The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
41 巻, 4 号
選択された号の論文の17件中1~17を表示しています
  • Hideyuki ADACHI, Tadao SHOJI
    1986 年 41 巻 4 号 p. 431-435
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    Characteristics of the interaction of verapamil with serotonin receptors were studied in rat brain membranes using a radioligand binding technique. While verapamil competed for the [3H]ketanserin binding sites at low concentrations with the Ki value of 0.41 μM, much higher concentrations were needed to inhibit the binding of [3H]serotonin to its binding sites, indicating higher affinity of verapamil binding for 5-HT2 than 5-HT1 receptors. The inhibitory action of verapamil on the [3H]ketanserin binding was stereoselective; the (-)isomer was about ten times more potent than the (+)isomer. The interaction of verapamil with [3H]ketanserin was competitive and reversible. While D600, a verapamil derivative, also competed for the [3H]ketanserin binding sites, nifedipine and nicardipine had practically no ability to inhibit the ligand binding to 5-HT1 or 5-HT2 receptors. Although diltiazem competed for 5-HT2 receptors, the affinity was much less than verapamil and D600.
  • Toyokazu HIRANUMA, Tetsuo OKA
    1986 年 41 巻 4 号 p. 437-446
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The contents of [Met5]-enkephalin and its four hydrolysis products, Tyr, Tyr-Gly, Tyr-Gly-Gly, and Tyr-Gly-Gly-Phe, in the sample obtained after enkephalin was incubated with tissues in either the absence or the presence of the peptidase inhibitor were estimated by high performance liquid chromatography combined with electrochemical detection in order to elucidate the effect of the peptidase inhibitor on enkephalin hydrolysis. Free Tyr was the major degradative product in the absence of the peptidase inhibitor, while the major hydrolysis product was the Tyr-Gly-Gly fragment in the presence of amastatin in both total homogenates and membrane fractions prepared from either the myenteric plexus-longitudinal muscle strip of guinea-pig ileum or the striatum of guinea-pig brain. Additionally, captopril significantly decreased the generation of Tyr-Gly-Gly in the presence of amastatin in both ileal and striatal membrane fractions. Moreover, thiorphan significantly prevented the formation of Tyr-Gly-Gly in the presence of both amastatin and captopril in both membrane preparations. Finally, when [Met5]-enkephalin was incubated with either an ileal or a striatal membrane fraction for 60 min at 37°C in the presence of three peptidase inhibitors, amastatin, captopril, and thiorphan, approximately 98 or 94%, respectively, of enkephalin remained intact. The results indicated that [Met5]-enkephalin was almost exclusively hydrolyzed by three distinct enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive peptidyl dipeptidase A, and thiorphan-sensitive endopeptidase-24.11 in both ileal and striatal membrane fractions.
  • Masako OKAZAKI, Eiji FURUYA, Yumi SHIN, Koji SAKAMOTO
    1986 年 41 巻 4 号 p. 447-458
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The time course of alterations in coagulative and fiblinolytic activities was studied in CCl4-induced liver disease in mice. Liver disease was induced by administration of 20% CCl4 in olive oil (p.o.). After single administration of CCl4, significant prolongation of r and k values and decrease in the ma value of thromboelastogram and apparent prolongation of PT and PTT were seen at 24 hr. Fibrinogen content decreased from 12 to 72 hr after single administration, while a mild but significant decrease in fibrinogen was observed after multiple administrations. The activity of factor XI II increased from 5 to 12 hr and then decreased from 24 to 168 hr after single administration. The activity of the hepaplastintest and Antithrombin III decreased apparently after single and multiple administrations. The plasminogen content and the activity of α2-plasmin inhibitor decreased severely after single and multiple administrations. These results indicate that the coagulative and fibrinolytic activities were decreased to the most lowest value at 24 or 48 hr after single administration of CCl4, and the severe suppression of fibrinolysis and the mild decrease in coagulative activity were observed after multiple administrations of CCl4. The reason for the different effects between single and multiple administrations on coagulative and fibrinolytic systems was discussed.
  • Kazuo HONDA, Chieko NAKAGAWA, Osamu INAGAKI, Masayuki SHIBASAKI, Toich ...
    1986 年 41 巻 4 号 p. 459-466
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The pharmacological activities of the enantiomers of amosulalol (YM-09538), a combined α- and β-adrenoceptor antagonist, and the corresponding desoxy derivative (YM-11133) were investigated in the cardiovascular system of rats. The optical isomers of amosulalol and YM-11133 antagonized the vasopressor effect of phenylephrine and the positive chronotropic effect of isoproterenol in normotensive pithed rats. Based on DR2 values (μg/kg, i.v.) obtained from Schild plots, (+)-amosulalol and YM-11133 (DR2=30) were approximately 10 times more potent than (-)-amosulalol (DR2=324) in blocking α1-adrenoceptors. For β1-adrenoceptors, in contrast, (-)-amosulalol (DR2=107) was approximately 60 times more potent than (+)-amosulalol (DR2=6460), which was almost equipotent with YM-1 1133 (DR2=3250). The results indicate that the optical isomers of amosulalol interact differently with α- and β-adrenoceptors. The effects of these phenethylamines on blood pressure and heart rate were studied in urethaneanesthetized rats (i.v.). The rank order of hypotensive potency in anesthetized rats ((+)-=desoxy>(-)-form) was consistent with the rank order of α1-adrenoceptor antagonism in pithed rats. In contrast, (-)-amosulalol having a more potent β1-adrenoceptor antagonist activity than (+)-amosulalol and YM-11133 only produced dose-dependent bradycardia at the hypotensive doses. The results indicate that the vascular α1- and cardiac β1 -adrenoceptor blocking activities of the optical isomers of amosulalol contribute to their hypotensive and bradycardia, respectively. Thus, the racemate of amosulalol appears to exert an overall activity reflecting the activities of the individual isomers.
  • Toshihiko MURASE, Hiroshi HAZAMA, Hiroyasu OKUNO, Yasuko SHIOZAKI, Yos ...
    1986 年 41 巻 4 号 p. 467-473
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The effects of H2-antagonists on acetaminophen-induced hepatic injury were examined. Rats were administered acetaminophen at the dose of 800 mg/kg body, 60 hr after injection of 3-methylcholanthrene. As an H2-antagonist, cimetidine (200 mg/kg), ranitidine (50 mg or 100 mg/kg), or famotidine (20 mg or 40 mg/kg) was administered before and after acetaminophen injection. The group administered only acetaminophen had been severely damaged as evaluated by changes in serum transaminase, P-450 content, aminopyrine demethylation, glutathione content and histological study, but administration of 200 mg cimetidine together with acetaminophen significantly reduced the hepatic injury to nearly the control level. Ranitidine had no protective effect against hepatic injury at the dose of 50 mg, which appears to have the same antacid effect as 200 mg cimeitdine, whereas it had a slight but significant protective effect as evaluated by the transaminase level, glutathione content and histological study at the dose of 100 mg. Famotidine had no effect against acetaminophen induced hepatic injury. Because famotidine had no effect, the protection by H2-antagonist against acetaminopheninduced hepatic injury cannot be explained by the decrease in hepatic blood flow alone. Therefore, inhibition of P-450 activity seems to be more important for reducing the generation of the reactive metabolites of acetaminophen than hepatic blood flow decrease.
  • Taeko HATA, Tomitaro KITA, Takashi HIGASHIGUCHI, Seiji ICHIDA
    1986 年 41 巻 4 号 p. 475-485
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The cholinergic activities in SART (specific alternation of rhythm in temperature)-stressed (repeated cold-stressed) rats, which are diseased rats with vagotonic-type dysautonomia, were examined with the following results. 1) A decreased content of total acetylcholine (T-ACh) and increased activities of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) in the basal ganglia and an increase in the T-ACh content and decrease in the AChE activity in the duodenum of SART-stressed rats reached the respective plateaus on day 5 of stress, which were maintained thereafter. CAT activity, however, in the hypothalamus was activated most on day 2. 2) These changes in SART-stressed rats were different from those in simple cold-stressed rats. 3) Subdiaphragmatic vagotomy inhibited the appearance of the changes in the duodenum, but not those in the hypothalamus of SART-stressed rats. 4) The sedative analgesic Neurotropin® prevented all the changes in SART-stressed rats described above. These results suggest that cholinergic neurons may be activated in both the hypothalamus and basal ganglia of the brain of SART-stressed rats, and the characteristic peripheral changes of the cholinergic system in the duodenum of SART-stressed rats may be under the control of the parasympathetic center.
  • Ryuya YANAGIHASHI
    1986 年 41 巻 4 号 p. 487-495
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The effect of nigral electrical stimulation on regional blood flow in the caudate nucleus and the cerebral cortex, and the influence of several drugs on these effects were examined in reserpinized or non-reserpinized cats. A doublethermistor element was inserted into the left caudate nucleus, and a plate-type thermocouple element was put on the left cerebral cortex. The left substantia nigra was electrically stimulated for 10 sec through a concentric bipolar electrode with a diameter of 0.3 mm (30 Hz, 1 msec, 10-30 V). In non-reserpinized cats, the nigral stimulation caused a decrease in striatal blood flow, increase in cortical blood flow and rise in mean blood pressure. Hexamethonium (3 mg/kg, i.v.) blocked completely the rise in mean blood pressure following nigral stimulation, but did not affect a decrease in striatal blood flow, indicating that a decrease in striatal blood flow following nigral stimulation was not due to the activation of the peripheral sympathetic nervous system.Nigral-induced decrease in striatal blood flow in non-reserpinized cats was blocked by haloperidol (0.1 mg/kg, i.v.), methysergide (1 mg/kg, i.v.) and reserpine (2 mg/kg, i.v.), but not by phentolamine (7 mg/kg, i.v.). In reserpinized cats, nigral stimulation caused an increase in striatal blood flow in contrast to a decrease in non-reserpinized cats. After administration of 5-HTP (50 mg/kg, i.v.) in reserpinized cats, nigral stimulation decreased the striatal blood flow. On the other hand, after administration of L-DOPA (30 mg/kg, i.v.) in reserpinized cats, nigral stimulation increased striatal blood flow. These results suggest that a decrease in striatal blood flow following nigral stimulation is due to the activation of a serotonergic mechanism mediated by dopaminergic neurons.
  • Hiroaki ARAKI, Yoshimi UCHIYAMA, Kazuaki KAWASHIMA, Hironaka AIHARA
    1986 年 41 巻 4 号 p. 497-504
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The effect of bilateral electrolytic lesioning of the anterior and posterior parts of the basal forebrain (BF) on learning behavior and changes in neurotransmitters in the central nervous system was investigated in rats. The posterior BF lesion caused more severe impairment than the anterior BF lesion in the acquisition of conditioned avoidance response in a two-way shuttle box. A severe deficit in acquisition of passive avoidance response was produced by the posterior BF lesion. Choline acetyltransferase (CAT) activity was decreased significantly in the parietal cortex but not in the occipital cortex in anterior BF-lesioned rats. However, it was not decreased in posterior BF-lesioned rats. The contents of monoamines in the hippocampus was decreased more significantly by the posterior BF lesion than by the anterior BF lesion. These results suggest that the impairment of memory in posterior BF-lesioned rats may be related mainly to monoaminergic function rather than to cholinergic deficit.
  • Hajime YASUHARA, Yuji KIUCHI, Katsuji OGUCHI, Donald S. DAVIES, Colin ...
    1986 年 41 巻 4 号 p. 505-510
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The effects of amiflamine on tyramine deamination were studied using isolated loops of intestine in anesthetized dogs. In the pretreatment experiment, dogs were dosed with amiflamine (3.5 mg/kg/day) once daily for 3 days, with the study being carried out 3 hr after the final dose. [14C] Tyramine (50 mg and 50 μCi) in 10 ml of normal saline was introduced into the isolated loops of gut, and tyramine and p-hydroxyphenylacetic acid in the venous blood were separated by HPLC and measured by scintillation spectrometry. In the untreated dogs, approximately 15% of the tyramine passed through the gut wall unchanged. When tyramine and amiflamine (0.06 to 3.5 mg/kg) were administered simultaneously to the gut loop, about 27 to 65% of the tyramine passed through the gut wall unchanged. On the contrary, after pretreatment with amiflamine for 3 days, percentage of tyramine passing through the gut wall was not increased in comparison with the control. These results suggest that pretreatment with amiflamine does not produce drug concentrations in the lining cells of the gut sufficient to effectively inhibit the deamination of oral tyramine, which is administered at least 3 hr after the final dose of amiflamine.
  • Toshifumi KAGIYA, Shuji UCHIDA, Atsushi MIZUSHIMA, Hiroshi YOSHIDA
    1986 年 41 巻 4 号 p. 511-517
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The inhibitory action of a muscarinic agonist on the contractile response of cardiac muscle is transient due to short-term desensitization of muscarinic cholinergic receptors. Studies were made on the binding of the muscarinic antagonist L-[3H]-quinuclidinyl benzilate ([3H]QNB) to the muscarinic receptor in the membrane fraction of ventricular muscle of guinea pigs desensitized by perfusion with carbachol for 10 min. Desensitization did not change the maximum binding or equibilium dissociation constant (Kd) of [3H]QNB, but shifted the inhibition curves of [3H]QNB binding by carbachol to the right both in the presence and absence of 5 -guanylyl 1midodiphosphate (GppNHp). Analysis of these inhibition curves with a multiple site model suggested that superhigh and high affinity agonist binding sites were converted to low affinity sites in the desensitized state. GppNHp has additive effects to the prior exposure to carbachol, suggesting a different site of action from short-term exposure of agonist. We conclude that agonist-induced short-term desensitization of the muscarinic receptor of ventricular muscle is caused by reduction in the affinity of the receptor for agonist without reduction in its amount or affinity for antagonist.
  • Takeshi TADANO, Shin-Etsu SATOH, Kensuke KISARA
    1986 年 41 巻 4 号 p. 519-523
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    Head-twitches have been regarded as an experimental model of hallucination, and we have recently observed that p-hydroxyamphetamine (p-OHA) markedly induced head-twitches in mice. The present work was undertaken to study possible participation of a serotonergic system in the mechanism of headtwitches induced by p-OHA. Head-twitches induced by p-OHA continued for 20-80 min, and the peak time of this effect was approximately 30-40 ruin after the administration. The i.c.v. administration of p-OHA (20, 40, 80 and 160 μg/mouse) produced characteristic head-twitches in a dose-dependent manner. Simultaneous injection of serotonin (10 μg/mouse, i.c.v.) and p-OHA caused a 2-2.5-fold increase in the number of head-twitches compared with non-serotonin controls. Pretreatment with p-chlorophenylalanine (200 mg/kg, i.p. and 500 μg/mouse, i.c.v.), in contrast, reduced head-twitches as did the pretreatment with cyproheptadine or dimethothiazine. These results suggest that p-OHA-induced head-twitches may involve the central serotonergic system which may exert an excitatory effect on head-twitches.
  • Takahide NOMURA, Masakatsu TACHIBANA, Hiroshi MAEKAWA, Hiroko NOMURA, ...
    1986 年 41 巻 4 号 p. 525-532
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    Studies were conducted to clarify the effects of vasopressin, angiotensin II and phenylephrine on hepatic ketogenesis and fatty acid synthesis. Hepatocytes from fed rats were incubated with oleate or octanoate. Vasopressin stimulated fatty acid synthesis as well as lactate and pyruvate accumulation in the presence of oleate. In accordance with this action, vasopressin caused a marked decrease in ketogenesis from oleate. When octanoate was added as a substrate, vasopressin failed to inhibit ketogenesis. Neither angiotensin II nor phenylephrine affected ketogenesis or fatty acid synthesis. The results in the present study show that there are vasopressin-mediated reciprocal changes in ketogenesis from oleate and fatty acid synthesis in isolated hepatocytes.
  • Issei TAKAYANAGI, Katsuo KOIKE, Osamu MAEDA, Masami ISHIZUKA
    1986 年 41 巻 4 号 p. 533-536
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    A difference in alpha-adrenoceptor mechanisms in vasa deferentia isolated from 3 weeks old and 40 weeks old rats were studied by analysis of the concentration-response curve of norepinephrine and Scatchard plot of specific [3H]-prazosin binding to microsomal fractions. The efficacy of norepinephrine and capacity of the maximum binding sites of[3H]-prazosin estimated in 40 weeks old rats were larger than those in the 3 weeks old rats, while there was no difference in the affinity of norepinephrine estimated in the 3 weeks old rats and in the 40 weeks old rats. The increase of efficacy for norepinephrine in the vas deferens from the 40 weeks old rats is due to the increase in the total concentration of alphaadrenoceptors.
  • Kimiko KAWAI, Shigetoshi CHIBA
    1986 年 41 巻 4 号 p. 537-540
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    The stainless steel cannula inserting method was used to observe vascular effects of 9 vasoactive substances on the isolated, perfused canine femoral artery and vein. In the vein, the order of potency for inducing vasoconstriction was norepinephrine>histamine=phenylephrine=serotonin>prostaglandin F > ATP > xylazine > tyramine >> KCl. It was demonstrated that the cannula inserting method is useful for observations of venous vascular reactivity.
  • Ikuko SHIMIZU, Mizuo MIYAZAKI, Noboru TODA
    1986 年 41 巻 4 号 p. 541-544
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    With advancing age from 2 to 12 years, contractions of isolated beagle cerebral arteries mediated by histamine H1 and serotonin receptors increased, whereas those induced by noradrenaline and angiotensin II did not differ. Relaxations by vasodilator substances, such as prostaglandin (PG) I2, isoproterenol, adenosine and K+ (5 mM), and by stimulation of vasodilator nerves in the adult and senescent beagle arteries did not significantly differ.
  • Hironori TANAKA, Yoshimi KUWAHARA, Susumu OKABE
    1986 年 41 巻 4 号 p. 545-549
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    Repeated administration of histamine-2HCl (40 mg/kg×4) significantly augmented mepirizole (200 mg/kg) or cysteamine (300 mg/kg)-induced duodenal and gastric lesions in rats within 6 hr. Most of the duodenal lesions were penetrating ulcers and were located over the entire duodenum. Gastric lesions were mainly located in the antrum adjacent to the duodenum. Indomethacin pretreatment did not significantly augment the duodenal lesions induced by mepirizole or cysteamine, but did augment the gastric lesions induced by these compounds.
  • Yasuyuki FURUKAWA, Kimiaki SAEGUSA, Shigetoshi CHIBA
    1986 年 41 巻 4 号 p. 550-553
    発行日: 1986年
    公開日: 2006/09/15
    ジャーナル フリー
    Intramural parasympathetic nerve stimulation (5 Hz, 2 min) after propranolol treatment evoked negative chronotropic and inotropic responses in the isolated dog atrium. The cardiac responses were not maintained during stimulation; they reached maximum values and then faded back toward their control values (“fade” response). 4-Aminopyridine increased the maximum values of both responses, and it increased the fade of the chronotropic response but not that of the inotropic response. These results suggest that the fade response to parasympathetic nerve stimulation is modulated at the parasympathetic nerve terminals of the isolated dog atrium.
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