The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
69 巻, 1 号
選択された号の論文の10件中1~10を表示しています
  • Kinya Kuriyama, Seitaro Ohkuma
    1995 年 69 巻 1 号 p. 1-8
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    Nitric oxide (NO), an unstable radical formed via oxidative deamination of L-arginine by NO synthase, has the activity to evoke release of several neurotransmitters including acetylcholine, catechol-amines and neuroactive amino acids. N-methyl-D-aspartate (NMDA) receptor stimulation also causes neurotransmitter release through NO formation, which is supported by the data that extracellular hemoglobin ompletely abolishes the stimulatory effect of NMDA on neurotransmitter release. In addition, NO formed by NMDA receptor activation exhibits its stimulatory action on neurotransmitter release extracellularly. A product formed by the reaction of NO and superoxide, peroxynitrite, is also considered to be partly involved in NO-evoked neurotransmitter release. The removal of Ca2+ or Na+ significantly reduces the release of GABA evoked by an NO generator, S-nitroso-N-acetylpenicillamine (SNAP), and simultaneous withdrawal of these ions completely abolishes the SNAP-induced release of GABA. Either in the presence or absence of Ca2+, GABA transport inhibitors such as nipecotic acid dose-dependently suppress the SNAP-induced GABA release in the presence of Na+. These results indicate that NO-evoked neurotransmitter release is mediated by two distinct release systems, a Ca2+-dependent system and the reverse process of a Na+-dependent carrier-mediated transport system.
  • Shingo Yano, Yuko Kiyota, Masayuki Yamamoto, Kazuo Watanabe
    1995 年 69 巻 1 号 p. 9-15
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    The non-adrenergic non-cholinergic (NANC) relaxatory response in mouse isolated whole stomach was investigated by electrical vagal stimulation (EVS) to clarify whether nitric oxide (NO) mediates vagal NANC transmission. The stomach was mounted in an organ bath, and the intragastric pressure was measured. Dual electrodes were placed on the esophagus. In the presence of atropine, propranolol and phentolamine, EVS induced a marked gastric relaxation. The response was frequency-dependent, and reproducible by repeated stimulation. The response was blocked by hexamethonium and NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor, and significantly depressed by methylene blue, a soluble guanylate cyclase inhibitor, but not by hemoglobin, a radical trapping agent. The inhibitory effect of L-NNA was reversed by L-arginine, a substrate for NO synthase, but not by D-arginine. Exogenous NO caused a relaxation that was inhibited by hemoglobin and methylene blue, but not by L-NNA. The electrical field stimulation also elicited a gastric relaxation that was inhibited by L-NNA and methylene blue, but not by hexamethonium and hemoglobin. These results suggest that the inhibitory NANC response to EVS in the mouse stomach is largely mediated by release of NO, and it is exclusively due to stimulation of vagal preganglionic neurons.
  • Norihisa Inazu, Tomoko Fujii
    1995 年 69 巻 1 号 p. 17-22
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    We investigated the effects of maternal parathyroidectomy on day 5 of pregnancy on the ovarian carbonyl reductase (CR) in the offspring of rats. Changes in the ovarian CR of the offspring were examined at 4 and 8 months of age. In 8-month-old female offspring, the ovarian weight and the ovarian CR activity were significantly higher in rats from parathyroidectomized mothers than in rats from sham-operated mothers, and the offspring of the parathyroidectomized mothers showed the regular 4-day estrous cycles at 8 months of age, while the offspring of the sham-operated mothers were in the state of persistent estrus. Furthermore, intense immunostaining was found in the theca interna cells and the interstitial gland cells in the ovary of rats from the parathyroidectomized mothers, whereas in the ovary of the age-matched normal rats, immunostaining was faint. These results suggest that the maternal parathyroidectomy affect the activity and localization of CR in the ovary of female offspring.
  • Nagao Suzuki, Tomoko Shibayama, Terumi Mambo, Yasuo Gomi
    1995 年 69 巻 1 号 p. 23-28
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    Spontaneous tone of longitudinal muscle in guinea pig ileum was investigated in three types of preparations, intact segment preparation, segment preparation deprived of the mucosal layer and longitudinal strip preparation. Tone was defined as the sustained contraction that was lost by 10-7 M atropine in the isotonically recorded manner. The magnitudes of tone were constant for at least 3 hr in the two types of segment preparations. Contractions in response to 10-6 M acetylcholine, which were induced 9 times with an interval of 20 min between each induction, were almost identical throughout the period. In the longitudinal strip preparation, on the other hand, the tone gradually decayed and was eventually lost, while the amplitudes of acetylcholine-induced contractions were reciprocally increased. The tone in the intact segment preparation was reduced to 19% of the control by tetrodotoxin (3 x 10-7 M), to 51 % by indomethacin (3 x 10-6 M) and to 26% by N6-cyclopentyladenosine (10-7 M), but was not affected by AA-861 (3 x 10-6 M) or CP-96, 345 (3 x 10-7 M). In the three types of preparations, the dose-response curves for acetylcholine were alike with similar EC50s. These results suggest that the tone of longitudinal muscle was mainly induced due to neural activity in the myenteric plexus of guinea pig ileum and that sensitivity to acetylcholine was not affected by the neural activity.
  • Jun Tamaoki, Mitsuko Kondo, Atsushi Chiyotani, Hisashi Takemura, Kimio ...
    1995 年 69 巻 1 号 p. 29-35
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    The effect of Saiboku-to (TJ-96), an antiasthmatic Kampo medicine, on the generation of nitric oxide (NO) from cultured canine tracheal epithelium was investigated using a highly specific amperometric sensor for this molecule in vitro. Immersion of the NO-selective electrode in the medium containing tracheal epithelial cells detected the baseline current of 16.8 - 57.0 pA, which corresponded to an NO concentration ([NO]) of 39.7 ± 8.1 nM. Addition of TJ-96 increased [NO] in a concentration-dependent manner, the maximal increase from the baseline level and the concentration of TJ-96 required to produce a half-maximal effect (EC50) being 127.5 ± 20.1 nM (P < 0.001) and 86 ± 9 μg/ml, respectively. Pretreatment of cells with NG-nitro-L-arginine methylester (L-NAME) greatly inhibited the TJ-96-induced increase in [NO], whereas NG-nitro-D-arginine methylester (D-NAME) had no effect, and this inhibition was reversed by L-arginine but not by D-arginine. Cytochemical staining of the epithelial cells showed marked reactivity of NADPH diaphorase activity. These results suggest that NO is spontaneously released by the airway epithelium and that TJ-96 stimulates the epithelial NO generation.
  • Shinji Uchida, Takashi Morishita, Yutaka Ikeda, Toshihiro Akashi
    1995 年 69 巻 1 号 p. 37-41
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    The anti-inflammatory effect of flurbiprofen tape (FP-T) by topical application was investigated, and the findings were compared with the results of oral administration of flurbiprofen to adjuvant arthritic rats. The topical application of FP-T significantly suppressed both applied and non-applied hind paw edema, with a potency similar to that seen with the oral administration of flurbiprofen. Body weight also increased with these treatments. Plasma levels of flurbiprofen differed little between topical application of FP-T and oral administration of flurbiprofen. Gastric damage induced by topical application of FP-T was significantly less than that seen in case of oral administration of flurbiprofen. These results suggest that the anti-inflammatory effects of FP-T cannot be entirely explained by flurbiprofen permeating inflamed tissue below the application site; rather, flurbiprofen penetrating into the systemic circulation may explain these actions.
  • Toshihiko Murayama, Haruko Oda, Asako Watanabe, Yasuyuki Nomura
    1995 年 69 巻 1 号 p. 43-51
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    Phospholipase A2 has recently been proposed as the effector enzyme involved in the receptor-mediated release of arachidonic acid (AA). Released AA and its metabolites have been demonstrated to play an important role in the regulation of cell functions. [3H]AA release from prelabeled PC12 cells was stimulated by a Ca ionophore such as ionomycin or A23187. Although ATP and its effective analogs, adenosine 5’-O-(3-thiotrisphosphate) (ATPγS), 2-methylthio ATP and 3’-O-(4-benzoyl)benzoyl ATP, did not stimulate [3H]AA release on their own, they did enhance Ca ionophore-stimulated [3H]AA release. The effect of ATP analogs was dose-dependent. ADP, UTP, GTP, ITP, αβ3-methylene ATP, βγ-methylene ATP and 8-bromo ATP showed no effect or very limited effect. The effect of ATPγS was antagonized by suramin, a putative P2Y receptor antagonist. The effective ATP analogs also increased [Ca2+], (cytosolic free Ca2+ concentration) via Ca 2+ influx. However, the addition of 50 mM KCl or 10 μM bradykinin, which are well-known to increase [Ca2+]; by different pathways, did not stimulate [3H]AA release, either with or without the Ca ionophore. The addition of phorbol 12-myristate 13-acetate, an activator of protein kinase C, showed no effect on [3H]AA release, either with or without the Ca ionophore. These data suggest that 1) ATP increased Ca ionophore-stimulated AA release via a P2Y-like ATP receptor, and that 2) the elevation of [Ca2+]; by ATP does not quantitatively explain the ATP-stimulated AA release in PC12 cells.
  • Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Sakiko Higashinakagaw ...
    1995 年 69 巻 1 号 p. 53-60
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-melinamide or CL-277, 082.
  • Hideo Inoue, Nobuyuki Nagata, Yasuko Koshihara
    1995 年 69 巻 1 号 p. 61-68
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    We investigated the involvement of serotonin (5-HT) in mouse ear edema induced by topical application of capsaicin (250μg/ear). Application of capsaicin to the ear caused degranulation of mast cells in skin connective tissue. Capsaicin-induced ear edema was significantly inhibited by preadministration of 5-HT2 receptor antagonists such as ketanserin (2 mg/kg, i.v.) and LY 53857 (1 mg/kg, i.v.), but not 5-HT1-, 5-HT3- and 5-HT4-receptor antagonists. Intradermal injection of α-methyl 5-HT (5-HT2-receptor agonist) and 5-HT into ear skin produced edema formation more potently than 8-OH-DPAT (5-HT1A agonist) and 2-methyl 5-HT (5-HT3 agonist). 5-HT2 antagonists markedly suppressed the edema response to 5-HT and its receptor agonists, whereas any antagonist for 5-HT1, 5-HT3 and 5-HT4-receptors had no effect. Furthermore, 5-HT2-receptor antagonists partly prevented ear edema in response to substance P (SP), a putative mediator of capsaicin-induced edema, and compound 48/80, a releaser of vasoactive amines from mast cells. These results suggest that 5-HT released from mast cells is partly involved in the development of capsaicin-induced mouse ear edema via 5-HT2 receptors in the ear skin.
  • Yasuhiro Kita, Shinichi Fukuyama, Yoshimi Hirasawa
    1995 年 69 巻 1 号 p. 69-74
    発行日: 1995年
    公開日: 2006/04/07
    ジャーナル フリー
    The aim of this study was to clarify the difference in the profiles of nitric oxide (NO) formation of three NO releasers and to examine the correlation between NO formation from these drugs and their biological activities in rats. (±)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and 3-morpholinosydnonimine (SIN-1) spontaneously generated nitrite, an oxidative product of NO, in sodium phosphate buffer (PB) solution. On the other hand, sodium nitroprusside (SNP) did not generate nitrite. The rank order of the concentrations of nitrite generated was SIN-1 › FK409 » SNP. In biological studies using rats, these drugs showed anti-platelet effects and in vitro vasorelaxant and hypotensive effects with potencies in the rank order of FK409 › SIN-1 › SNP and SNP › FK409 › SIN-1, respectively. These drugs generated nitrite with concentrations in the rank order of FK409 › SIN-1 › SNP and SNP › FK409 › SIN-1 in rat plasma and in PB solution with L-cysteine (Cys), respectively. In conclusion, three NO releasers liberate NO with NO-releasing rates of different rank orders under different incubation conditions, and the anti-platelet effects and vasorelaxant and hypotensive effects of these NO releasers closely correlate with NO formation from the compounds in the plasma and PB solution with Cys, respectively, but not with that in PB solution without Cys.
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