Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
95 巻 , 2 号
選択された号の論文の22件中1~22を表示しています
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  • Eiichi Tachikawa
    2004 年 95 巻 2 号 p. 139
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
  • Eiichi Tachikawa, Kenzo Kudo
    2004 年 95 巻 2 号 p. 140-144
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    The root of Panax ginseng C.A. MEYER has been reported to have an anti-stress action. Therefore, the effects of ginseng components on functions of adrenal medulla, which is one of the most important organs responsive to stress, were investigated in vitro. First, the components of ginseng were mainly divided into two fractions, that is, the saponin-rich and non-saponin fractions. The saponin-rich fraction greatly reduced the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine (ACh), whereas the non-saponin fraction did not affect it at all. The protopanaxatriol-type saponins inhibited the ACh-evoked secretion much more strongly than the protopanaxadiol-type. On the other hand, the oleanane-type saponin, ginsenoside-Ro, had no such effect. Recent reports have demonstrated that the saponins in ginseng are metabolized and absorbed in digestive tracts following oral administration of ginseng. All of the saponin metabolites greatly reduced the ACh-evoked secretion. M4 was the most effective inhibitor among the metabolites. M4 blocked ACh-induced Na+ influx and ion inward current into the chromaffin cells and into the Xenopus oocytes expressing human α3β4 nicotinic ACh receptors, respectively, suggesting that the saponin metabolites modulate nicotinic ACh receptors followed by the reduction of catecholamine secretion. It is highly possible that these effects of ginsenosides and their metabolites are associated with the anti-stress action of ginseng.
  • Hisao Nishijo, Teruko Uwano, Yong-Mei Zhong, Taketoshi Ono
    2004 年 95 巻 2 号 p. 145-152
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    Ameliorating effects of red ginseng on learning and memory deficits due to hippocampal lesions and aging were reviewed; the performance of young rats with selective hippocampal lesions with or without red ginseng (p.o.), and aged rats with or without red ginseng (p.o.) in the spatial learning tasks was compared with that of sham-operated or intact young rats. Each rat was tested with 3 types of spatial learning tasks (distance movement task, DMT; random reward place search task, RRPST; and place learning task, PLT) in a circular open field using intracranial self-stimulation (ICSS) as reward. The results in the DMT and RRPST indicated that motivational and motor activity of young rats with hippocampal lesions with and without ginseng and aged rats with and without ginseng were not significantly different from that of control young rats. However, young rats with hippocampal lesions without ginseng and aged rats without ginseng displayed significant deficits in the PLT. Treatment with red ginseng significantly ameliorated place-navigation deficits in young rats with hippocampal lesions in the PLT. Similarly, red ginseng improved performance of aged rats in the PLT. The results, along with previous studies showing significant effects of red ginseng on the central nervous system, suggest that red ginseng ameliorates learning and memory deficits through effects on the central nervous system, partly through effects on the hippocampal formation. However, its mechanisms are still unclear, and further studies are required.
  • Hideo Hasegawa
    2004 年 95 巻 2 号 p. 153-157
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    Orally ingested ginsenoside passes through the stomach and small intestine without decomposition by either gastric juice or liver enzymes into the large intestine, where ginsenoside is deglycosylated by colonic bacteria followed by transit to the circulation. Colonic bacteria cleave the oligosaccharide connected to the aglycone stepwise from the terminal sugar to afford the major metabolites, 20S-protopanaxadiol 20-O-β-D-glucopyranoside (M1) and 20S-protopanaxatriol (M4). These metabolites are further esterified with fatty acids. The resultant fatty-acid conjugates are still active molecules that are sustained longer in the body than parental metabolites. Accumulating evidence strongly suggests that ginsenoside is a prodrug that is activated in the body by intestinal bacterial deglycosylation and fatty acid esterification.
  • Hitoshi Kaneko, Kozo Nakanishi
    2004 年 95 巻 2 号 p. 158-162
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    We are exposed to many external and internal stresses in this day and age. Stress weakens the function of immune systems in living organisms and disturbs homeostasis. As a result, stress induces various psychosomatic diseases. Thus, ways of reducing stress and thus protecting humans from disease must be developed. One such method is called “the prevention of Mibyou” in Kampo, the Chinese traditional medicine. Many studies have reported the direct effects of medical ginseng on damaged target organs and recovery from disease. It also increases immune potential and may maintain homeostasis of living organisms through the autonomic-endocrine systems. It is also thought to prevent the development of disease. We studied and considered the action of medical ginseng on living organisms that were exposed to various stresses such as cold environment and industrial work. Furthermore, we confirmed the preventive effects of medical ginseng on the common cold symptom complex, including flu, by clinical observation. Here, we report our experiences.
Full Papers
  • Takeshi Goto, Naoko Tomizawa, Eiji Kobayashi, Akio Fujimura
    2004 年 95 巻 2 号 p. 163-173
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    We prepared a colon cancer-bearing Yoshida sarcoma rat model to examine the dose-response relationship of antitumor activity of intracolonically or orally administered 5-fluorouracil (5-FU; 45, 30, 20, 13, and 8 mg/kg). At doses of ≥20 mg/kg and ≥30 mg/kg, the 5-FU intracolonic and oral administration groups each showed a statistically significant difference in antitumor activity against the control group (P<0.05, Williams’ test). A statistically significant dose-response relationship was noted in the two routes of administration, with an ED50 value of 29 mg/kg. White blood cell count tended to decrease at high doses when 5-FU was administered intracolonically and showed a statistically significant decrease at doses of ≥30 mg/kg when 5-FU was administered orally. Regarding the time-course of body weight, even the 5-FU highest dose (45 mg/kg) intracolonic administration group showed no inhibited body weight increase compared to the control group. However, the 5-FU (≥20 mg/kg) oral administration groups showed a statistically significant difference in body weight increase against the control group. These facts suggested that the intracolonic administration of 5-FU, while exhibiting more potent antitumor activity than that observed in oral administration, allows an extensive reduction in its toxicities compared to oral administration.
  • Naoko Tanaka, Kumiko Kawasaki, Namie Nejime, Yoko Kubota, Kazuki Nakam ...
    2004 年 95 巻 2 号 p. 174-180
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    We investigated the effects of P2-receptor agonists on cell size, intracellular calcium levels ([Ca2+]i), and permeation of FITC-labeled dextran (FD-4) as well as the relationship between these effects in human umbilical vein endothelial cells (HUVEC). FD-4 concentration, cell size, and [Ca2+]i were analyzed by HPLC with fluorescence, phase contrast microscopic imaging, and fluorescent confocal microscopic imaging, respectively. The P2Y1-receptor agonists 2-methylthio ATP (2meS-ATP) and ADP decreased cell size and increased [Ca2+]i in HUVEC. The P2Y2-receptor agonist UTP increased [Ca2+]i, but did not influence cell size. The P2X-receptor agonist α,β-methylene ATP did not induce either response. The decrease in size and increase in [Ca2+]i by 2meS-ATP were blocked by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, P2Y1-antagonist), thapsigargin (Ca2+-pump inhibitor), and U73122 (phospholipase C inhibitor). Furthermore, 2meS-ATP (P2Y1-receptor agonist) enhanced permeation of FD-4 through the endothelial cell monolayer. The 2meS-ATP-induced enhancement of the permeation was also prevented by PPADS, thapsigargin, and U73122. These results indicate that activation of P2Y receptors induces a decrease in cell size, an increase in [Ca2+]i, and may participate in facilitating macromolecular permeability in HUVEC.
  • Akiko Sakaue, Motoko Honda, Mitsuo Tanabe, Hideki Ono
    2004 年 95 巻 2 号 p. 181-188
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    The effects of various sodium channel blocking agents on acute thermal and mechanical nociception, as assessed using the plantar and tail pressure tests, respectively, were compared with the effects of morphine. The drugs used were mexiletine, lidocaine, carbamazepine, phenytoin, eperisone, tolperisone, and zonisamide. The sodium channel blocking agents exhibited a rather preferential elevation of the threshold for thermal nociception. By contrast, morphine produced similar analgesic effects on thermal and mechanical nociception. In the sciatic nerve isolated from mice, mexiletine, lidocaine, eperisone, and tolperisone impaired the propagation of low frequency action potentials (evoked at 0.2 Hz). Carbamazepine, phenytoin, and zonisamide generated a more frequency-dependent local anesthetic action with their obvious effects on higher frequency action potentials (evoked at 5 and/or 10 Hz). Our results show that sodium channel blocking agents have a preferential antinociceptive action against thermal stimulation that is likely to be attributed to their local anesthetic action.
  • Ivan Kocic, Yuji Hirano, Masayasu Hiraoka
    2004 年 95 巻 2 号 p. 189-195
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/05/29
    ジャーナル フリー
    The aim of this study was to investigate the influence of hypotonic challenge on the effects of potassium channel openers (PCO), rilmakalim and pinacidil, on activation of the ATP-sensitive K+ current. The whole cell configuration of the patch-clamp technique was applied to guinea pig ventricular myocytes exposed to isotonic and hypotonic solutions. Difference in osmolarity was about 100 mOsm due to different mannitol concentrations. Rilmakalim, a second generation PCO [(3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-l-pyrrolidinyl)-6-phenylsulfonylchromanhemihydrate], activated time-independent K+ current in the isotonic solution with pD2 (−log EC50) = 6.42 ± 0.12 and Emax = 19.74 ± 2,16 pA/pF, n = 7, at 0 mV. The effects of the cyanoguanidine compound pinacidil were similar to those of rilmakalim, but the action appeared slower and with about 600-fold less potency than the former. Efficacy of rilmakalim, but not pinacidil, was enhanced in hypotonic solution, with Emax = 30.87 ± 5.40 pA/pF (P<0.05, n = 7), and the current was completely inhibited by glibenclamide. Additionally, rilmakalim concentration-effects correlation coefficient (R) decreased from 0.96 to 0.86 and Hill’s coefficient increased from 1.21 to 1.45. Pretreatment with phalloidin (20 μM), a cytoskeleton stabilizer, prevented an intensification of the effects of rilmakalim in hypotonic solution and returned R and Hill’s coefficients to the control values. We conclude that osmotic stress increases efficacy of rilmakalim to activate KATP channels in guinea pig ventricular myocytes due to the specific interaction with actin filaments.
  • Minoru Yoshiyama, Yasuhiro Nakamura, Takashi Omura, Tetsuya Hayashi, Y ...
    2004 年 95 巻 2 号 p. 196-202
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/05
    ジャーナル フリー
    In this study, we investigated whether the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy-5-ethoxyaniline) might have a protective effect against myocardial ischemia-reperfusion injury in rats. In particular, we focused on cardiac function using Doppler echocardiography and cardiac gene expression. We intravenously administered either SEA0400 and delivery vehicle or only the vehicle (as a control) to Wistar rats 5 min before ischemia was induced. Reperfusion was performed after 30 min of ischemia. At 1 week after ischemia-reperfusion injury, we assessed hemodynamics by inserting a polyethylene-tubing catheter, cardiac function by Doppler echocardiography, and myocardial mRNA expression was determined by Northern blot analysis. Left ventricular (LV) end-diastolic dimensions (LVDd) and LV end-diastolic volume (LVEDV) were significantly increased in the ischemia-reperfusion rat model group compared to the control group. The SEA0400-treated group had a significantly attenuated LVDd (P<0.05) and LVEDV (P<0.01) increase, compared to the vehicle-treated group. A decrease in the LV ejection fraction (P<0.05) was significantly prevented in the SEA0400-treated group compared to the vehicle-treated group. Moreover, mRNA expression of plasminogen activator inhibitor-1 in the non-infarcted LV of the SEA0400-treated group was significantly lower than in the vehicle-treated group (P<0.05). This study demonstrates that the NCX is an important mechanism for cell death in myocardial ischemia and reperfusion in rats. SEA0400 may prove to be a promising new drug in the clinical treatment of myocardial ischemia and reperfusion.
  • Hiroyuki Okamoto, Toshihiro Unno, Daisuke Arima, Maki Suzuki, Hai-Dun ...
    2004 年 95 巻 2 号 p. 203-213
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/05
    ジャーナル フリー
    In guinea pig single ileal smooth muscle cells held under voltage-clamp, the role of phospholipase C (PLC) in activation of the muscarinic receptor-operated cationic current (Icat) was studied. U73122, a PLC inhibitor, prevented the generation of Icat by the muscarinic agonist carbachol. The effect did not involve muscarinic receptor block since it also blocked Icat which was evoked by GTPγS applied intracellularly to activate G proteins bypassing muscarinic receptors. Also, neither cationic channel block nor other possible nonspecific actions seemed to be involved since its analogue (U73343), structurally close but deficient of the PLC-inhibiting activity, did not significantly affect carbachol- or GTPγS-evoked Icat. Antibodies against the α subunits of Gq/G11 proteins (Gαq/Gα11-antibody) blocked only the small component of carbachol-evoked Icat, which was associated with an increase in [Ca2+]i linked to an increase in Gq/11 protein-regulated PLC activity. 1-Oleoyl-2-acetyl-sn-glycerol (OAG), an analogue of diacylglycerol (DAG) produced via PLC-catalyzed metabolism, produced no or only a small current by itself, with the carbachol-evoked Icat remaining unchanged. These results provide evidence for the importance of PLC in Icat generation, and they also strongly suggest that the activity of PLC involved in the primary activation of Icat is neither under regulation by Gq/11 proteins nor dependent on the action of DAG.
  • Gang Zhu, Motohiro Okada, Daishi Uchiyama, Tadashi Ohkubo, Shukuko Yos ...
    2004 年 95 巻 2 号 p. 214-227
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/05
    ジャーナル フリー
    Phencyclidine (PCP) produces schizophrenia-like psychosis and acute PCP-intoxications; however, whether glutamate/NMDA-receptor blockade by PCP modulates or not these mechanisms has remained to be clarified. To clarify this mechanism, we determined interaction among voltage-gated Na+-channel inhibitor, tetrodotoxin (TTX), Golgi-disturbing-agent, brefeldin-A (BFA), and PCP on releases of glutamate, GABA, and monoamine in prefrontal-cortex (pFC), using microdialysis. PCP increased basal monoamine release, whereas it decreased basal GABA release, without affecting glutamate release. PCP increased K+-evoked monoamine release, whereas it decreased K+-evoked glutamate and GABA releases. TTX reduced basal monoamine and GABA releases without affecting glutamate release, whereas BFA did not affect them. Interestingly, BFA and TTX inhibited PCP-associated basal monoamine release and abolished PCP-induced reduction of basal GABA release without affecting glutamate release. BFA and TTX reduced K+-evoked releases of all neurotransmitters. BFA inhibited PCP-associated K+-evoked monoamine release, but TTX did not affect them. PCP-induced reduction of K+-evoked GABA and glutamate releases was abolished by TTX and BFA. These results indicate that PCP reduces GABAergic transmission via NMDA-receptor blockade and activates intracellular endoplasmic-reticulum-associated signal-transduction, resulting in enhancement of monoaminergic transmission in pFC. Thus, these PCP properties support the hypothesis that mechanisms of the neurological symptoms of acute PCP-intoxication, convulsion, and rhabdomyolysis may be involved in both reduction of GABAergic-transmission and activation of endoplasmic-reticulum-associated signal-transduction induced by PCP.
  • Tsuneo Inoue, Muneshige Kaibara, Yasuko Sakurai-Yamashita, Masahiro Ka ...
    2004 年 95 巻 2 号 p. 228-233
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/05
    ジャーナル フリー
    The objective of this study was to evaluate serum nitrite and nitrate (nitrite/nitrate) concentrations that affect adversely pregnancy outcome. Pregnant rats, from day 2 to day 8 of pregnancy, were daily given subcutaneously several doses (5, 10, and 30 mg/rat) of diethylenetriamine-nitric oxide (DETA/NO). Serum nitrite/nitrate concentrations were measured using an HPLC system. Serum nitrite/nitrate concentrations increased dose-dependently with DETA/NO. Effects of DETA/NO on pregnancy outcome were assessed on day 14 of pregnancy. In rats given 5 mg DETA/NO, there was a significant increase in serum nitrite/nitrate concentrations (49.2 vs 24.6 μmol/l, P<0.001), and both placental weight and fetal weight decreased compared to control rats. Macroscopic bleeding in placenta was frequently observed in rats given DETA/NO. We further studied effects of DETA/NO on cultured trophoblastic BeWo cells. DETA/NO added to the culture medium increased nitrite/nitrate concentrations in the medium in a dose-dependent manner. Nitrite/nitrate concentrations in the medium over four times the concentration of control decreased progesterone in the medium at 24 h after the application of DETA/NO. The hormonal secretion was not affected by DETA only. This study shows for the first time nitrite/nitrate concentrations affecting adversely pregnancy outcome and function of the trophoblastic cells.
  • Yoshiaki Noda, Keitaro Hashimoto
    2004 年 95 巻 2 号 p. 234-239
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/05
    ジャーナル フリー
    In vivo antiarrhythmic effects of diltiazem hydrochloride and nifekalant hydrochloride, a pure class III antiarrhythmic drug (Vaughan Williams’ classification), on adrenaline induced ventricular arrhythmias were examined in halothane anesthetized guinea pigs. Continuous adrenaline infusion (12.5 μg/kg per min) induced ventricular arrhythmias. Arrhythmogenicity was significantly increased with vagotomy and higher concentration of halothane. After injection of diltiazem at 0.5 mg/kg, the arrhythmic ratio (the number of ventricular ectopic beats divided by the total heart beats) was significantly reduced compared with the predrug control value (0.69 vs 0.04, P<0.05). No significant change of arrhythmic ratio was observed after injection of nifekalant (0.57 vs 0.61, ns). After administration of nifekalant, the mean minimum adrenaline infusion rate that induced ventricular arrhythmia decreased from 9.29 to 6.43 μg/kg per min. On the other hand, before administration of diltiazem, the mean arrhythmogenic rate of adrenaline was 8.50 μg/kg per min, but ventricular arrhythmias were no longer induced during continuous infusion of diltiazem at 0.5 mg/kg per min. These results were qualitatively consistent with previous experiments using the canine halothane-adrenaline model. In conclusion, the halothane-adrenaline arrhythmia model using the in vivo guinea pig is useful for screening drugs with potential anti- or pro-arrhythmic properties.
  • Nicolle C.L. McNaughton, Ceri H. Davies, Andrew Randall
    2004 年 95 巻 2 号 p. 240-247
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/12
    ジャーナル フリー
    We examined if a range of carbonic anhydrase inhibitors (CAIs) interacted with the high-voltage activated voltage-sensitive calcium channels (VSCCs) encoded by the human α1E subunit. Whole-cell recordings were made from HEK293 cells stably expressing human α1Eβ3-mediated calcium channels. SNX-482 (an α1E inhibitor) blocked α1E-mediated VSCCs with an IC50 close to 10 nM. The anticonvulsant CAI ethoxyzolamide also inhibited these currents, with an IC50 close to 1 μM, and produced an accompanying 20-mV hyperpolarizing shift in the steady-state inactivation profile. Other structurally diverse CAIs (e.g., acetazolamide and benzolamide) produced approximately 30 – 40% inhibition of α1Eβ3-mediated Ca2+ currents at 10 μM. Topiramate (10 μM), an anticonvulsant with CAI activity, inhibited these currents by 68 ± 7%. This off-target activity of CAIs at VSCCs may contribute to some of the effects they produce both in vitro and in vivo.
  • Jinfeng Hu, Meiyu Geng, Jing Li, Xianliang Xin, Jia Wang, Minke Tang, ...
    2004 年 95 巻 2 号 p. 248-255
    発行日: 2004年
    公開日: 2004/06/23
    ジャーナル フリー
    In this paper, we investigated interactions of the acidic oligosaccharide sugar chain (AOSC), derived from brown algae Echlonia kurome OKAM, with amyloid beta protein (Aβ). We observed that AOSC inhibited the toxicity induced by Aβ in both primarily cortical cells and the SH-SY5Y cell line. We also observed that AOSC inhibited the apoptosis induced by Aβ in SH-SY5Y by reducing the elevated level of intracellular calcium concentration ([Ca2+]i) and suppressing the generation of reactive oxygen species. Surface plasmon resonance analysis demonstrated that AOSC had affinity for both freshly-dissolved Aβ and 48-h incubated Aβ. Furthermore, AOSC blocked the fibril formation of Aβ, which may be responsible for its anti-cytotoxic effects. Thus, our results indicate that AOSC might be a potentially therapeutic compound for Alzheimer’s disease.
  • Xiaoxing Yin, Yindi Zhang, Haiwei Wu, Xiang Zhu, Xiaogang Zheng, Shaoj ...
    2004 年 95 巻 2 号 p. 256-266
    発行日: 2004年
    公開日: 2004/06/23
    ジャーナル フリー
    Diabetic nephropathy (DN) has become the leading cause of end stage failure, but no renoprotective treatment has been very available for use in DN. Astragalus saponin I (AS I), a component extracted from Astragalus membranaceus BUNGE, was studied in experimental DN induced by administration of streptozotocin in male rats. The early DN rats were treated with 3 doses of AS I for 8 weeks to analyze its efficacy with different parameters. By comparison with vehicle-treated DN rats, the renal hypertrophy, the oxidative stress intensity, and the blood glucose level of DN rats were ameliorated by AS I. Also, the microalbuminuria level, advanced glycated end-products either in serum or in kidney cortex, and the aldose reductase activity were significantly reduced. Furthermore, the expression of transforming growth factor β1 mRNA in kidney cortex by RT-PCR analysis was markedly declined. Both the relative grade of mesangium hyperplasia by microscopical observation and the thickness of glomerular base membrane by electron microscope measurement were decreased significantly. Therefore, the results suggest that AS I has therapeutic effects on several pharmacological targets in the progress of DN and is a potential drug for prevention of early stage DN.
  • Seongchun Kwon, Lian Hua Fang, Bokyung Kim, Tae-Seon Ha, Sang Jin Lee, ...
    2004 年 95 巻 2 号 p. 267-272
    発行日: 2004年
    公開日: 2004/06/23
    ジャーナル フリー
    We investigated whether p42/p44 mitogen-activated protein kinase (MAPK) and/or p38 MAPK participates in the regulation of vascular smooth muscle contraction by endothelin-1 (ET-1) in Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR). ET-1 (10 nM) induced a sustained contraction in WKY and SHR aortas. PD98059 (100 μM), an inhibitor of p42/p44 MAPK kinase, partially attenuated the ET-1-induced contraction in WKY and SHR. However, SB203580 (10 μM), an inhibitor of p38 MAPK, relaxed the ET-1-induced contraction to the resting levels in SHR, but not in WKY. ET-1 (10 nM) increased phosphorylation of both p42/p44 MAPK and p38 MAPK in WKY and SHR. However, in SHR, p38 MAPK phosphorylation in response to ET-1 stimulation was increased more than in WKY. PD98059 (100 μM) and SB203580 (10 μM) abolished the phosphorylation of p42/p44 MAPK and p38 MAPK in response to ET-1 stimulation in WKY and SHR, respectively. On the other hand, SB203580 (10 μM) did not affect myosin light chain (MLC) phosphorylation in response to ET-1 (10 nM) stimulation in WKY and SHR. From these results, it is concluded that p42/p44 MAPK and/or p38 MAPK partially regulates the ET-1-induced vasoconstriction in WKY. However, p38 MAPK, rather than p42/p44 MAPK, activation plays an important role for the maintenance of ET-1-induced vasoconstriction in SHR through a MLC phosphorylation-independent pathway.
  • Mingyu Xia, Dong Wang, Minwei Wang, Shin-ichi Tashiro, Satoshi Onodera ...
    2004 年 95 巻 2 号 p. 273-283
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/12
    ジャーナル フリー
    Dracorhodin perchlorate inhibited proliferation of several tumor cell lines. The drug induced oligonucleosomal fragmentation of DNA in HeLa cells and increased caspase-3, -8, -9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase-dependent DNase, and poly-(ADP-ribose) polymerase. It also increased caspase-1 activity and a caspase-1 inhibitor, Ac-YVAD-cmk, and a caspase-10 inhibitor z-AEVD-fmk, also reduced dracorhodin-perchlorate-induced HeLa cell death. Dracorhodin perchlorate decreased the expression of anti-apoptotic mitochondrial protein, Bcl-XL, but not Bcl-2; and it increased the expression of pro-apoptotic protein, Bax. Dracorhodin perchlorate induced a sustained generation of reactive oxygen species (ROS) in HeLa cells; caspase-1 inhibitor, Ac-YVAD-cmk, and caspase-3 inhibitor, z-DEVD-fmk, attenuated the generation of ROS. Taken together, our results indicate that dracorhodin perchlorate alters the intracellular redox status, changed the balance of Bcl-XL and Bax protein expression, and induces apoptosis through caspase pathways in HeLa cells.
  • Dong-Soon Im, Hideaki Tomura, Masayuki Tobe, Koichi Sato, Fumikazu Oka ...
    2004 年 95 巻 2 号 p. 284-290
    発行日: 2004年
    公開日: 2004/06/23
    [早期公開] 公開日: 2004/06/12
    ジャーナル フリー
    We previously reported that sphingosine 1-phosphate (S1P) induces inhibition of adenylyl cyclase and activation of phospholipase C via independent G protein-coupled receptors in adult rat hepatocytes. Although S1P activation of phospholipase C and subsequent increase of intracellular Ca2+ concentration were enhanced during the primary culture of hepatocytes, S1P inhibition of adenylyl cyclase remained unchanged. Here, we addressed whether enhancement of S1P-induced actions is dependent on change of status from the differentiated (G0) phase to proliferating (G1/S) phase in hepatocytes. By employing cell-density-dependency of the transition (G0-G1) of hepatocytes in primary culture in vitro, it was found that the enhancement of phospholipase C activation by S1P was dependent on cell density and correlated to the G0-G1 transition. The correlation was further confirmed in vivo by 70% hepatectomy as a proliferating hepatocytes model. Northern blot analysis suggested an enhanced expression of S1P2 receptor in proliferating hepatocytes.
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