree of H+ back-diffusion. These results suggest that capsaicin-sensitive sensory nerves contribute to the recovery of gastric mucosal integrity after damage, probably by maintaining GMBF responses associated with H+ back-diffusion and preventing the later extension to gross damage in the presence of acid.
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  • Yasukuni Hirouchi, Hideo Naganuma, Yukinori Kawahara, Ryuzo Okada, Aki ...
    1993 Volume 63 Issue 4 Pages 487-493
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    The protective effect of N-acyl amino acids (NAAs) against cephaloridine (CER)-induced nephrotoxicity was studied in rabbits. A large single intravenous dose of CER (more than 100 mg/kg) induced severe proximal tubular necrosis. Simultaneous treatment with several NAAs (at dosages of 100, 200 mg/kg, etc., i.v.), such as N-benzoyl-β-alanine (NBBA), N-benzoyl-6-aminocaproic acid, and Nα, ε-dibenzoyl-D, L-lysine, remarkably suppressed the histopathological damage in the kidney induced by CER. NAAs have generally low toxicity in laboratory animals (e.g., the LD50 of NBBA was more than 3, 000 mg/kg, i.v. in rats), and NAAs were suggested to be good candidates for reducing the nephrotoxicity of CER and other β-lactam antibiotics.
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  • Nobuyuki Kishibayashi, Shunji Ichikawa, Toshihide Yokoyama, Akio Ishii ...
    1993 Volume 63 Issue 4 Pages 495-502
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    We investigated the effects of KF18259 (endo-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-isobutyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylate hydrochloride), a novel 5-HT3-receptor antagonist, in a variety of rat models, which are assumed to be mediated via 5-HT3 receptors, in comparison with those of YM060 ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4, 5, 6, 7-tetrahydro-1H-benzimidazole hydrochloride), granisetron and ondansetron. KF18259 inhibited wrap-restraint stress-induced defecation. The doses of KF 18259 to inhibit wrap-restraint stress-induced defecation were lower than those to inhibit the 5-HT-induced von Bezold-Jarisch reflex and the cisplatin-induced slowing of gastric emptying. In contrast, the doses of YM060, granisetron and ondansetron to inhibit these three responses were similar. Moreover, KF18259 inhibited the wrap-restraint stress-induced propulsive motility of the proximal and distal colon. The effect of KF18259 on the distal colon was as potent as that on defecation and was more potent than that on the proximal colon. These results indicate that KF18259 potently inhibits the distal colonic function. KF18259 may be a useful tool for the discrimination of the 5-HT3-receptors located on the distal colon and other tissues.
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  • Hitoshi Kontani, Masumi Jinkawa, Takeshi Sakai
    1993 Volume 63 Issue 4 Pages 503-511
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    We studied the effect of levcromakalim on the function of the urinary tract in rats. Using anesthetized rats, ureteral peristaltic movement of only the ureter region or the ureter with the kidney was in duced by fluid infusion into the ureter lumen. Levcromakalim (0.03 and 0.3 mg/kg, i.v.) exerted a stronger inhibitory effect on the peristaltic movement of the ureter region distant from the pelvis than on that near the pelvis, and the inhibitory effect of levcromakalim (0.03 mg/kg, i.v.) was not antagonized by glibenclamide (0.1 mg/kg, i.v. or 10 mg/kg, i.p.). Topical application of levcromakalim (injection volume, 0.1 ml; 10-4 or 10-3 M), which was injected via a vessel near the ureter inhibited ureteral peristaltic movement and the inhibitory effect levcromakalim (10-4 M), was not antagonized by glibenclamide (10-3M) injected via the same route. Levcromakalim (0.3 mg/kg, i.v.) did not interrupt micturition in anesthetized and conscious rats. In conscious rats, the micturition interval was prolonged; and in anesthetized rats, the peak pressure during micturition was reduced. After injection of levcromakalim (0.3 mg/kg, i.v.), vesicoureteral reflux did not occur. In the movements of the ureter, urinary bladder and urethra, levcromakalim exerted the strongest inhibitory effect on the ureteral peristalsis.
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  • Hideaki Kusaka, Akira Karasawa
    1993 Volume 63 Issue 4 Pages 513-519
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Effects of repeated administration of KW-3902, a novel adenosine A1-receptor antagonist, on its pharmacological actions were studied with regards to: 1) in vivo adenosine A1-antagonism, 2) diuretic effects and 3) renal protective effects against glycerol-induced acute renal failure (ARF). After repeated oral administration of KW-3902 (0.1 mg/kg/day) for 24 days, neither enhancement of the sensitivity to 5''-N-ethylcarboxamidoadenosine (NECA) nor reduction of the inhibitory effect of KW-3902 on the NECA-induced bradycardic response were observed. After repeated oral administration of KW-3902 (0.01 and 0.1 mg/kg/day) for 20 days, the diuretic effects of KW-3902 did not change. Renal protective effects against glycerol-induced ARF were not reduced by repeated oral administration of KW-3902 (0.01 and 0.1 mg/kg/day) for 23 days. These results suggest that repeated oral administration of KW-3902 has no effect on its pharmacological actions. Additionally, changes in serum parameters, which occurred after repeated administration of furosemide or trichlormethiazide, were minimal after repeated oral administration of KW-3902 (0.001-1 mg/kg/day) for 27 days. From these results, KW-3902 proved to be a diuretic which has renal protective effects with less side effects.
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  • Katsuya Higo, Akira Karasawa
    1993 Volume 63 Issue 4 Pages 521-523
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    The antithrombotic effects of the thromboxane (TX) A2-receptor antagonist and aspirin were determined using a photochemically-induced arterial thrombosis model in the femoral arteries of guinea pigs. KW-3635 (sodium (E)-11-[2-(5, 6-dimethyl-1-benzimidazolyl)ethylidene]-6, 11-dihydrodibenz[b, e]-oxepine-2-carboxylate monohydrate) and BM-13505, both of which are TXA2-receptor antagonists, and aspirin inhibited the thrombus formation at the doses that inhibited the ex vivo platelet aggregation induced by sodium arachidonate (100 μM) or collagen (3 μg/ml). These results support the notion that TXA2 is an important mediator in the present model of arterial thrombogenesis.
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  • Atsushi Tomaru, Akio Ishii, Nobuyuki Kishibayashi, Akira Karasawa
    1993 Volume 63 Issue 4 Pages 525-528
    Published: 1993
    Released on J-STAGE: April 12, 2006
    JOURNAL FREE ACCESS
    Colonic motility was measured with three catheter pressure transducers that were inserted into the descending colon at the distance of 4 cm, 6 cm and 8 cm from the anal verge in anesthetized rats. Colonic infusion of glycerol (65%, 2 ml/kg) induced large phasic pressure changes with high amplitude and long duration. Some of the pressure changes propagated over all the three recording sites, appearing to be equivalent to giant migrating contractions. These glycerol-induced large propulsions were abolished by lidocaine (5%, 2 ml/kg, intracolon), hexamethonium (10 mg/kg, i.v.) or clonidine (30 μg/kg, i.v.); and they were almost entirely suppressed by atropine (3 mg/kg, i.v.), suggesting the principal involvement of the cholinergic neural pathway.
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