The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 38, Issue 3
Displaying 1-15 of 15 articles from this issue
  • Kazuaki NAITO, Taku NAGAO, Minezo OTSUKA, Shoichi HARIGAYA, Hiromichi ...
    1985 Volume 38 Issue 3 Pages 235-241
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Denopamine is a new orally active cardiotonic agent. The present experiment was carried out to characterize the binding affinity and selectivity of this drug for β-adrenergic receptor subtypes. Binding studies were performed using 3H-dihydroalprenolol as the radioligand. Binding affinities of denopamine and some β-agonists for rat heart membranes (KiH), which contain predominantly the β1-subtype, were in the order of isoproterenol (Iso, 14.1 nM)>prenalterol (158)>norepinephrine (Nor, 227)≥epinephrine (Epi, 248)>denopamine (545)≥ dobutamine (645)>procaterol (1440)>terbutaline (6420). In rat lung membranes (predominantly β2-subtype), the order of potency (KiL) was Iso (20.6 nM)>procaterol (70.2)>Epi (136)>prenalterol (412)>dobutamine (735)≥Nor (744)>denopamine (2205)>terbutaline (2500). The β12-selectivity as judged from the KiL/KiH values was in the order of denopamine (4.1)>Nor (3.3)>prenalterol (2.6)> Iso (1.5)>dobutamine (1.1)>Epi (0.55)>terbutaline (0.39)> procaterol (0.05). Practolol, a β1-antagonist, showed a high β1-selectivity (KiL/KiH=15.3). In the presence of guanine nucleotide (GTP), the denopamine radioligand competition curve showed a rightward shift, and its Hill coefficient increased like other agonists, although the degree of the shift was less than that observed with full agonists such as Iso. These results essentially correspond with the pharmacological and biochemical properties of denopamine and confirm the β1-selectivity and the agonist property of this compound.
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  • Tsugutaka ITO, Kiyoshi FURUKAWA, Tadahiko KARASAWA, Toshiaki KADOKAWA, ...
    1985 Volume 38 Issue 3 Pages 243-251
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Two types of spinal reflex responses, extensor reflex and ventral root potential, were compared physiologically and pharmacologically in acute and chronic spinal cord transected rats. The recovery curve of the extensor reflex, recorded as evoked electromyogram, in chronic spinal rats was strikingly different from that in acute spinal rats. Namely, shortening of the reflex amplitude suppression period (stimulus interval: 20 msec) and appearance of the supernormal period (30-60 msec) were observed in chronic spinal rats. The recovery curves of ventral root potential (monosynaptic reflex) and M wave were almost the same in both preparations. In the frequency depression curve, the amplitude of the extensor reflex in chronic spinal rats was higher at high frequency stimulation than that in acute spinal rats. 5 Hydroxytryptophan, 5-methoxy-N, N-dimethyltryptamine and quipazine enhanced the extensor reflex in chronic spinal rats with a potency of 200-400, 8 and 4 times stronger than that in acute spinal rats, respectively. These drugs did not show consistent effects on the monosynaptic reflex of ventral root potential in chronic spinal rats. These results strongly suggest that the spinal interneurons where descending serotonergic fibers terminate become supersensitive and functionally modified in chronic spinal rats. It is speculated that the supersensitivity of these interneurons may play an important role in spasticity.
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  • Hiroshi OHTSUKI, Koji TAKEUCHI, Susumu OKABE
    1985 Volume 38 Issue 3 Pages 253-257
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    We studied the effects of various agents, which influence gastric acidity and bile acids, on compound 48/80 (48/80)-induced gastric lesions in rats. 48/ 80-Induced gastric lesions were produced by repeated intraperitoneal administration of 48/80 at 0.75 mg/kg once daily for 4 days. Test agents were given orally twice daily (30 min before and 9 hr after 48/80 administration) for 4 days. Al(OH)3 and sucralfate at 2000 mg/kg/day, a weak antacid dose, significantly inhibited (about 50-60%) the development of 48/80-induced lesions. Propantheline at 60 mg/kg/day and omeprazole at 60 or 200 mg/kg/day, which reduced gastric secretion for more than 12 hr, also significantly inhibited (about 30-40%) these lesions. Cimetidine at 200 mg/kg/day, which reduced gastric secretion for only 5 hr, had little effect on the lesion formation. Cholestyramine, which is a potent bile acids binding agent, had no effect on 48/80-induced lesions in doses of 600 or 2000 mg/kg/day. These results suggest that gastric acid, but not bile acids, is partly involved in the pathogenesis of 48/80-induced gastric lesions.
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  • Koichiro KAWASHIMA, Yuko MIWA, Kazuko FUJIMOTO, Junko MATSUMOTO, Miyak ...
    1985 Volume 38 Issue 3 Pages 259-265
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Effects of bunitrolol on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious, unrestrained spontaneously hypertensive (SHR) rats at rest and during handling stress. Propranolol was employed as a reference drug. Plasma drug concentrations were determined to related with the cardiovascular effects of the drugs. Bunitrolol produced a tachycardia for the first 2 hr and a significant reduction in resting MAP at 3 and 4 hr after the oral dose (5 mg/kg) when plasma bunitrolol concentration was less than 10 ng/ml, indicating the difference between cardiac and vascular beta adrenoceptors in sensitivity to intrinsic sympathomimetic action or direct vasodilator action. Propranolol (5mg/kg) produced no discernible effects on resting MAP and HR. Stress-induced tachycardia was significantly inhibited by both drugs throughout the experiment, while significant inhibition of hypertensive response was observed only at 4 hr after the treatment. Both bunitrolol and propranolol were rapidly absorbed from the gastrointestinal tract. Plasma half-life of these drugs were almost the same values of around 2 hr. These results indicate that dose size, plasma concentrations, and procedures and the timing of blood pressure measurement are the important factors to be considered when the antihypertensive effect of beta-blockers is studied in SHR rats.
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  • Takayoshi HIDAKA, Kazuyuki TAKEO, Kazunori HOSOE, Ikuo KATSUMI, Toshia ...
    1985 Volume 38 Issue 3 Pages 267-272
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    The effect of α-(3, 5-di-tert-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), a new anti-inflammatory compound, on arachidonate lipoxygenase and cyclooxygenase was investigated. KME-4 showed a dose-dependent inhibition of 5-lipoxygenase activity in both the cytosol (IC50: 0.85 μM) and ionophore A23187-stimulated cells (IC50: 11.5 μM) of guinea pig peritoneal polymorphonuclear leukocytes. KME-4 was also found to inhibit rabbit platelet cyclooxygenase (IC50: 0.44 μM), but had no inhibitory effect on platelet 12-lipoxygenase at concentrations up to 100 μM, whereas BW755C inhibited both enzymes in the same range of concentrations. The results indicate that KME-4 is a dual 5-lipoxygenase and cyclooxygenase inhibitor which is different from BW755C in affecting 1 2-lipoxygenase. These effects may provide information for understanding the pharmacological activity of KME-4.
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  • Takushi X. WATANABE, Hirofumi SOKABE, Koichiro KAWASHIMA
    1985 Volume 38 Issue 3 Pages 273-279
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Nipradilol and prizidilol are β-adrenoceptor blocking drugs with vasodilator action. These drugs lowered blood pressure (BP) in spontaneously hypertensive (SHR) rats acutely (24 hr) and subacutely (3 weeks) at doses of 10 and 20 mg/kg per day, p.o., respectively. Nipradilol decreased plasma renin concentration in acute and subacute studies, whereas it was unchanged with prizidilol treatment. Paradoxical effects of these drugs on BP were analyzed further: BP determined indirectly at the tail was slightly higher in SHR rats than the control, whereas BP determined directly through an aortic cannula without anesthesia, restraint, or prewarming was lower. We found that the discrepancy between BP values determined directly and indirectly was due to the increase in BP by prewarming stress during the determination by the tail cuff method.
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  • Rie MIYOSHI, Shozo KITO, Kumiko MIZUNO
    1985 Volume 38 Issue 3 Pages 281-285
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    The technique of in vitro autoradiography which was developed by Kuhar and others was applied to the rat brain with use of 3H-flunitrazepam (flu) as a radioactive ligand. The cerebral cortex, hippocampus, substantia nigra and cerebellar cortex were rich in 3H-flu binding sites. To differentiate the benzodiazepine receptor (BZR) subtype, the authors used a type 1 specific ligand, either triazolopiridazine (Cl 218872) or methyl-β-carboline-caboxylate (β-CCM), as an unlabeled displacer. The preparations were exposed on a 3H-sensitive film and then the film was developed. Computer-analysis of thus obtained autoradiographic pictures revealed that type 2 binding sites were distributed evenly within the rat brain, but with slight predominance in the hippocampus. After adding β-CCM, no silver grains were noticed in the cerebellum and substantia nigra. These data meant that these two structures contained essentially type 1 BZR, while the hippocampus contained both type 1 and type 2 receptors. Autoradiographically, characteristic distribution of BZR represented by 3H-flu binding was considerably lost by adding a type 1 specific ligand, and this treatment caused the silver grains to be evenly distributed. These data suggest that the BZR which is directly associated with characteristic pharmacological actions such as anxiolytic and hypnotic effects is type 1, and type 2 binding sites have a less characteristic distribution pattern and might be pharmacologically less specific.
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  • Mikio ITO, Akira FUJII, Yoshio SUZUKI
    1985 Volume 38 Issue 3 Pages 287-293
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Healing promoting action of teprenone on acetic acid ulcer in rats was assessed in comparison to that of cimetidine and proglumide by histological measurements. Teprenone (100 mg/kg×2/day, p.o.) decreased the macroscopic ulcer index and the defective area in the ulcerated region by 32.0% and 33.3%, respectively. In addition, this drug increased the decreasing index of exposed ulcer floor and the mucosal regeneration index by 28.1% and 38.0%, respectively. However, the thickness of the ulcer base and the development index of collagen fibers were little affected by this drug. Cimetidine (100 mg/kg×2/day, p.o.) showed a 27.2% decreasing action on the macroscopic ulcer index and a 31.3% increasing action on the thickness of the ulcer base, but failed to increase the mucosal regeneration index. Specimens from the cimetidine-treated rats were characterized by marked granulation proliferation beneath the ulcer floor. The upper layer of the granulation tissue was very rich in inflammatory cells. Proglumide (250 mg/kg×2/day, p.o.) was scarcely effective on any parameters. These results indicate that teprenone remarkably promotes the regeneration of the defective mucosa during the ulcer healing process, and the effectiveness of cimetidine according to the macroscopic observation may be due to excessive formation of granulation tissue in the defective region.
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  • Hitoshi KONTANI, Ryozo KOSHIURA
    1985 Volume 38 Issue 3 Pages 295-303
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    We examined the effects of morphine and morphine-related compounds on the rate of afferent discharges from the pulmonary receptors in bullfrog. Morphine (1×10-5-1×10-3 M) decreased the rate of spontaneous afferent discharges in a concentration-dependent manner, but hardly affected the rate of afferent discharges synchronized with lung inflation. Dihydrocodeine, naloxone and dextrorphan had the same effects as morphine. Levallophan (1×10-4 M), pentazocine (1×10-4 M) and pethidine (1×10-3 M) clearly decreased both rates of the spontaneous afferent discharges and the afferent discharges synchronized with lung inflation. In the presence of naloxone or levallorphan at the concentration of 1×10-5 M, morphine (1×10-5 and 1×10-4 M) caused an additive decrease in the rate of afferent discharges. Dextromethorphan and apomorphine at the concentration of 1×10-4 M caused an increase in the rate of spontaneous afferent discharges followed by decrease in both rates of the spontaneous afferent discharges and the afferent discharges synchronized with lung inflation. When dextromethorphan or apomorphine was washed out and the rates of afferent discharges were almost restored to the levels before application of each drug, reapplication of these drugs caused no increase in the rate of spontaneous afferent discharges, but the drugs inhibited the generation of afferent discharges. All of these drugs did not affect the flow rate of perfusion solution from the pulmonary vein.
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  • Atsushi MIYAMOTO, Hideyo OHSHIKA
    1985 Volume 38 Issue 3 Pages 305-311
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    The mechanism of isoproterenol-induced inhibition of potassium release from rat parotid slices has been determined. Spontaneous potassium release from the slices was significantly inhibited by isoproterenol at concentrations above 10-6 M. This isoproterenol effect was completely abolished in the presence of propranolol (10-5M) and ouabain (10-3 M) and was abolished during Na+-exclusion from the incubation medium. Isoproterenol caused an enhancement of the microsomal Na+, K+-ATPase activity at concentrations above 10-5 M, and this activity was inhibited by propranolol (10-5 M). The stimulatory effect of isoproterenol on the Na+, K+-ATPase exhibited a strong correlation with the inhibition of potassium release on each dose of isoproterenol. Moreover, dibutyryl cyclic AMP at concentrations above 10-4 M inhibited potassium release in a dose-dependent manner and cyclic AMP caused an enhancement of the microsomal Na+, K+-ATPase activity. These results suggest that the inhibitory effect of isoproterenol on potassium release is clearly derived from the elevated Na+, K+-ATPase activity and that it may in part be mediated by cyclic AMP.
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  • Kunihisa MIWA, Noboru TODA
    1985 Volume 38 Issue 3 Pages 313-320
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Relaxant responses to vasodilators, including nitroglycerin, sodium nitroprusside, prostaglandin I2 sodium salt (PGI2), prostaglandin E1 (PGE1), diltiazem hydrochloride and adenosine, were compared in helical strips of dog coronary arteries of different sizes and in coronary and mesenteric arterial strips. The relaxant responses to nitroglycerin, sodium nitroprusside, diltiazem and adenosine were significantly greater in coronary arteries than in mesenteric arteries, whereas the responses to PGI2 and PGE1 in these arteries did not significantly differ. In coronary arteries of different sizes, the relaxation induced by nitroglycerin was in the order of large>medium>small -size, while in contrast, the relaxations by adenosine, PGI2 and PGE1 were greatest in the small-size arteries and least in the large-size arteries. The relaxant responses to sodium nitroprusside and diltiazem did not differ in the coronary arteries of different sizes. Nitroglycerin, sodium nitroprusside and diltiazem appear to dilate coronary arteries more predominantly than mesenteric arteries. The preferential dilator action of PGI2 and PGE1 on distal coronary arteries, like that of adenosine, may lead more blood to re-distribute to the non-ischemic region of the heart in anginal patients.
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  • Jen-Tzaw HUANG, Takehiro NAKAJIMA
    1985 Volume 38 Issue 3 Pages 321-324
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Contractions of vas deferentia induced by KCl or field stimulation were not different between mature and old rats. The effect of trypsin or BaCl2 but not bradykinin or carbachol on contraction induced by field stimulation was significantly different between mature and old rats. The increase of twitching contractions by trypsin may be due to its effect on presynaptic α-adrenoceptors. Trypsin treatment did not qualitatively alter the responses produced by agonists in the vas deferentia of mature and old rats.
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  • Yumi KATANO, Mikio NAKAZAWA, Norio SHIMAMOTO, Ken SAKAI, Kazuki MATSUI ...
    1985 Volume 38 Issue 3 Pages 325-328
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    Chronic chemical denervation of the sympathetic nervous system with 6-OH dopamine resulted in an augmentation of the coronary blood flow (CBF) increase inherent in the canine heart-lung preparation, but not in an augmented accumulation of 6-keto PGF in the circulating blood. In denervated HLP, 6-keto PGF was lower and the vasodilator response to PGI2 larger at the start of the experiments. It was concluded that exaggerated increase in CBF was due to a potentiation of the vasodilator response to PGI2.
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  • Toshimitsu UCHIYAMA, Madeleine LEMEIGNAN, Paul LECHAT
    1985 Volume 38 Issue 3 Pages 329-333
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    In the curarized preparation, 3, 4-diaminopyridine (3, 4-DAP) and 4-aminopyridine (4-AP) were equiactive in their ability to antagonize d-tubocurarine caused complete depression of the indirectly elicited twitches of the sciatic nervetibialis anterior muscle preparation in anesthetized rats. In the non-curarized preparation, 3, 4-DAP showed 2.3 to 4.0 times stronger augmentation of the indirectly elicited twitches than 4-AP, but both the drugs increased equivalently and slightly the maximally elicited twitches of the chronically denervated muscle. The results suggest that the difference of their prejunctional effects is masked by the postjunctional effects of d-tubocurarine in the indirectly elicited twitches.
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  • Shiroh KISHIOKA, Sadako TAMURA, Yoshiyuki IGUCHI, Masanobu OZAKI, Hiro ...
    1985 Volume 38 Issue 3 Pages 334-336
    Published: 1985
    Released on J-STAGE: September 15, 2006
    JOURNAL FREE ACCESS
    The effects of morphine, adrenocorticotropic hormone (ACTH) and formalin on plasma corticosterone levels were investigated in the nucleus reticularis gigantocellularis (NRGC)-lesioned rats. ACTH (1.0 U/kg) or formalin (6.4%, 0.2 ml/rat) elevated plasma corticosterone in both sham-lesioned and NRGC-lesioned rats at the same degree, while morphine (10 mg/kg) also elevated plasma corticosterone in sham-lesioned rats, the elevation of which was significantly reduced by NRGC-lesioning. These findings suggest that the NRGC is involved in the corticosterone-increasing effect of morphine, but not involved in the effect of ACTH or formalin.
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