The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
83 巻, 1 号
選択された号の論文の11件中1~11を表示しています
Reviews
  • Juan Tamargo
    2000 年 83 巻 1 号 p. 1-19
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    A progressively increasing number of cardiac and noncardiac drugs prolong the ventricular action potential duration(QT interval of the electrocardiogram)and cause a distinctive polymorphic ventricular tachycardia termed torsades de pointes(TdP)that can degenerate into ventricular fibrillation and sudden cardiac death.Drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general and selectively blocking the rapidly activating delayed rectifier channel IKr.Coassembly of HERG(human−ether−ago−go−related gene)α−subunits and MiRP1(MinK−related peptide 1)β−subunits recapitulate the behavior of native human IKr and mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT.Thus, drug−induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital LQTS.In patients with silent forms of the congenital LQTS associated with mutations in IKr, arrhythmic symptoms developed almost exclusively after exposure to QT−prolonging drugs.This review centers on the possible cellular mechanisms underlying drug−induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.
  • Makoto Tominaga, David Julius
    2000 年 83 巻 1 号 p. 20-24
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    Capsaicin, the main pungent ingredient in ‘hot’ chili peppers, elicits burning pain by activating specific(vanilloid)receptors on sensory nerve endings.The cloned capsaicin receptor(VR1)is a nonselective cation channel with six transmembrane domains that is structurally related to a member of the TRP(transient receptor potential)channel family.VR1 is activated not only by capsaicin but also by increases in temperature that reach the noxious range(>43°C).Protons potentiate the effects of capsaicin or heat on VR1 activity by markedly decreasing the capsaicin concentration or temperature at which the channel is activated.Furthermore, a significant increase in proton concentration(pH<5.9)can evoke channel activity at room temperature.The analysis of single−channel currents in excised membrane patches suggests that capsaicin, heat or protons gate VR1 directly.VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain.VRL−1, a VR1 homologue, is not activated by vanilloids or protons, but can be activated by elevation in ambient temperature exceeding 52°C.These findings indicate that related ion channels may account for thermal responsiveness over a range of noxious temperature.
Full Papers
  • Keiichi Tabata, Kinzo Matsumoto, Hiroshi Watanabe
    2000 年 83 巻 1 号 p. 25-30
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    We previously reported that paeoniflorin but not albiflorin, components of peony root, produced ameliorative effects on scopolamine−induced spatial cognitive impairment in rats.In this study, we examined the effects of paeoniflorin and muscarinic receptor antagonists on long−term potentiation(LTP)of population spike recorded from the CA1 region of rat hippocampal slices.Bath applications of an M1− and M2−receptor antagonist scopolamine and a selective M1−receptor antagonist pirenzepine, at a concentration of 10 μM, significantly suppressed LTP, whereas AF−DX116, a selective M2−receptor antagonist, failed to affect it.Paeoniflorin(0.1−1μM), which alone was ineffective on LTP induction, significantly reversed the suppressive effects of scopolamine and pirenzepine(10μM).In contrast, albiflorin(0.1−1μM)had no effect on the scopolamine−induced LTP suppression.These results suggest that paeoniflorin reversal of the muscarinic M1−receptor−mediated inhibition of LTP may be implicated in the ameliorative effect of paeoniflorin on spatial cognitive impairment caused by cholinergic dysfunction.
  • Ying-Liang Wu, Masami Yoshida, Hiroyuki Emoto, Hideo Ishii, Kiminori K ...
    2000 年 83 巻 1 号 p. 31-38
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    In the present study, we investigated the effects of acute and chronic systemic administration of MCI−225(4−(2−fluorophenyl)−6−methyl−2−(1−piperazinyl)thieno[2, 3−d]pyrimidine monohydrate hydrochloride), a newly−developed selective noradrenaline(NA)reuptake inhibitor with 5−HT3−receptor−blocking action, on extracellular NA levels in the hypothalamus of stressed and non−stressed rats by utilizing intracerebral microdialysis.Acute administration of MCI−225(3 and 10 mg/kg, p.o.)significantly and dose−dependently increased extracellular NA levels in the hypothalamus in non−stressed rats.Footshock for 20 min also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI−225.Although chronic administration of MCI−225(3 or 10 mg/kg, p.o.for 14 days)did not alter the basal extracellular NA levels in the hypothalamus, the stress−induced increases in extracellular NA levels were significantly lower in rats chronically treated with MCI−225(10 mg/kg)than those of rats pretreated with vehicle for the same period.The increase in extracellular NA levels induced by MCI−225 challenge(3 or 10 mg/kg, p.o.)were not different between rats chronically treated with MCI−225 or vehicle.These results suggest that MCI−225 enhances extracellular NA levels in the hypothalamus in both non−stressed and stressed rats by inhibiting NA uptake and that chronic systemic administration of MCI−225 did not alter basal extracellular NA levels, but reduced the increase in NA release caused by footshock stress.These data suggest the possibility that MCI−225 might possess anxiolytic and/or antidepressant properties.
  • Makoto Tsunoda, Kazuko Takezawa, Tomofumi Santa, Yasuhiro Ina, Ken Nag ...
    2000 年 83 巻 1 号 p. 39-45
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    We previously reported a highly sensitive chemiluminescence high−performance liquid chromatographic method to determine catecholamines in plasma.In this study, we employed this method to measure the cardiac function and plasma norepinephrine(NE)concentration in conscious rats.Benidipine, 1, 4−dihydropyridine calcium antagonist(4 mg/kg), and β−blocker(propranolol, 30 mg/kg)were administered orally to conscious spontaneously hypertensive rats(SHRs)and Wistar−Kyoto(WKY)rats, and blood pressure, heart rate and plasma NE levels were measured.Plasma NE concentration was used as an index of sympathetic nervous system activity in conscious rats.The basal plasma NE levels were significantly higher in SHRs than in WKY rats(P<0.05), indicating the activity of the basal sympathetic nervous system in SHRs was elevated.The sensitivity of the baroreflex−mediated sympathetic nervous response was reduced in SHRs as compared to that in WKY rats.The concomitant administration of benidipine and a β−blocker decreased heart rate without affecting the baroreflex−mediated sympathetic nervous response, indicating that propranolol might suppress mainly the cardiac β−adrenoceptor.The present study suggested the high activity of the basal sympathetic nervous system and the reduced response of the baroreflex−mediated sympathetic nervous system in SHRs compared to WKY rats in the conscious condition.
  • Ikuko Kimura, Ritsu Honda, Hisashi Okai, Motonori Okabe
    2000 年 83 巻 1 号 p. 47-55
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    Vascular endothelial growth factor(VEGF)has been claimed to be a major positive regulator of angiogenesis in diabetic retinopathy and atherosclerosis.Diabetic state−induced alteration of the phenotypes and the influence of 12−h pretreatment with VEGF were examined after a further 12−h treatment with only 1% fetal bovine serum in subcultured endothelial cells(EC)derived from rat thoracic aorta.By flow cytometric cell cycle analysis, VEGF showed quite different transition patterns from those of platelet−derived growth factor(PDGF)in 5−day(at the progression phase)cultured normal rat EC even though VEGF belongs to the PDGF family.VEGF promoted cell cycle transition from the G0 to the G1 phase at 3 ng/ml, but at 30 ng/ml, VEGF weakly inhibited it compared with the effect of PDGF.The streptozotocin−diabetic state promoted cell cycle transition of EC from the G0 to the G1 phase.The promotion by the low concentration of VEGF was observed even at the point of 35−day culture(angiogenic EC at the competence phase in normal state).The diabetic state enhanced EC proliferation rather than tube formation, and the tube formation was scarce.The promotion of cell cycle transition by VEGF may aggravate furthermore diabetic angiopathy due to the leaky constitution of blood vessels.
  • Shinji Teramoto, Masashi Suzuki, Takeshi Matsuse, Takeo Ishii, Yoshino ...
    2000 年 83 巻 1 号 p. 56-62
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    We examined the effects of angiotensin−converting enzyme(ACE)inhibitors on spontaneous or stimulated generation of reactive oxygen species(ROS)by bronchoalveolar lavage(BAL)cells prepared from 6 patients with chronic obstructive pulmonary disease(COPD)and from age−matched control subjects without COPD.The ROS produced by BAL cells were measured by the lucigenin−dependent chemiluminescence method.The application of ACE inhibitors into culture media containing BAL cells inhibited spontaneous and stimulated generation of ROS by BAL cells from COPD patients and control subjects in an ambroxol−concentration−dependent manner.Alacepril, an ACE inhibitor bearing SH−group, inhibited the oxygen radical production and generation by BAL cells from COPD patients in a dose−dependent fashion.Approximately 0.6−0.7 mM of alacepril inhibited 50% of the ROS production by BAL cells from COPD patients, whereas a slightly higher concentration(3 mM)of lisinopril, an ACE inhibitor not bearing an SH−group, was necessary to inhibit the production of ROS.These results suggest that an ACE inhibitor may act as an pulmonary antioxidant in patients with COPD.
  • Yasuhito Arakida, Keiko Ohga, Kiyomi Suwa, Yohei Okada, Hiroki Morio, ...
    2000 年 83 巻 1 号 p. 63-72
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    The antagonistic activity of oral YM158(3−[(4−tert−butylthiazol−2−yl)methoxy]−5′−[3−(4−chlorobenzenesulfonyl)propyl]−2′−(1H−tetrazol−5−ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene(LT)D4 and thromboxane(TX)A2 receptors, was investigated.Oral YM158 caused dose−dependent inhibition of LTD4−induced increases in plasma leakage and LTD4− or U46619−induced increases in airway resistance, with ED50 values of 6.6, 8.6 and 14 mg/kg, respectively.The dose−range of YM158’s inhibitions was almost the same for both LTD4 and TXA2 receptors, and repeated oral doses did not affect its efficacy.Furthermore, oral YM158 inhibited antigen−induced bronchoconstriction.Although the potency of pranlukast for LTD4 receptor antagonism(ED50=0.34 mg/kg)is greater than that of YM158(ED50=8.6 mg/kg), the doses of both pranlukast and YM158 for significant inhibition of the antigen−evoked airway response were the same, indicating that the TXA2 receptor antagonism of YM158 plays an important role in its anti−asthmatic effects.In conclusion, YM158 promises to be a novel agent for treating bronchial asthma.
  • Hisayoshi Doi, Minako Kaburaki, Hirotaka Inoue, Kuniharu Suzumura, Hir ...
    2000 年 83 巻 1 号 p. 73-81
    発行日: 2000年
    公開日: 2001/01/31
    ジャーナル フリー
    TA−993(cis−(−)−2−(4−methylphenyl)−3−acetoxy−2, 3−dihydro−5−(2−dimethylaminoethyl)−8−methyl−1, 5−benzothiazepine−4(5H)−one maleate), a new 1, 5−benzothiazepine derivative, has a selective increasing action on limb blood flow in addition to an antiplatelet action.In this report we studied the effect of TA−993 on a time dependent decrease in developed tension of electrically−induced contraction of tibialis anterior muscle in a rat model of peripheral circulatory insufficiency induced by occlusion of abdominal aorta.In our preparation, the developed tension decreased by 20−30% in a sham−operated group and 30−40% in an abdominal aorta−occluded group at the end of the experimental period of 60 min.Intraduodenal administration(i.d.)of TA−993(10 mg/kg)to the abdominal aorta−occluded rats ameliorated the decrease in developed tension to the level of the sham−operated group.Moreover, TA−993 at 10 mg/kg, i.d.significantly increased femoral arterial blood flow supplied through collateral circulation and decreased the whole blood viscosity in this model.These results suggest that TA−993 improves dysfunction of skeletal muscle contraction due to peripheral circulating insufficiency through an increase in collateral blood flow and an improvement of red blood cell deformability.
Short Communications
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