The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 64 , Issue 4
Showing 1-11 articles out of 11 articles from the selected issue
  • Kazushi Sakurai, Katsuya Yamasaki
    1994 Volume 64 Issue 4 Pages 229-234
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Intragastric administration of 6% H2O2 induces gastric mucosal hemorrhagic lesions in rats. Intraperitoneal administration of rebamipide at 10 to 100 mg/kg dose-dependently prevented the H2O2-induced mucosal lesions. The fact that cimetidine, ranitidine and omeprazole could not prevent the gastric mucosa from developing H2O2-induced lesions indicates that acid secretion might not be the main cause of these lesions. The protective effect of rebamipide was partially reduced by indomethacin and completely blocked by diethyl maleate, a glutathione depressor. Gastric mucosal glutathione level and glutathione peroxidase and superoxide dismutase (SOD) activities were significantly decreased by 6% H2O2 instillation. Rebamipide at 100 mg/kg significantly inhibited the decreases in gastric mucosal glutathione level and SOD activity. These results suggest that H2O2-induced gastric mucosal lesions might partially involve a decrease in defense activities against reactive oxygen species and that the protective effect of rebamipide might be related to its ability to improve oxidative stress in gastric mucosa.
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  • Hisakuni Hashimoto, Satoshi Imamura, Kazuyuki Ikeda, Mitsuyoshi Nakash ...
    1994 Volume 64 Issue 4 Pages 235-241
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Previous studies showed that volatile anesthetics depressed ventricular delayed activation in a canine myocardial infarction model. It is well known that class I antiarryhthmic drugs depress the ventricular activation in the infarcted myocardium. In the present study, we examined the electrophysiologic interaction between volatile anesthetics (sevoflurane, isoflurane) and class I antiarrhythmic drugs (lidocaine, procainamide) in effects on the ventricular delayed activation in a canine myocardial infarction model. The conduction time of the premature stimulation-induced ventricular excitation was measured in both normal and infarcted zones of the ventricle. An interval from the premature stimulus artifact to the epicardial activation was measured on bipolar electrograms as an index of conduction time, i.e., activation time. In the infarcted zone, the volatile anesthetics and class I antiarrhythmic drugs prolonged the activation time in the infarcted zone, and the combination of the volatile anesthetics and the class I antiarrhythmic drugs markedly prolonged the activation time or blocked the delayed activation. In the normal zone, a similar synergistic interaction was observed, but the effect of these drugs was less compared with that in the infarcted zone. From these results, possible mechanisms to explain the synergistic interaction were discussed.
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  • Ermin Wang, Katsutoshi Yayama, Masaoki Takano, Hiroshi Okamoto
    1994 Volume 64 Issue 4 Pages 243-250
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    To determine the source of angiotensinogen excreted in urine, urine angiotensinogen was measured in male and female rats during growth. Angiotensinogen in 24-hr urine, measured by direct radioimmunoassay with antibody against rat angiotensinogen, increased fourfold in males between the ages of 5 and 7 weeks, whereas no significant changes were observed in females or castrated males. Plasma levels of angiotensinogen, in contrast, showed no significant differences between these groups at any age. Castration of adult males caused a significant reduction of urinary angiotensinogen after 4 weeks. Consecutive s.c. administration of 17a-methyltestosterone for 3 weeks in castrated males resulted in a threefold increase in the urinary excretion of angiotensinogen, as well as a twofold increase in the renal expression of angiotensinogen messenger RNA (mRNA). Renal levels of angiotensinogen mRNA in intact adult males were about threefold higher than those in females and castrated males, whereas there were no significant differences in hepatic angiotensinogen mRNA between these animals. These results suggest that the sexual differences in the urinary excretion of angiotensinogen are primarily due to the androgen-dependent dimorphic expression of angiotensinogen mRNA in the kidney; thus, levels of angiotensinogen in urine might reflect intrarenal production.
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  • Hirotoshi Arai, Masaya Nakagawa, Kikuko Tanada, Hidetoshi Yamaguchi, S ...
    1994 Volume 64 Issue 4 Pages 251-256
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Histamine H2-antagonistic properties of the novel H2-antagonist T-593, (±)-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N''-[2-[[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-N"-(methylsulfonyl) guanidine were investigated on the histamine-induced positive chronotropic responses in isolated guinea pig right atria. T-593 at 3 × 10-1-3 × 10-6 M suppressed the maximal responses of the histamine concentration-response curves in a concentration-dependent fashion, indicating that T-593 is an unsurmountable antagonist. The pD''2 values were 5.50 for T-593 and 5.61 for famotidine; and the IC50 values at 1 × 10-5 M histamine were 1.05 × 10-6 M for T-593, 1.59 × 10-6 M for ranitidine and 1.67 × 10-7 M for famotidine. T-593 is a racemic compound composed of two enantiomers, (-)-T-593 and (+)-T-593. The histamine H2-antagonistic activity of (-)-T-593 was 1.5-fold more potent than that of racemic T-593, but (+)-T-593 scarcely inhibited the histamine-induced positive chronotropic response. Histamine H2-antagonism by racemic T-593 was mainly attributed to (-)-T-593. Isoproterenol-induced positive chronotropic responses were not affected by T-593 even at 3 × 10-5 M. Pretreatment of ranitidine for 10 min prior to application of T-593 protected H2-receptors from unsurmountable antagonism by T-593. Reversibility of H2-antagonism was determined every 1 hr after a 30-min treatment of H2-antagonists. T-593 inhibited the positive chronotropic responses for over 6 hr in contrast to fast recovery from inhibition by ranitidine or famotidine. This result showed that T-593 is a slowly dissociable, long-acting histamine H2-antagonist.
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  • Masao Kozuka, Kazuo Kobayashi, Nobuyoshi Iwata
    1994 Volume 64 Issue 4 Pages 257-264
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Changes in local cerebral glucose utilization (LCGU) of the postischemic rat brain were investigated using the rat four-vessel occlusion model. Following 20 or 30 min of ischemia, LCGUs of the cerebral cortices, striatum and hippocampus were decreased at 1 and 3 days postischemia, but were recovered at 7 days postischemia. Effects of repeated administration of RS-8359, (±)-4-(4-cyanoanilino)-7-hydroxycyclopenta(3, 2-e)pyrimidine, (30 mg/kg × 2/day, p.o., 4 days) were examined at 3 days postischemia following 20 min of ischemia. Compared with the sham-operated group, the LCGUs of 22 out of 34 structures examined in the ischemic-control group were significantly reduced. In the RS-8359-treated group, however, significant reduction was observed in only 9 structures. Compared with the ischemic-control group, RS-8359 significantly ameliorated the reduction of LCGU in 12 structures. These results suggest that RS-8359 has beneficial effects on reduced glucose metabolism in the postischemic brain.
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  • Hideaki Sakaguchi, Akira Nishio
    1994 Volume 64 Issue 4 Pages 265-272
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    The mechanisms underlying the enhanced contractile response to phenylephrine (PE) and increased susceptibility to nifedipine of de-endothelialized thoracic aorta isolated from rats with dietary magnesium deficiency (Mg-deficient rats) were examined by functional and radioligand binding studies. Enhanced PE-induced contractions and increased susceptibility to nifedipine in Mg-deficient rats were not observed in the presence of 10 μM H7. PE significantly decreased the KD value without changing Bmax in the binding of [3H]PN200-110 to de-endothelialized aortic strips. The KD value obtained in the Mg-deficient rats was significantly smaller than that in the controls. Nifedipine displaced the binding of [3H]PN200-110 concentration-dependently, and the pKi value in Mg-deficient rats was significantly larger than that in the controls. A combination of PE and H7 abolished this difference. These results indicate that the modulation of L-type Ca2+ channels via the stimulation of α1-adrenoceptors may be involved in the enhancement of vasoconstriction and increased susceptibility to nifedipine in aortas isolated from Mg-deficient rats. The H7-sensitive mechanisms may play an important role in these phenomena.
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  • Hisashi Kuribara
    1994 Volume 64 Issue 4 Pages 273-280
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Behavioral effects of p.o. administration of SUN 8399, a selective 5-HT1A agonist, on the operant behavior under a MULT VI 1.5 min/FR 5-punishment schedule of food reinforcement and on the ambulatory activity were evaluated in mice, and the characteristics were compared with those of other 5-HT1A agonists, buspirone and tandospirone, and the benzodiazepine diazepam. Diazepam (3 and 10 mg/kg) significantly increased the punished response without eliciting any significant change in the non-punished response; i.e., showing anticonflict action. SUN 8399 (3-30 mg/kg) and buspirone (1-10 mg/kg) did not significantly change either the punished or non-punished responses. Tandospirone significantly increased the non-punished response at 10 mg/kg, but significantly decreased both the punished and non- punished responses at 30 mg/kg. The single administration of SUN 8399 (10 mg/kg), buspirone (3 and 30 mg/kg) and tandospirone (10 and 30 mg/kg) significantly increased the ambulatory activity, while diazepam tended to decrease it. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was reduced by buspirone (10 and 30 mg/kg) and tandospirone (10 and 30 mg/kg), but enhanced by diazepam (3 and 10 mg/kg). Buspirone (30 mg/kg), tandospirone (10 and 30 mg/kg) and diazepam (3 and 10 mg/kg) significantly reduced the ambulation-increasing effect of scopolamine (0.5 mg/kg, s.c.). SUN 8399 (3-100 mg/kg) did not modify the effects of either methamphetamine or scopolamine. The present results suggest that 5-HT1A agonists scarcely show anticonflict action on the Geller-type conflict behavior in mice. However, SUN 8399 possesses different behavioral characteristics from those of the other two 5-HT1A agonists in terms of interactions with methamphetamine and scopolamine.
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  • Kozo Yao, Hideaki Kusaka, Jun-ichi Sano, Kiyoshi Sato, Akira Karasawa
    1994 Volume 64 Issue 4 Pages 281-288
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Using various models of acute renal failure (ARF) in rats, the diuretic effects of 8-(noradamantan-3-yl)-1, 3-dipropylxanthine (KW-3902), a novel adenosine A1-receptor antagonist (0.01 and 0.1 mg/kg, p.o.), were determined and compared with those of furosemide (30 mg/kg, p.o.) and trichlormethiazide (TCM; 1 mg/kg, p.o.). In cisplatin-induced ARF rats, KW-3902 and TCM, but not furosemide, increased Na excretion. KW-3902 did not affect creatinine clearance (CORE), while TCM decreased CCRE. In gentamicin-induced ARF rats, KW-3902 increased urine volume (UV) and Na excretion. In glycerol-induced oliguric ARF rats, KW-3902, but not furosemide or TCM, increased UV, Na and K excretion and tended to improve the depressed CCRE, suggesting that the improvement of renal hemodynamics might also contribute to the diuretic effect of KW-3902. In glycerol-induced polyuric ARF rats, only KW-3902 significantly increased UV and Na excretion. These results demonstrate that KW-3902 induces natriuretic effects in various models of ARF and that the effect of KW-3902 is more prominent than those of furosemide and TCM. The present results suggest that endogenous adenosine may be involved in various forms of ARF via adenosine A1-receptors.
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  • Nobuyuki Kishibayashi, Akio Ishii, Akira Karasawa
    1994 Volume 64 Issue 4 Pages 289-295
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    KW-5092 ({1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]ethyl]-2-imidazolidinylidene} propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity. The present study examined the effects of KW-5092 on intestinal contraction and on acetylcholine (ACh) release in the isolated longitudinal muscle-myenteric plexus preparation of guinea pig ileum. In the electrically stimulated preparation, KW-5092 enhanced the contraction at 10-9 M to 3 × 10-6 M and potentiated the ACh release at 10-8 M to 3 × 10-6 M. In the unstimulated preparation, KW-5092 at 10-8 M to 10-4 M evoked the contraction and ACh release. Both the contraction and the ACh release by KW-5092 were abolished by tetrodotoxin (10-7 M) or removal of external Ca2+, and the evoked contraction was abolished by atropine (10-7 M). The ACh release by KW-5092 was not affected by hexamethonium (3 × 10-5 M), suggesting that the nicotinic receptor is not involved in the ACh release. Neostigmine, whose AChE inhibitory activity is equipotent to that of KW-5092, did not evoke ACh release even at 3 × 10-6 M, indicating that the ACh release by KW-5092 is not due to its AChE inhibitory activity. The present results suggest that KW-5092 evokes ACh release by stimulating a cholinergic pathway and that the ACh release by KW-5092 may contribute to its gastroprokinetic effects.
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  • Kensuke Orito, Teruyuki Yanagisawa, Norio Taira
    1994 Volume 64 Issue 4 Pages 297-301
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    The functionally responsible sites for the blocking action of tetraalkylammonium ions (TAAs) in ATP-sensitive K+ (KATP) channels opened by levcromakalim were estimated in canine coronary artery. Tetraethylammonium (TEA) and tetrabutylammonium (TBA) inhibited the levcromakalim-induced relaxation in a noncompetitive manner. Analyses of the noncompetitive antagonism revealed that the binding constant of TBA was about 900 times lower than that of TEA, although the reported affinity of TBA for the internal binding site in various K+ channels was only 10 times higher than that of TEA. TBA is much more lipid-soluble and permeable through membranes than TEA. Thus, TBA blocks KATP channels by binding to a possible high-affinity internal site for TAAs, whereas TEA seems to bind to the external site.
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  • Tetsuo Hayashi, Kiyofumi Yamada, Takaaki Hasegawa, Seiichi Ishihara, T ...
    1994 Volume 64 Issue 4 Pages 303-306
    Published: 1994
    Released: April 10, 2006
    JOURNALS FREE ACCESS
    Using in vitro autoradiography, we investigated the effects of Kamikihito (KKT), a traditional Chinese medicine, on the specific binding of [3H]quinuclidinyl benzilate (QNB) and [3H]N-(1-[2-thienyl]cyclohexyl)-3, 4-piperidine (TCP) in the rat brain. The Bmax but not the Kd values for [3H]QNB binding to the caudate/putamen and accumbens in aged rats were lower than those in young rats. The [3H]TCP binding was also decreased in aged rats compared with that in young rats. Long-term administration of KKT modulated the [3H]QNB binding in young but not aged rats.
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