The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 30 , Issue 6
Showing 1-21 articles out of 21 articles from the selected issue
  • Tadao SHOJI, Yoshiharu DAIKU, Toshiji IGARASHI
    1980 Volume 30 Issue 6 Pages 763-772
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Postsynaptic α-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxy-benzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo α-adrenoceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The α-blocking effect of E-643 was reversible. E-643 protected α-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the α-adrenoceptors.
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  • Eiichiro OKABE, Masakazu OYAMA, Toshiki TANAKA, Takahiko SHIMURA, Haru ...
    1980 Volume 30 Issue 6 Pages 773-781
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Anaphylactic shock was induced with ovalbumin in sensitized rats and the relationship between PGE2 and cyclic nucleotides in lung tissue and plasma histamine during anaphylactic shock was studied. PGE2 level and cyclic AMP/cyclic GMP ratio decreased with this ovalbumin-challenge, and the former reached a minimum value 40 sec after the challenge while the latter reached a minimum value 20 sec later. The plasma histamine level was elevated and reached a maximum value concomitant with the minimum value in the cyclic AMP/cyclic GMP ratio. Dibutyryl cyclic AMP elevated the PGE2 level significantly and inhibited the ovalbumin-induced elevation of plasma histamine, however, this effect was abolished by the administration of indomethacin. PGE2 infusion elevated the cyclic AMP level as well as the cyclic AMP/cyclic GMP ratio, in a time-dependent manner, and inhibited the oval burnin-induced elevation of plasma histamine during 10 min infusion. There was a significant correlation between the cyclic AMP level and the cyclic AMP/cyclic GMP ratio, both elevated by PGE2 infusion. Thus, anaphylactic elevation of the plasma histamine level results from a decrease in the levels of PGE2 in lung tissue rather than a decrease in the cyclic AMP/cyclic GMP ratio, albeit these decreases being coincident during anaphylactic shock.
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  • Tomiko ASANO, Akira MIZUTANI
    1980 Volume 30 Issue 6 Pages 783-788
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    To elucidate the physiological role of benzodiazepine receptors in convulsion, these receptors were studied in the brain of the Mongolian gerbil (Meriones unguiculatus), an animal model used for the study of epilepsy. Benzodiazepine binding sites in the gerbil brain were demonstrated using [3H]diazepam. The binding was saturable and stereospecific. Benzodiazepines inhibited [3H]diazepam binding to the membranes and their ability to inhibit the binding closely correlated with their potency as anti-convulsants. These results showed that the characteristics of the benzodiazepine receptors in the Mongolian gerbil were similar to those obtained from rat and human brain. Seizures increase the specific binding of [3H]diazepam to the membranes of all regions of the gerbil brain, the most remarkable increase seen in the striatum. Time course studies showed that the increase reached a maximum 10 min after the seizure and the binding returned to the control level within 20 min. The increase in specific [3H]diazepam binding was due almost entirely to shifts in the affinity of [3H]diazepam for its receptors. Thus, the seizures may not be due to changes in the benzodiazepine receptors, and seizures produce an increase in receptor binding, which may be related to a physiological modification of excessive excitation.
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  • Tomio SEGAWA, Tadashi MIZUTA
    1980 Volume 30 Issue 6 Pages 789-793
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    The levels of [3H]-5-HT and [3H]-5-HIAA in P2-fraction from rats treated with a single dose of imipramine were lower at 2, 5 and 10 min after intraventricular administration of [3H]-5-HT, compared with control animals, though these levels were statistically insignificant. Thereafter, however, the values became higher than in the controls. After long-term administration of imipramine, the levels of [3H]-5-HT and [3H]-5-HIAA in P2-fraction were, at any time after intraventricular administration of [3H]-5-HT, significantly lower than those in the fraction from controls. The endogenous contents of tryptophan and 5-HIAA were not altered either with a single dose or by long-term administration of imipramine, however, the content of endogenous 5-HT was decreased by long-term administration of imipramine. These results indicate that the rate of disappearance of 5-HT from presynaptic neurons was accerelated by long-term administration of imipramine.
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  • Nobuhiro MIYAKOSHI, Minoru TANAKA, Hideyo SHINDO
    1980 Volume 30 Issue 6 Pages 795-805
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    The distribution and metabolism of L-DOPA-14C and L-5-HTP-14C in the cat brain were examined by means of autoradiography and chromatography. The results revealed that an appreciable amount of radioactivity in the gray matter, but not the white, and that the localization profiles of radioactivity of L-DOPA and L-5-HTP significantly differed. After L-DOPA-14C administration, a high accumulation was found in the caudate nucleus, putamen and pallidum. With L-5-HTP-14C administration, high radioactivity was observed in the hypothalamus, raphe nucleus, substantia nigra, inferior olivalis and caudate nucleus. An analysis of the main metabolites of both amino acids in various regions of the brain was also made. When L-DOPA was given, a high concentration of dopamine was detected in the caudate nucleus, followed by the hypothalamus. In the case of L-5-HTP, a high concentration of serotonin was detected in the hypothalamus and the medulla oblongata. These results suggest that amines derived from exogenously administered L-DOPA and L-5-HTP accumulate in the brain regions known as the corresponding amine rich regions, under physiological conditions.
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  • Naohisa ISHIKAWA, Tomohiro ICHIKAWA, Tatsuro SHIGEI
    1980 Volume 30 Issue 6 Pages 807-818
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Using isolated dog veins, we examined whether correlations exist between the regional differences in sensitivity to drugs and their embryogenesis. Twelve different veins were dissected. In the analysis, the data obtained previously for the inferior vena cava were also included. Spiral strips were prepared and the contractile responses to cumulative application of norepinephrine (NE), 5-hydroxytryptamine (5-HT), histamine (Hist) and acetylcholine (ACh) were recorded isometrically. For each drug, a histogram was drawn by stacking the overlapping ranges (mean±S.E.) of the pD2 value for each vein. The histogram indicated the number of veins which could share the same pD2 value. We obtained the following results: (I) Veins of the body wall had high sensitivity to NE (pD2 >6.40) and 5-FIT (pD2 >6.60) and veins of the intestinal system, except for the splenic vein, were not so sensitive to NE and 5-HT, but exhibited high sensitivity to Hist (pD2 >4.60), (2) the middle segment of inferior vena cava responded similarly to portal and mesenteric veins; (3) the responses of splenic vein to the agents used were quite different from those of portal and mesenteric veins. These results suggest possible correlations between the responsiveness of venous smooth muscles and embryogenesis of the venous system.
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  • Takushi X. WATANABE, Koichiro KAWASHIMA, Ken SAITO, Hirofumi SOKABE
    1980 Volume 30 Issue 6 Pages 819-827
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Antihypertensive effects of captopril, an orally active converting enzyme inhibitor were examined in the young and adult stroke-prone SHR (SHRSP) rats. The treatment was initiated at 6-7 and 14-18 weeks of age, and was continued for 12 and 17 weeks, respectively. The dosage of captopril was changed stepwise 3-30 and 3-100 mg/kg, orally per day in the young and adult rats, respectively. The effects of hydralazine were also determined for comparison. Captopril had a chronic antihypertensive effect when given in doses of 30 mg/kg in the young and 100 mg/kg in the adult rats. Captopril had no significant effect on heart rate throughout the experiments, while hydralazine increased the heart rate. Treatment with captopril decreased the incidence of vascular disease in the young and the severity in the adult rats, respectively. A decrease in incidence of cerebral stroke in the adult SHRSP was also apparent. More than a ten fold increase in plasma renin activity and about a two fold increase in kidney renin activity were observed in both the young and adult SHRSP at the end of the treatments. The results demonstrate the efficacy of long-term treatment with captopril in the management of hypertensive disease in SHRSP rats.
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  • Yukio YONETANI, Mitsuo ISHII, Kazumi IWAKI
    1980 Volume 30 Issue 6 Pages 829-840
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Effects of antihypertensive and uricosuric drugs were studied on the plasma and urinary levels of uric acid in oxonate-treated rats. We made use of animals with a catheterized aorta to successively collect blood samples and this procedure simplified the evaluation of progressive changes of plasma uric acid, under successive loading with potassium oxonate. The plasma uric acid level of the oxonate-treated rats was increased even with a single administration of diuretic chlorothiazides, furosemide, diazoxide and also uricosuric drugs such as tienilic acid and probenecid. On the other hand, a wellmaintained plasma uric acid level was also produced by exogenously administered uric acid in rats which had been given allopurinol and potassium oxonate. Diazoxide, tienilic acid and probenecid increased the plasma uric acid, while diuretic chlorothiazides did not. Furosemide tended to decrease the plasma uric acid level at the early stage of administration to rats treated with allopurinol, oxonate and uric acid, but increased these levels several hours later when the effect was studied by uric acid loading test with rats treated with allopurinol and oxonate. These effects also appeared as changes in the urine-excreted uric acid. Thus, the oxonate-treated rats demonstrated an acutely induced hyperuricemia not only with certain antihypertensives, but also with uricosuric drugs. The utility of these procedures for evaluating the hyperuricemic and uricosuric effects of drugs is discussed.
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  • Tetsuya KAMATAKI, Mebae ANDO, Kenji ISHII, Ryuichi KATO
    1980 Volume 30 Issue 6 Pages 841-851
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Addition of diethylaminoethyl 2, 2-diphenylvalerate-HCl (SKF 525-A) to the incubation mixture containing liver microsomes or purified cytochrome P-450 (PCB P-450) from PCB (KC-500)-treated rats resulted in non-competitive inhibition of 7-ethoxycoumarin O-deethylation activity whereas the addition to the incubation mixture containing purified cytochrome P-448 (PCB P-448) showed a competitive inhibition. Fortification of PCB-induced microsomes with purified NADPH—cytochrome P-450 reductase enhanced the O-deethylation activity. With the reductase-fortified microsomes, SKF 525-A inhibited the O-deethylation in a competitive manner. Based on these results, we confirmed that SKF 525-A inhibits non-competitively and competitively, depending on the species of cytochrome P-450. Our results also support the view that in microsomes from PCB-treated rats, PCB P-450 rather than PCB P-448 is mainly involved in the O-deethylation reaction, presumably due to the presence of a limited amount of NADPH—cytochrome P-450 reductase in microsomes.
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  • Osamu YAGASAKI, Masaaki TAKAI, Iwao YANAGIYA
    1980 Volume 30 Issue 6 Pages 853-860
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    The effects of the radial distension of the intestinal wall and the increased intraluminal pressure on the liberation of prostaglandins (PGs) were studied with the isolated guinea pig ileum. Both procedures were accompanied by an increased output of a prostaglandin-like substance and the release was proportional to the degree of distension or intraluminal pressure. Thin-layer chromatography coupled with bioassay suggested that this substance may be a mixture of PGF, PGE2 and PGE1. The existence of the former two types of PGs were prominent. The distension-induced release of PG-like substance was assumed to be not mediated by nerve excitation since tetrodotoxin failed to inhibit the release. The increased output of the PG-like substance was not maintained after distension of the intestinal wall, despite continued application of stimulus, indicating that actual tissue deformation is an essential condition leading to increased PG output. It is concluded that distension of the intestinal wall to its circumferential direction is an appropriate stimulus for the release of PG-like substance from the small intestine. The present results favor the view that prostaglandins may participate in the peristaltic activity.
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  • Sumie KAWANO, Toshiko NAKAO, Kogo HIRAGA
    1980 Volume 30 Issue 6 Pages 861-870
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Five week-old, Wistar-JCL male and female rats and C57BL/6N male mice given a 0.5% butylated hydroxytoluene (BHT)-containing diet for 6 days produced a marked increase in hepatic weight and microsomal protein content. However, the augmentations of cytochrome P-450 content and drug oxidation activities were much more significant, i.e. 2.5-fold and more than three-fold increases were observed on a body weight basis, respectively. BHT-induced cytochrome P-450 cannot be distinguished from phenobarbital (PB)-induced cytochrome in many respects we have examined: i.e. 1) a broad substrate specificity; 2) absence of the blue shift in the CO-binding difference spectrum; 3) no rise in the peak height ratio of ethylisocyanide difference spectrum; 4) absence of α-naphthoflavone inhibition of p-nitroanisole demethylase activity; 5) marked increases of 50, 000 and 54, 000 molecular weight polypeptides in SDS-polyacrylamide gel electrophoresis. However, the induction of 46, 000 molecular weight polypeptide by BHT in rats was more conspicuous than that by PB, and this induction was not observed in mice. In contrast to this marked induction, the administration of BHT to MC nonresponsive DBA/2N mice produced neither hepatic enlargement nor induction of cytochromes, but did produce an extremely high mortality.
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  • Issei MATSUBARA, Joji KAMIYA, Shoichi IMAI
    1980 Volume 30 Issue 6 Pages 871-879
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    In order to search into the underlying mechanisms of ECG changes suggestive of ischemia observed in humans and in rabbits after administration of 5-fluorouracil (5-FU), experiments were performed in anesthetized open-chest guinea pigs. The substance produced similar ECG changes in this species as well, after a rather long latent period of around 3 hours after intravenous administration. The incidence of ECG abnormality in animals given 60 mg/kg was 7/7, while that in animals given 30 mg/kg was 4/9. With 10-20 mg/kg, ECG changes were not observed during an experimental period as long as 5 hours. Associated with these ECG changes, a depletion of the high-energy phosphate compounds of the ventricular myocardium was observed. Analysis of tricarboxylic acid cycle (TCA cycle) intermediates revealed an accumulation of citrate within the myocardium, suggesting a malfunction of TCA cycle resulting from an inhibition of aconitase by fluorocitrate, as a cause of depletion of the high-energy phosphates. It is highly probable that the accumulation of citrate was due to the formation of fluoroacetate, an inhibitor of aconitase, from 5-FU via α-fluoro-β-alanine, a major degradation product of 5-FU, for it is known that β-alanine is usually converted to acetate.
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  • Kazushige SAKAI, Yasuhiro OHBA, Michitaka AKIMA, Hiroshi KAMIYAMA, Yos ...
    1980 Volume 30 Issue 6 Pages 881-890
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Pharmacodynamics and metabolism of N-(2-hydroxyethyl) nicotinamide nitrate (SG-75) were investigated in rats in relation to its main metabolic product. When SG-75 was orally administered, SG-75 and SG-86, a denitrate compound of SG-75, appeared in the blood. Within 7 hr, approximately 60% of the administered SG-75 were recovered in the urine as SG-86. When administered intraduodenally, SG-75 was rapidly absorbed and transferred in an unaltered form into the portal vein. SG-75 possessed hypotensive and coronary vasodilating actions, while SG-86 had little effect on the cardiovascular system. The coronary vasodilating effects of SG-75 (0.3-30 μg i.a.) were unaffected by the continuous infusion of SG-86 into the coronary perfusion system, even in large doses (50 μg/min, or 500 μg/min).
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  • Tohru NAKAJIMA, Isami KURUMA
    1980 Volume 30 Issue 6 Pages 891-898
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    The dopamine receptor of rat kidney particulate preparation was identified and characterized by the use of 3H-haloperidol binding. Binding of 3H-haloperidol to the kidney particulate preparation was slow and saturable. The dissociation constants (KD) were 0.41 nM and 5.88 nM, respectively, according to the model of two classes of independent binding sites. Maximal binding of high affinity site was obtained with 166 fmole/mg protein which was about 40% of the total receptor density. A wide variety of neuroleptics at specifically low concentrations in nanomolar range inhibited the 3H-haloperidol binding. There was an excellent correlation between the affinity of numerous neuroleptics for the kidney particulate preparation and that for the brain striatum.
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  • Keiji KOMORIYA, Kenji HOSHINA, Akira OHTSU, Noriyuki SAITO, Seizi KURO ...
    1980 Volume 30 Issue 6 Pages 899-904
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Administration of carrageenin or adjuvant to rats to induce inflammation produced increases in the plasma haptoglobin level. Simultaneously, there was an increase in the activity of the plasma inhibitor of prostaglandin E2 synthesis. Partially purified haptoglobin inhibited the microsomal over-all conversion of arachidonic acid to prostaglandin E2. The addition of the haptoglobin inhibited two heme-dependent reactions catalyzed by a purified enzyme of seminal vesicle microsome, i.e., the prostaglandin G2 synthesis from arachidonic acid and the conversion of prostaglandin G2 to H2. However, the plasma inhibitory activity was accounted for only partially by the haptoglobin contained in the plasma from treated rats.
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  • Shizuko TAKANO, Kunio SAKURAI, Takehiko SUZUKI
    1980 Volume 30 Issue 6 Pages 905-912
    Published: 1980
    Released: December 19, 2006
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    Effects of tiaramide, aspirin and indomethacin were studied on rabbit platelet aggregation in vivo and on platelet electrophoretic mobility. When tiaramide (6 mg/kg), aspirin (30 mg/kg) or indomethacin (1.3 mg/kg) was injected into the ear vein of rabbit during 60 sec, tiaramide only inhibited ADP-induced aggregation, 20 min after the injection. All three drugs prevented collagen-induced aggregation 20 and 120 min after the injection. Tiaramide and aspirin prevented aggregation 24 hours later. The inhibitory effects on the aggregation of tiaramide are presumably independent of prostaglandin synthesis, because malondialdehyde (a metabolite of PGG2) production was not influenced. Tiaramide reduced cyclic AMP levels in platelets after 20 min incubation, despite the ability of this agent to inhibit platelet aggregation. Tiaramide, aspirin and indomethacin per se has no effect on platelet electrophoretic mobility, while tiaramide prevented the decrease in the mobility produced by ADP. Tiaramide and aspirin also depressed the decrease in the mobility produced by collagen.
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  • Takashi DAN, Munekazu GEMBA
    1980 Volume 30 Issue 6 Pages 913-917
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
    Effects of Ca2+ antagonists, verapamil and diltiazem, on uptake and release of Ca2+ by microsomes of the renal cortex were studied. Verapamil inhibited the ATP-dependent Ca2+ uptake by renal microsomes. Addition of 0.8 mM verapamil was required to produce 50% inhibition of the ATP-dependent Ca2+ uptake. Diltiazem also depressed the Ca2+ uptake of the microsomes. The inhibitory effect of both drugs on the Ca2+ uptake was not due to an increased permeability for Ca2+, since release of Ca2+ from the microsomes was not significantly affected by either drug. It is proposed that verapamil and diltiazem inhibit Ca2+ transport by interfering with an active process of Ca2+ accumulation in microsomes of the renal cortex.
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  • Makoto SATO, Kazuo FURUTA, Azuma YAMAGUCHI
    1980 Volume 30 Issue 6 Pages 919-922
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
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  • Minoru OHTSUKA, Jo MORI, Sueo MUKUMOTO, Shigenobu KUMADA
    1980 Volume 30 Issue 6 Pages 922-924
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
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  • Kenji OHMORI, Sadayoshi YAMANAMI, Katsuichi SHUTO, Hirofuto MARUMO
    1980 Volume 30 Issue 6 Pages 925-927
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
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  • Yuichiro ARAI, Tadamasa UESATO, Sadayuki SHO, Kazuya KAMIJO
    1980 Volume 30 Issue 6 Pages 928-930
    Published: 1980
    Released: December 19, 2006
    JOURNALS FREE ACCESS
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