The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 55 , Issue 4
Showing 1-17 articles out of 17 articles from the selected issue
  • Yuji Odagaki, Tsukasa Koyama, Shigehiro Matsubara, Itaru Yamashita
    1991 Volume 55 Issue 4 Pages 407-414
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    The effects of lithium on the β-adrenoceptor-adenylate cyclase system in cerebral cortical membranes of rats were investigated. Lithium chloride inhibited adenylate cyclase activity in a concentration-dependent manner in vitro. However, relatively high concentrations of lithium were needed for this inhibition; and at 1 mM, no significant reduction in adenylate cyclase activity was seen under any condition. Administration of lithium carbonate for 21 days decreased the maximum number of [3H]dihydroalprenolol binding sites without changing the apparent dissociation constant. Activation of adenylate cyclase by (-)-isoproterenol in the presence of 1 μM guanyl-5'-ylimidodiphosphate (Gpp(NH)p) was significantly attenuated in lithiumtreated rats compared with the controls. Lithium treatment reduced the Gpp(NH)pstimulated adenylate cyclase activity in the presence of 10 μM (-)-isoproterenol, but not in the absence of this β-adrenergic receptor agonist. Basal activity or adenylate cyclase activity stimulated by forskolin or manganese was not affected, whereas the activity stimulated by sodium fluoride was significantly attenuated by long-term lithium treatment. These results indicate that chronic lithium treatment induces subsensitivity in the β-adrenoceptor-adenylate cyclase system, for which down-regulation of β-adrenergic receptors is chiefly responsible.
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  • Satoshi Yamazaki, Makoto Kawamura, Mariko Kitsukawa, Kentaro Ando, Iss ...
    1991 Volume 55 Issue 4 Pages 415-424
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Re-peated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Con-cerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimu-li. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.
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  • Hideaki Nagaya, Nobuhiro Inatomi, Hiroshi Satoh
    1991 Volume 55 Issue 4 Pages 425-436
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Antisecretory effects of a substituted benzimidazole, (±)-2-[[[3-methyl-4-(2, 2, 2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (AG-1749) were compared with those of a histamine H2-receptor antagonist, famotidine. AG-1749 in-hibited acid formation regardless of the stimulant in isolated canine parietal cells, while famotidine inhibited the histamine-stimulated acid formation selectively. In pylorus-ligated rats, AG-1749 suppressed basal acid secretion, histamine-, bethanechol-, pentagastrin-, 2-deoxy-D-glucose- and stress (restraint and water-immersion)-induced acid secretion; ID50 values were 1.0-6.0 mg/kg. On the other hand, famotidine only partially inhibited the acid secretion induced by 2-deoxy-D-glu-cose or stress, although it suppressed the acid secretion stimulated by other secretagogues several times more potently than AG-1749. The antisecretory effect of AG-1749 lasted longer than that of famotidine, especially in the case of bethanechol-stimulated acid secretion. In Heidenhain pouch dogs, both AG-1749 and famotidine potently inhibited histamine-, bethanechol-, pentagastrin- and peptone meal-stimulated acid secretion, but the inhibitory effect of famotidine was short-lived in the case of bethanechol- and pentagastrin-stimulated acid secretion. These results suggest that AG-1749 persistently inhibits acid secretion induced by both peripheral and central stimuli and suggest that the antisecretory effect of famotidine depends on the nature of the stimuli.
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  • Nobuhiro Inatomi, Hideaki Nagaya, Kenji Takami, Akio Shino, Hiroshi Sa ...
    1991 Volume 55 Issue 4 Pages 437-451
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    The effects of (±)-2-[[[3-methyl-4-(2, 2, 2-trifluoroethoxy-2-pyridyl]methyl]-sulfinyl]-1H-benzimidazole (lansoprazole, AG-1749) and famotidine on various experimental ulcers in rats were compared. AG-1749 inhibited reflux esophagitis; gastric lesions induced by water-immersion stress, aspirin or ethanol; and duodenal ulcers induced by cysteamine or mepirizole in a dose-dependent manner: the ID50 values were0.7, 2.4, 0.7, 8.5, 1.1 and 0.3 mg/kg, p.o. or i.d., respectively. Famotidine inhibited reflux esophagitis with an ID50 value of 12.9 mg/kg, but did not cause 50% inhibition of ethanol-induced gastric lesions even at 100 mg/kg, although it showed almost the same or a little stronger potency on other experimental ulcers: ID50 values were 0.3-1.4 mg/kg. Significant aggravation of ethanol- or water-immersion stress-induced lesions was observed in rats given famotidine at 30 mg/kg twice daily for 4 days, but not in rats given AG-1749 at 10 mg/kg twice daily. Administration of AG-1749 for 14 consecutive days markedly accelerated the healing of acetic acid-induced gastric and duodenal ulcers, and the healing effect was significant at 10 and 30 mg/kg/day, p.o. Famotidine also accelerated the healing of ulcers, but its potency was less than that of AG-1749. The results of this study indicate that although AG-1749 is slightly less po-tent than famotidine in inhibiting acutely induced gastroduodenal lesions, this agent is superior to famotidine in promoting the healing of ulcers and in inhibiting reflux esophagitis and ethanol-induced gastric lesions.
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  • Kyoji Taguchi, Yukihiko Hagiwara, Yukiko Suzuki
    1991 Volume 55 Issue 4 Pages 453-459
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    We investigated the effects of β-phenylethylamine (PEA) on photicevoked potentials recorded from the cerebral cortex (visual cortex) in the anesthetized cat. The photic-evoked potential consisted of negative (N) and positive (P) components in the cerebral cortex, with peak times of 39.4 ± 15.4 msec and 57.5 ± 16.3 msec, respectively. Intravenous administration of PEA (6.5, 12.5 and 25 mg/kg) induced a dose-dependent decrease in the amplitude of the N component of photicevoked potentials. PEA-induced decreases in the amplitude of photic-evoked potentials (at 12.5 mg/kg) were antagonized by yohimbine (2 mg/kg). Prazocin (2 mg/kg, i.v.) and propranolol (0.5 mg/kg, i.v.) did not change the PEA-induced decrease of photic-evoked potentials. Methysergide (2 mg/kg, i.v.), haloperidol (1 mg/kg, i.v.) and naloxone (0.5 mg/kg, i.v.) also failed to alter the inhibitory effect of PEA. Pretreatment with α-methyl-p-tyrosine or reserpine did not completely attenuate the PEA-induced decrease of photic-evoked potentials. According to these results, PEA inhibits the photic-evoked potentials in the visual cortex partially through the noradrenergic α2-receptor.
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  • Toshihiro Shinosaki, Yukio Yonetani
    1991 Volume 55 Issue 4 Pages 461-468
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Stimulation of uric acid production by the well-known uricosuric drug probenecid was studied using potassium oxonate-treated rats and eviscerated rats subjected to functional hepatectomy. In oxonate-treated rats, probenecid was hyperuricosuric, increasing the glomerular-filtered amounts of uric acid and causing marked hyperuricemia. This could be completely blocked by combination dosing with allopurinol, an inhibitor of xanthine oxidase. In eviscerated rats subjected to functional hepatectomy, probenecid also increased plasma uric acid and urinary uric acid excretion, but when given together with allopurinol, the increase of plasma uric acid was abolished with a remarkable increase of plasma hypoxanthine and xanthine. When probenecid was given by combination dosing with propranolol, a beta adrenoceptor antagonist, the hyperuricemia was also completely blocked. Thus, probenecid is concluded to stimulate uric acid production, probably via some interaction with endogenous catecholamine, resulting in hyperuricemia in rats, although it is a practical hypouricemic drug in humans.
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  • Kazuhide Yoshida, Masaaki Yamazaki, Noboru Toda
    1991 Volume 55 Issue 4 Pages 469-475
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    In coronary, renal and femoral arteries and mesenteric veins isolated from Japanese monkeys, tachyphylaxis to angiotensin (ANG) II (10-7M)-induced contraction rapidly developed. Contractions caused by ANG II in coronary arteries were attenuated by treatment with indomethacin and aspirin and also by endothelium denudation. Indomethacin inhibited the response of the arteries with and without endothelium to a similar extent. OKY 046, a thromboxane A2 synthesis inhibitor, failed to inhibit the response. In contrast, contractions of renal arteries were potentiated and prolonged by the cyclooxygenase inhibitors. ANG II-induced contractions of mesenteric veins were prolonged but those of femoral arteries were not altered by indomethacin. It is concluded that ANG II contracts monkey coronary arteries, possibly due to the release of vasoconstrictor prostanoids but not thromboxane A2 from endothelial and subendothelial tissues and also due to its direct action on smooth muscle, whereas contractions of renal arteries and mesenteric veins are blunted by vasodilator prostanoids, possibly PGI2. Cylooxygenase products even if released do not appear to regulate femoral artery contractions produced by ANG II.
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  • Susumu Okabe, Yasushi Akimoto, Shinichi Yamasaki, Kayoko Kuwahara
    1991 Volume 55 Issue 4 Pages 477-491
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    We examined the effects of a new compound, NC-1300-0-3 {2-[2-N-methyl -N-(2-methylpropyl) amino] benzylsulfinyl benzimidazole}, on the gastric mucosal proton pump (H+, K+-ATPase) activity, gastric secretion and gastroduodenal lesions in rats. The compound potently inhibited the enzyme activity in a concentration-dependent manner, the IC50 being 5.3 × 10-6 M at pH 6.0 and 1.4 × 10-5 M at pH 7.4. NC-1300-0-3 markedly and persistently (for more than 24 hr) inhibited basal gastric secretion in male or female animals when administered by the p.o. route. The compound also significantly inhibited gastric secretion by the intraduodenal (i.d.), intragastric (after pylorus ligation) and i.p. routes, but only weakly by the s.c. route. Repeated p.o. administration of the compound for 1 week also significantly inhibited gastric secretion. Histamine-stimulated gastric secretion was also significantly inhibited by the i.d. administration of the compound. NC-1300-0-3, administered p.o., potently prevented water-immersion stress-, histamine-, indomethacin-, prednisolone and compound 48/80-induced gastric lesions. In addition, it also significantly prevented the formation of gastric lesions induced by various necrotizing agents. Mepirizole and cysteamine-induced duodenal ulcers were also prevented by the compound. The antisecretory and antilesion activities of NC-1300-0-3, administered p.o., were not altered on its combination with 2% NaHCO3.
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  • Fusao Ueda, Masayoshi Watanabe, Yoshihisa Hirata, Takashi Kyoi, Kiyosh ...
    1991 Volume 55 Issue 4 Pages 493-499
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Changes in the cyclic AMP (cAMP) content of the gastric mucosa induced by ulcerogenic stimuli were investigated in rats. Ligation of the pylorus for 5 hr produced no glandular mucosal lesion, but increased the cAMP content in the fundus and antrum. Aspirin produced glandular mucosal lesions in the pylorus-ligated rats and caused an increase of the cAMP content in the fundus and a decrease in the antrum. Irsogladine maleate (IM), an antiulcer agent, inhibited both the changes in the cAMP content and the mucosal damage induced by aspirin. IM increased the cAMP content in both regions, especially the antrum, in normal rats. Dibutyryl cAMP (dbcAMP) given orally prevented the gastric mucosal lesions induced by aspirin without affecting gastric secretion. These results suggest that 1) the changes in the cAMP content of the fundus and antrum induced by aspirin may be associated with the formation of glandular mucosal damage, 2) the antiulcer activity of IM may be ralated to an increase of the cAMP content in mucous cells, and 3) dbcAMP given orally may penetrate into the surface mucous cells and activate defensive functions. Thus, cAMP in the mucous cells may protect the gastric mucosa.
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  • Kenji Hirate, Hisashi Kuribara
    1991 Volume 55 Issue 4 Pages 501-511
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Behavioral effects of a dopamine uptake inhibitor, GBR-12909 (GBR), were evaluated by ambulatory activity in mice. The single administration of over 10 mg/kg of GBR, i.p. and p.o., significantly increased the ambulatory activity. The repeated administration of GBR, at only 10 mg/kg, produced a reverse tolerance to its ambulation-increasing effect. However, a cross-reverse tolerance was induced between GBR (10 and 20 mg/kg) and methamphetamine (2 mg/kg) in both directions. Furthermore, 5 mg/kg of GBR significantly enhanced the effects of methamphetamine, cocaine, imipramine, morphine, scopolamine and caffeine. R-THBP, a coenzyme of tyrosine hydroxylase, also enhanced the effect of GBR. In contrast, the ambulationincreasing effect of 10 mg/kg of GBR was markedly reduced by haloperidol, chlorpromazine, tetrabenazine, oxypertine, reserpine and α-methyl-p-tyrosine. On the other hand, the effect of GBR was only slightly and/or scarcely modified by apomorphine, caerulein, physostigmine, pilocarpine, N6-(L-2-phenylisopropyl)-adenosine and naloxone. The neurochemical experiment in rats, not in mice, revealed that GBR possessed more dominant action on dopaminergic systems than noradrenergic or serotonergic systems. However, the behavioral characteristics of GBR are similar to those of methamphetamine and cocaine, which possess less selective action than GBR on dopaminergic and noradrenergic systems.
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  • Issei Takayanagi, Shuji Onozuka, Katsuo Koike
    1991 Volume 55 Issue 4 Pages 513-522
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Sensitivity (pD2 value, negative logarithm of the molar concentration producing the half maximum response) and affinity (pKA value, negative logarithm of dissociation constant) of norepinephrine were determined in 6 arteries from rabbits. A positive correlation was found in the pD2 and pKA values of norepinephrine. The slope was not significantly different from 1. The pD2 and pKP (a negative logarithm of dissociation constant of a partial agonist) values of tizanidine, an α1-partial agonist, were also determined. There were positive correlations between the pD2 and pKP values of tizanidine and also between the two pD2 values of norepinephrine and tizanidine. The slopes were not significantly different from 1. These results suggest that the regional differences in pD2 values of norepinephrine and tizanidine in the arteries are partly due to the affinity and suggest that both drugs interact with one recognition site in the α1-adrenoceptors. The dissociation constants, KD values, and the maximum binding sites, Bmax, for [125I]-HEAT were also estimated by Scatchard analysis of the specific binding of [125I]-HEAT to the membrane fractions from rabbit arteries. The KD values for [125I]-HEAT were also identical. However, Bmax varied considerably among rabbit arteries. There was a positive correlation between the logarithm of Bmax and the pD2 values for norepinephrine. The present results suggest that the regional difference in the pD2 values for norepinephrine in rabbit arteries is due to variations in the affinities to the α1-adrenoceptors as well as the receptor densities.
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  • Mamoru Ono, Tetsuo Satoh
    1991 Volume 55 Issue 4 Pages 523-530
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    The pain response of mice to an injection of 0.5% formalin into the dorsal surface of a hindpaw is biphasic, with a first phase lasting for 5 min and a second phase lasting from 10 to 30 min post-injection. Intrathecal (i.t.) injection of [D-Pro2, D-Trp7, 9]-substance P inhibited the first phase, and i.t. cysteamine inhibited the second phase. Lappaconitine (LA) and morphine (MOR) inhibited both phases equally in a dose-dependent manner. Diclofenac inhibited both phases, but the second phase was inhibited by lower doses. An Lt. injection of substance P (SP) or somatostatin (SOM) produced a characteristic behavioral response (scratching, biting, and licking). This behavioral response to SP and SOM was inhibited by s.c., intracerebroventricular (i.c.v.), or Lt. injection of MOR. In contrast, LA inhibited the SP and SOM-induced response when injected s.c. or i.c.v., but had no effect when injected intrathecally. These results indicate that LA may act supraspinally to inhibit the transmission of nociceptive information by SP and/or SOM.
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  • Hiroyuki Mizuno, Nobuhisa Iwase, Yutaka Kawamura, Hiromitsu Ohno, Tomo ...
    1991 Volume 55 Issue 4 Pages 531-537
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    The effects of muscarinic antagonists on acetylcholine (ACh)- and histamine-induced nasal secretion were investigated in guinea pigs. Inhalations of flutropium (0.01 to 0.3%) and atropine (0.03 to 0.3%) into the nasal cavities dose-dependently inhibited the nasal secretion induced by ACh. The inhibitory action of flutropium was slightly stronger than that of atropine. Inhalations of pirenzepine (0.3%) and gallamine (0.3%) had no effect on the ACh-induced nasal secretion. However, 4DAMP dose-dependently inhibited the nasal secretion induced by ACh. Inhalations of flutropium (0.3%) and diphenhydramine (0.3%) showed a similar inhibitory action on the histamine-induced nasal secretion. These results suggest that 1) inhalation into the nasal cavities of flutropium was effective in experimental model of ACh and histamine-induced nasal secretion, 2) M3 cholinergic receptors may be dominant in the nasal secretion induced by ACh and 3) the experimental model of drug-induced nasal secretion in guinea pigs used in the present study can be employed to develop therapeutic drugs for nasal secretion.
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  • Masahiro Nishibori, Ryozo Oishi, Yoshinori Itoh, Kiyomi Saeki
    1991 Volume 55 Issue 4 Pages 539-546
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    The effect of 9-amino-1, 2, 3, 4-tetrahydroacridine (THA) on histamine N-methyltransferase (HMT), an enzyme catalyzing the methylation of histamine to form tele-methylhistamine in the brain, was studied in vitro using a partially purified enzyme preparation from bovine brain and in vivo in the mouse brain. THA inhibited the HMT activity in competitive and non-competitive mixed type manners with respect to histamine. The Ki and Ki' values were 75 nM and 1.2 μM, respectively. The IC50 values for THA, 9-aminoacridine and physostigmine in the inhibition of HMT determined at fixed concentrations of histamine (20 μM) and S-adenosylmethionine (50 μM) were 0.2, 0.37 and 20 μM, respectively. Neostigmine exhibited only 15% inhibition even at a concentration of 100 μM. THA (2-10 mg/kg, s.c.) dose-dependently inhibited HMT in the mouse brain. The inhibition of HMT by THA (10 mg/kg) was marked at 30 and 60 min after treatment, but disappeared by 120 min after. THA (10 mg/kg) significantly increased the histamine level and decreased the tele-methylhistamine level in the mouse brain. These results indicate that THA is a potent inhibitor of HMT.
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  • Toshihiro Dohi, Shin'ichi Anamura, Masaharu Shirakawa, Hiroshi Okamoto ...
    1991 Volume 55 Issue 4 Pages 547-550
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Eugenol dose-dependently inhibited 5-HETE (5-hydroxy-5, 8, 10, 14-eicosatetraenoic acid) and 15-HETE formation by human polymorphonuclear leucocytes. p-Chlorophenol, guaiacol and phenol also inhibited the lipoxygenases. Formation of HETEs by rat dental pulp was inhibited by eugenol and p-chlorophenol. The concentrations of the phenolics required to inhibit lipoxygenases were in the similar range with those used for inhibiting cyclooxygenase. These results showed that phenolic compounds inhibited lipoxygenases and thus suggest that these compounds may be dual inhibitors of lipoxygenase and cyclooxygenase.
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  • Masaaki Ishikawa, Kenroh Sasaki, Kimiko Nishimura, Yoshio Takayanagi, ...
    1991 Volume 55 Issue 4 Pages 551-554
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Carrageenan-induced inflammation and exposure to endotoxin considerably decreased the content of cytochrome P-450 and activities of ethylmorphine N-demethylase and meperidine N-demethylase, but did not decrease the activities of aniline hydroxylase or NADPH-cytochrome c reductase, compared with the respective activities in rats treated with carrageenan alone. These results suggest that under these experimental conditions, the two host-related environmental factors interact and enhance a decrease in rat hepatic microsomal drug metabolizing enzymes depending on the substrate used.
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  • Masakatsu Takahashi, Tomoko Okada, Hiroshi Kaneto
    1991 Volume 55 Issue 4 Pages 555-558
    Published: 1991
    Released: July 11, 2006
    JOURNALS FREE ACCESS
    Concomitant treatment with phentolamine, an α-blocker, or with propranolol, a β-blocker, suppressed the development of morphine tolerance in shamoperated (Sham) mice. In adrenalectomized (ADX) mice, daily morphine developed tolerance as well as in the Sham group, and concurrent phentolamine suppressed the development of tolerance, whereas such suppression by propranolol was abolished. Supplemental treatment of ADX mice with dexamethasone did not restore the suppressive effect of propranolol. These results suggest that defferent mechanisms underlie the prevention of tolerance development by α- and β-blockers, and that adrenal cortex does not seem to participate in the suppression by β-blockers.
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