The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
76 巻, 2 号
選択された号の論文の14件中1~14を表示しています
Review
  • Toshihiko Murayama, Yasuyuki Nomura
    1998 年 76 巻 2 号 p. 129-139
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    Nitrogen monoxide (NO) has been suggested to be involved in many physiological and pathological functions. In rat hippocampus, chemical NO donors stimulated noradrenaline release in the presence of thiols such as dithiothreitol and L-cysteine. S-Nitrosocysteine, which is proposed to be a stable and endogenous S-nitrosothiol molecule, stimulated noradrenaline release by itself. The effect of S-nitrosothiol on noradrenaline release was calmodulin-dependent and cyclic GMP-independent. S-Nitrosocysteine was incorporated into the slice via the L-type-like amino acid transporter. These findings suggest the physiological significance of S-nitrosocysteine on neurotransmitter release and propose the existence of a specific uptake system of S-nitrosothiols in neuronal tissues. In rat thymocytes, chemical NO donors inhibited DNA synthesis. Hydrocortisone treatment in vivo inhibited DNA synthesis via the expression of the inducible NO synthase protein, and the accumulation of NO and cyclic GMP. Although it is known that glucocorticoids regulate inducible NO synthase expression negatively in several types of cells in vitro, glucocorticoid treatment in vivo regulates the expression positively. In primary cultured rat glial cells, a combination of cytokines stimulated production of nitrite via expression of inducible NO synthase. In these cells, simultaneous addition of endothelin decreased inducible NO synthase expression induced by cytokines. On the other hand, pretreatment with endothelin for 24 hr enhanced the inducible NO synthase expression. Endothelin has two effects on inducible NO synthase expression, positive and negative, depending on treatment time. The actions of NO on the hippocampus and thymocytes and the regulation of inducible NO synthase expression in glial cells are discussed.
Regular Papers
  • Chang-Hui Liao, Feng-Ning Ko, Sheng-Chu Kuo, Che-Ming Teng
    1998 年 76 巻 2 号 p. 141-148
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    The antiplatelet mechanism of a synthetic compound, 2-chloro-3-methoxycarbonylpropionamido-1, 4-naphthoquinone (PP1D-1), was studied by employing washed rabbit platelets in vitro. PP1D-1 concentration-dependently inhibited thrombin (0.1 U/ml)-, platelet-activating factor (2 ng/ml)-, collagen (10 μg/ml)-, arachidonic acid (100 μM)- and U46619 (1 μM)-induced aggregation and ATP release in washed rabbit platelets. The IC50 values of PP1D-1 for aggregation induced by the above inducers are 17.9±1.7, 9.8±1.1, 3.9±0.4, 1.8±0.3 and 1.7±0.3 μM, respectively. PP1D-1 did not affect platelet thromboxane B2 or prostaglandin D2 formation induced by arachidonic acid, indicating that it did not affect cyclooxygenase and thromboxane synthase activities. PP1D-1 significantly inhibited the formation of inositol 1, 4, 5-trisphosphate caused by these five platelet stimulators. Moreover, PP1D-1 inhibited the increase in intracellular calcium concentration induced by these agents. On the contrary, PP1D-1 did not inhibit thapsigargin-elevated intracellular calcium concentration in indomethacin-pretreated platelets, indicating it did not influence the effect of thapsigargin. According to these data, PP1D-1 exerts antiplatelet effects mainly by inhibiting phosphoinositide turnover.
  • Kaori Hamada, Jun Yamazaki, Taku Nagao
    1998 年 76 巻 2 号 p. 149-154
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    The elevation of the myocardial extracellular potassium concentration ([K+]o) is known to shorten action potential duration, which may lead to the occurrence of arrhythmias. The aim of this study was to compare the mechanisms responsible for the shortening of monophasic action potential duration (MAPD) in hyperkalemic and myocardial ischemic hearts in anesthetized dogs. During a venous infusion of KCl for 5 min, [K+]o was increased and MAPD was significantly shortened. The ATP-sensitive K+ (KATP) channel blocker glibenclamide did not affect the shortening of MAPD during KCl-infusion, indicating that KATP channels are not involved in this mechanism. During 5-min occlusion of the left anterior descending coronary artery, [K+]o was increased, myocardial pH was decreased and MAPD was shortened. Glibenclamide completely abolished the shortening of MAPD, while partial elevation of [K+]o remained even in the presence of glibenclamide. This suggests that the shortening of MAPD is dependent mainly on the activation of KATP channels. Both models in the present study demonstrate that different types of potassium channels are involved in the regulation of action potential duration.
  • Koichiro Takahashi, Atsushi Shirahata, Shinji Fukushima, Satoshi Kokub ...
    1998 年 76 巻 2 号 p. 155-163
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    YM175 (disodium cycloheptylaminomethylenediphosphonate monohydrate) is a new-generation bisphosphonate with stronger inhibitory activity on bone resorption than first-generation bisphosphonates. In the present study, the effect of YM175 on hypercalcemia induced in rats by single administration of either parathyroid hormone-related protein (PTHrP) or concomitant administration of PTHrP and interleukin 1β (IL-1β) was investigated. YM175 (0.01 – 1 mg/kg, i.v.) inhibited the increase in serum free calcium concentration induced by continuous administration of PTHrP alone (3 μg/rat/day, s.c., 7 days) dose-dependently. The inhibitory effect of YM175 appeared the day after administration and remained 3 days after administration. The effect of YM175 reached a maximum 2 days after administration, at which time the ED50 value of YM175 was calculated to be 0.041 mg/kg, i.v., revealing a potency approximately 50- and 10-fold stronger than those of either pamidronate or alendronate, respectively. In contrast, elcatonin (1 – 10 units/kg, s.c.) only transiently inhibited PTHrP-induced free calcium increase. YM175 (0.1 – 3 mg/kg, i.v.) also inhibited the increase in the serum free calcium concentration induced by continuous concomitant administration of both PTHrP and IL-1β in a dose-dependent manner. These results indicated that YM175 is expected to be a useful drug for hypercalcemia associated with malignant tumors due to its efficacy and range of effect.
  • Mitsutoshi Kimura, Masahiko Ogihara
    1998 年 76 巻 2 号 p. 165-174
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    We investigated whether or not proliferation of adult rat hepatocytes induced by platelet-derived growth factor (PDGF) is affected by α1-adrenoceptor agonists such as phenylephrine during the early and late phases of primary culture. Adult rat hepatocytes underwent significant DNA synthesis after culture with 10 ng/ml of PDGF for 2 hr at a low cell density (3.3×104 cells/cm2). Under these culture conditions, the number of nuclei increased significantly during the 3.5-hr culture period. Hepatocyte DNA synthesis and proliferation induced by 10 ng/ml of PDGF decreased slightly as a result of increasing the initial plating density. An α1-adrenoceptor agonist, phenylephrine (10-6 and 10-5 M), alone did not affect hepatocyte DNA synthesis and proliferation, but markedly potentiated PDGF-induced hepatocyte DNA synthesis and proliferation. The phenylephrine effect was mimicked by phorbol myristate acetate (10-7 M), but not by ionomycin (10-5 M). The mitogenic effects of PDGF were almost completely blocked by treating hepatocytes with genistein (5×10-6 M), U-73122 (3×10-6 M), sphingosine (10-5 M), wortmannin (10-7 M) and rapamycin (10 ng/ml). These results demonstrate that PDGF can induce the proliferation of adult rat hepatocytes rapidly in primary culture, regardless of the initial plating density. The present results also suggest that following stimulation with PDGF, activation of tyrosine kinase, phospholipase C, phosphatidylinositol 3-kinase, protein kinase C (PKC) and p70 ribosomal protein S6 kinase is essential for the proliferation of adult rat hepatocytes. The co-mitogenic effects of phenylephrine may involve PKC activation.
  • Jun Hiroi, Takanori Sengoku, Kyoko Morita, Shinichi Kishi, Sachio Sato ...
    1998 年 76 巻 2 号 p. 175-183
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    The effect of tacrolimus hydrate (FK506) ointment on spontaneous dermatitis in NC/Nga (NC) mice was examined. FK506 ointment (0.1 – 1%) suppressed the development of dermatitis and was also therapeutically effective against established dermatitis. Increases in CD4-positive T cells (helper T cells), mast cells, eosinophils and immunostaining of interleukin (IL)-4, IL-5 and IgE were confirmed in the skin of the NC mice, and FK506 ointment suppressed all of these changes. Increased plasma IgE was also confirmed in the NC mice, and treatment with FK506 ointment reduced the plasma IgE level. These results suggested that FK506 suppressed the dermatitis by inhibiting the activation of inflammatory cells and by blocking the cytokine network in the skin of the NC mice. The commercially available steroid ointments showed only marginal effect on the development of dermatitis and showed some signs of side effects such as alopecia or atrophy of the skin. The effect of the steroids might have been masked by these side effects because the steroids showed similar inhibitory effects on the skin histopathological changes and the increase of plasma IgE. From these results, FK506 ointment can be expected to be a useful drug for atopic dermatitis.
  • Yoshihiro Hashimoto, Yukie Kurosawa, Koichi Minami, Keiko Fushimi, Hir ...
    1998 年 76 巻 2 号 p. 185-192
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    It is well-known that cardiac hypertrophy and arterial and renal dysfunction are serious complications of hypertension. Therefore, we investigated the chronic effects of 606A (2-propyl-3-[2′(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-5-acetyl-4, 5, 6, 7-tetrahydro imidazo[4, 5-c]pyridine-4-carboxylic acid disodium salt), a novel AT1-receptor antagonist, on these complications of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) using Wistar Kyoto rats (WKY) as the control. After 8 weeks treatment from 16 weeks of age with 606A by a subcutaneously implanted osmotic pump, cardiac function, cardiac weight, acetylcholine-induced endothelium-dependent relaxation in the isolated aorta and renal function were estimated. Furthermore, wall thickness of the left ventricle was studied morphologically. We found that 606A (0.3 mg, 1 mg and 3 mg/head/day) dose-dependently lowered blood pressure without any effects on heart rate in SHRSP. Long-term treatments with 606A significantly reduced cardiac weight, left ventricular wall thickness and left ventricular end diastolic pressure, whereas it did not affect cardiac contractility. Endothelium-dependent relaxation of the aorta was recovered, and total protein excretion as well as total protein excretion/creatinine excretion ratio was reduced to the level of WKY by the treatment. These results suggest that 606A not only has a hypotensive effect but also protects cardiac, renal and vascular tissues from complications of hypertension. Thus, 606A could be an useful drug for treatment of hypertension.
  • Ken-ichi Miyamoto, Ryoji Suzuki, Takashi Horita, Shinya Yamamoto, Yosh ...
    1998 年 76 巻 2 号 p. 193-198
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    To confirm the intracellular signal transduction in regulation of alkaline phosphatase (ALP) activity by calcitonin in kidney tubular cells, effects of several inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and cyclic AMP-dependent protein kinase (PKA) on the action of salmon calcitonin in porcine kidney tubular epithelial cells LLC-PK1 were examined. A confluent culture of LLC-PK1 cells was treated with calcitonin and inhibitors in Dulbecco’s modified Eagle’s medium supplemented with 0.1% bovine serum albumin, and intracellular cyclic AMP content and ALP activity were measured after incubation for 30 min and 48 hr, respectively. Calcitonin and PDE 4 inhibitors increased cyclic AMP level and ALP activity in the cells, and PDE 4 inhibitors synergistically potentiated the effects of calcitonin. Calcitonin induced ALP activation by treatment for the first 1 hr, as well as continuous treatment for 48 hr, while it never increased the enzyme activity just after 1-hr exposure. Rolipram, an inhibitor of PDE 4 isoenzyme, induced ALP activation by itself and in combination with calcitonin by only a long term treatment (48 hr). The activation of ALP by calcitonin and rolipram each alone and in combination was completely abolished by a PKA inhibitor, H-89. These results confirm that calcitonin induces ALP activation through the cyclic AMP-PKA pathway and that PDE 4 isoenzyme is closely associated with the calcitonin-receptor system and plays a major role in hydrolysis of cyclic AMP produced in the kidney tubular cells.
  • Nobuo Aikawa, Akira Karasawa
    1998 年 76 巻 2 号 p. 199-206
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    KW-5617 (zaldaride maleate), 1, 3-dihydro-1-[1-[(4-methyl-4H, 6H-pyrrolo[1, 2-α][4, 1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one maleate, is a selective calmodulin inhibitor. We studied the effects of KW-5617 on secretory diarrhea and gastrointestinal propulsion in rats, as compared with those of loperamide, a conventional anti-diarrheal drug. Diarrhea was induced in rats either by 16, 16-dimethyl prostaglandin E2 (500 μg/kg, i.p.) or by castor oil (1 ml/100 g body weight, p.o.). In the 16, 16-dimethyl prostaglandin E2 model, KW-5617 at the doses of 3 mg/kg (p.o.) and higher ameliorated the diarrhea. Similarly, loperamide improved the diarrhea, the activity of loperamide being equivalent to that of KW-5617. In the castor oil model, KW-5617 significantly delayed the onset of diarrhea at the doses of 3 mg/kg (p.o.) and higher, while loperamide delayed the onset of diarrhea at the doses of 0.3 mg/kg (p.o.) and higher. KW-5617 only at the high doses of 30 and 100 mg/kg (p.o.) reduced gastric emptying, small intestinal propulsion, proximal colonic propulsion and distal colonic propulsion. In contrast, loperamide at its anti-diarrheal doses inhibited gastrointestinal propulsion. Our results show that KW-5617, unlike loperamide, at its anti-diarrheal doses does not exert anti-propulsive effects in rats. KW-5617 may be a useful drug for the treatment of diarrhea in terms of less side effects such as constipation.
  • Jaw-Jou Kang, Yu-Wen Cheng, Wen-Mei Fu
    1998 年 76 巻 2 号 p. 207-212
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    The effects of boldine [(S)-2, 9-dihydroxyl-1, 10-dimethoxy-aporphine], a major alkaloid in the leaves and bark of Boldo (Peumus boldus Mol.), on neuromuscular transmission were studied using a muscle phrenic-nerve diaphragm preparation. Boldine at concentrations lower than 200 μM preferentially inhibited, after an initial period of twitch augmentation, the nerve-evoked twitches of the mouse diaphragm and left the muscle-evoked twitches unaffected. The twitch inhibition could be restored by neostigmine or washout with Krebs solution. The twitches evoked indirectly and directly were both augmented initially, suggesting that the twitch augmentation induced by boldine was myogenic. Boldine inhibited the acetylcholine-induced contraction of denervated diaphragm dose-dependently with an IC50 value of 13.5 μM. At 50 μM, boldine specifically inhibited the amplitude of the miniature end plate potential. In addition, boldine was similar to d-tubocurarine in its action to reverse the neuromuscular blocking action of α-bungarotoxin. These results showed that the neuromuscular blockade by boldine on isolated mouse phrenic-nerve diaphragm might be due to its direct interaction with the postsynaptic nicotinic acetylcholine receptor.
  • Seiichi Komori, Toshihiro Unno, Takahisa Nakayama, Hidenori Ohashi
    1998 年 76 巻 2 号 p. 213-218
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    Smooth muscle cells of guinea pig ileum express both M2 and M3 subtypes of muscarinic receptors. Under voltage clamp, activation of the muscarinic receptors with carbachol (CCh) induces Ca2+-activated K+ current (IK-Ca) and nonselective cationic current (Icat). Receptor subtypes mediating the current responses were characterized by using pirenzepine, AF-DX116, 4-DAMP and atropine, which have different profiles of the affinity constants for muscarinic receptor subtypes. The muscarinic antagonists inhibited either CCh-evoked IK-Ca or Icat with different potencies. Their relative potencies for IK-Ca and Icat inhibition resembled the relative affinity constants for M3 and M2 subtypes, respectively. Thus, the IK-Ca is mediated via the M3 subtype and the Icat via the M2 subtype.
Short Communications
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