The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 90, Issue 2
Displaying 1-16 of 16 articles from this issue
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Review
  • Orphan G Protein-Coupled Receptors and Beyond
    Dong-Soon Im
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 101-106
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.101
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    Since the first discovery of mammalian receptors for adrenaline (β2) and acetylcholine (M1) in 1986, many G protein-coupled receptors for known ligands have been cloned by protein purification, PCR (polymerase chain reaction) and low stringency hybridization, and they have been identified by expression cloning techniques. Now we are almost out of the known ligands pool. However, through the achievement of the Human Genome Project, numerous orphan receptors (whose natural ligands are not yet found) are also available for analysis. In this review, I would like to review recent achievements in the discovery of natural ligands, to describe useful orphan receptor strategies, and to predict the future of reverse pharmacology.
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  • Effects of Meluadrine Tartrate and Ritodrine Hydrochloride on Oxytocin-Induced Uterine Contraction, Uterine Arterial Blood Flow and Maternal Cardiovascular Function in Pregnant Goats
    Yoshio Matsuda, Satoshi Kouno, Hiroshi Sakamoto, Tsuyomu Ikenoue
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 107-113
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.107
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    This study was designed to elucidate the effects of meluadrine tartrate on oxytocin-induced uterine contraction and maternal hemodynamics in unanesthetized, chronically instrumented pregnant goats. After the administration of meluadrine tartrate or ritodrine hydrochloride to pregnant goats, changes in heart rate (HR), arterial blood pressure (AOP), and arterial blood pH and gasses (PO2 and PCO2) in the mother, as well as changes in intrauterine pressure (IUP) and uterine arterial blood flow (UBF), were measured. The escalating administration of meluadrine tartrate (0.03, 0.1, 0.3 and 1 μg · kg−1 · min−1) or ritodrine hydrochloride (1, 3, 10 and 30 μg · kg−1 · min−1) to the maternal femoral vein caused a marked and similar inhibition in oxytocin-induced uterine contraction (a rise in IUP). By these escalating dosings, maternal HR was increased dose-dependently in both treatment groups; however, the degree of the HR increase in the meluadrine tartrate-treatment group was significantly less than that in the ritodrine hydrochloride-treatment group. Furthermore, the degree of the UBF decrease in the meluadrine tartrate-treatment group was significantly less than that in the ritodrine hydrochloride-treatment group. The present study suggests that meluadrine tartrate has a mild influence on the maternal cardiovascular function relative to the effects of ritodrine taking the potent efficacy on oxytocin-induced uterine contraction into account.
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  • Effects of Meluadrine Tartrate on Maternal Metabolic Responses and Fetal Hemodynamics in Pregnant Goats
    Yoshio Matsuda, Satoshi Kouno, Hiroshi Sakamoto, Tsuyomu Ikenoue
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 114-120
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.114
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    This study was designed to elucidate the effects of meluadrine tartrate on maternal metabolic responses and fetal hemodynamics in unanesthetized, chronically instrumented pregnant goats. After the administration of meluadrine tartrate to pregnant goats or directly to fetuses, changes in heart rate (HR), arterial blood pressure and arterial blood pH, gasses, electrolytes and metabolic responses were measured. The constant administration of meluadrine tartrate (0.1 μg · kg−1 · min−1) to pregnant goats resulted in the increases of maternal HR, glucose and free fatty acid and the decrease of maternal blood K+ concentration. The direct escalating administration of meluadrine tartrate (0.01, 0.03 and 0.1 μg · kg−1 · min−1) did not increase the fetal HR, while ritodrine hydrochloride (0.3, 1 and 3 μg · kg−1 · min−1) to fetuses increased the fetal HR dose-dependently. The present study suggests that meluadrine tartrate has a mild influence relative to the effects of ritodrine to the maternal metabolic responses and fetal cardiovascular function.
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  • Effect of Betaxolol on Aspartate Aminotransferase Activity in Hypoxic Rat Retina In Vitro
    Satoko Endo, Hiroshi Tomita, Sei-ichi Ishiguro, Makoto Tamai
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 121-124
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.121
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    We investigated the effect of betaxolol on the decrease of mitochondrial aspartate aminotransferase (mAAT) activity in rat retinas induced by hypoxia in vitro. It is reported that mAAT decreases in ischemic or hypoxic retina and that the decrease is caused by Ca2+-dependent proteases such as calpain. Betaxolol is a compound that has β1-adrenergic receptor blocking and voltage-dependent calcium channel blocking properties. The rat eye cups were maintained with Locke’s solution saturated with 95% air – 5% CO2. The eye cups were immersed in glucose-free Locke’s solution saturated with 95% N2 / 5% CO2 (hypoxic solution). Ninety minutes of hypoxia caused a 20% decrease in mAAT activity. The eye cups incubated with the hypoxic solution containing 1 mM EGTA, 10 μM MK-801 or 100 μM betaxolol were protected from the decrease in mAAT activity, so that the residual mAAT activity was 50%, 45% or 40%, respectively, compared to the eye cups incubated in hypoxic solution alone, which had a 100% decrease in mAAT activity. In addition, co-incubation with EGTA and betaxolol had a greater protective effect against the mAAT decrease than a single application. This additive effect of betaxolol was dose-dependent. These results suggested that betaxolol had a protective effect against the decrease of mAAT caused by hypoxia and indicated that betaxolol might inhibit the Ca2+ release from intracellular Ca2+ stores.
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  • Modulation by Mibefradil of the Histamine-Induced Ca2+ Entry in Human Aortic Endothelial Cells
    Kazuto Yazawa, Kyoichi Ono, Toshihiko Iijima
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 125-130
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.125
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    The effect of mibefradil, known as a T- and L-type Ca2+ channel antagonist, on the histamine-induced Cl− current and Ca2+ entry was investigated in human aortic endothelial cells by the fluorescence measurement of intracellular Ca2+ concentration ([Ca2+]i) combined with the patch clamp method. Mibefradil (10 μM) inhibited both the Cl− current and Ca2+ entry in a concentration-dependent manner with an IC50 value of 4.8 and 2.6 μM for the Cl− current and [Ca2+]i, respectively. These values were comparable to those reported for the inhibition of the T-type Ca2+ channel and other Cl− channels. The suppression of Ca2+ entry is not caused by the inhibition of the Cl− current and the resulting depolarization since the inhibition was still observed under the voltage clamp condition. These results suggest that mibefradil is a potent blocker not only for the agonist-induced Cl− current but also Ca2+ entry channels in vascular endothelial cells.
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  • Effects of KMD-3213, a Uroselective α1A-Adrenoceptor Antagonist, on the Tilt-Induced Blood Pressure Response in Normotensive Rats
    Katsuyoshi Akiyama, Masachiyo Hora, Ryoichi Yamagishi, Makio Kitazawa
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 131-137
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.131
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    KMD-3213 ((−)-1-(3-hydroxypropyl)-5-((2R)-2-{[2-({2-[(2,2,2-trifluoroethyl)oxy]phenyl}oxy)ethyl]amino}propyl)-2,3-dihydro-1H-indole-7-carboxamide), an α1A-adrenoceptor antagonist with potency similar to that of tamsulosin, is under development for the treatment of bladder outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we investigated the effects of KMD-3213 on the tilt-induced blood pressure response in anesthetized normotensive rats. Male normotensive Sprague-Dawley rats were placed in the supine position on a board under cocktail anesthetization (α-chloralose, urethane and sodium pentobarbital). The arterial blood pressure was measured from the carotid artery. The animals were given consistent 45° head-up tilt from the horizontal position, following the transient decrease in the blood pressure, and then recovery of the blood pressure to the normal level. Significant orthostatic hypotension was seen with intravenous administration of both prazosin and tamsulosin at doses over 3 μg/kg, and these drugs completely blocked the tilt-induced blood pressure responses at 30 μg/kg. On the other hand, these responses were still retained when KMD-3213 was administered intravenously at a dose up to 75 μg/kg of KMD-3213. Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These results indicate that KMD-3213 is not likely to induce orthostatic hypotension and would be a useful compound for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia.
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  • The mRNA Expression of Serotonin 2C Subtype Receptors Uncoupled With Inositol Hydrolysis in NG108-15 Cells
    Michihisa Tohda, Monrudee Sukma, Yasuyuki Nomura, Hiroshi Watanabe
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 138-144
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.138
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    Cell culture systems seem to be useful for clarifying the cellular physiological mechanisms of serotonin 2C subtype receptors (5-HT2CR) and related drug action mechanisms. However, there are still few reports about cells that contain intrinsic 5-HT2CR. This report demonstrates by using RT/PCR that 5-HT2CR mRNA exists in splicing variant forms in NGI08-15 cells. The PCR results using a pair of primers that recognized sequences near the third intracellular loop site showed two neighboring bands at about 500 bp upon electrophoresis in acrylamide gels. The sequence analysis demonstrated that one band was the rat 5-HT2CR sequence and the other one was that of the mouse. Serotonin, however, did not enhance the inositol phosphates formation in NG108-15 cells. It has been reported that post-translational modifications of RNA, splicing and editing, occur at the site of the second intracellular loop domain in 5-HT2CR mRNA. Accordingly, a pair of primers that recognized this site were designed. The molecular size of the PCR product was shorter than that expected based on the sequence of the native 5-HT2CR. The fragment lacked the 95 nucleotides of native 5-HT2CR mRNA. This seems to be the reason why serotonin did not enhance inositol phosphates formation in NG108-15 cells.
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  • Involvement of the NMDA-Nitric Oxide Pathway in the Development of Hypersensitivity to Tactile Stimulation in Dental Injured Rats
    Norifumi Yonehara, Katsuhiko Amano, Yoshinori Kamisaki
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 145-155
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.145
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    To investigate mechanisms in pathological pain conditions as the hyperalgesia and allodynia observed after dental surgery, we employed a rat dental-injury model involving the simultaneous pulpectomy to a lower incisor and extraction of an ipsilateral upper incisor. We found that hypersensitivity to tactile stimulation developed on both ipsilateral and contralateral sides in the dental-injured rats 5 days after the surgery and that this lasted for at least 30 days. Recovery from hypersensitivity to tactile stimulation was achieved by the intraperitoneal (i.p.) administration of MK-801 (0.05 mg/kg) or NG-monomethyl-L-arginine monoacetate (L-NMMA: 10 – 100 mg/kg), but not attained by NG-monomethyl-D-arginine monoacetate (D-NMMA: 100 mg/kg). This recovery effect of L-NMMA (50 mg/kg) was inhibited by pretreatment with L-arginine (600 mg/kg). In the trigeminal nucleus caudalis (SpVc), the changes in nitric oxide (NO) levels invoked by the intravenous (i.v.) administration of N-methyl-D-aspartate (NMDA; 10 mg/kg) were found to be significantly larger in the dental-injured rats than in sham-operated rats. The number of neuronal NO synthase (nNOS)-positive neurons increased in layers I-II and III-IV in the SpVc on both sides of the dental-injured rats. These results suggest that hypersensitivity to tactile stimulation developed following dental injury, and that NMDA receptor/NOS/NO production pathways in the SpVc may be involved in pathological conditions.
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  • Responses of Exposure to Cigarette Smoke at Three Dosage Levels on Soleus Muscle Fibers in Wistar-Kyoto and Spontaneously Hypertensive Rats
    Toshiaki Nakatani, Toshikatsu Nakashima, Taizo Kita, Akihiko Ishihara
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 157-163
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.157
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    Fiber type distributions, cross-sectional areas (CSAs) and succinate dehydrogenase (SDH) activities in the soleus (SOL) muscle in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were determined after exposure to cigarette smoke at three different dosage levels using a smoking machine. The rats were exposed to cigarette smoke at a rate of 15 puffs/min, for 20 min/day with 23 cigarettes (low-dosage), 26 cigarettes (medium-dosage) or 30 cigarettes (high-dosage) for 8 weeks. There were no effects on the body weight, SOL weight, fiber type distribution, CSA or SDH activity of WKY after exposure to cigarette smoke, irrespective of the dosage level. In contrast, the body weights of SHR were lower after exposure to cigarette smoke, irrespective of the dosage level. The SOL weights of SHR were lower after exposure to cigarette smoke at the medium- and high-dosage levels. A lower percentage of type I fibers, a higher percentage of type IIA fibers and a smaller CSA of both type I and type IIA fibers were observed in SHR after exposure to cigarette smoke at the high-dosage level, but not at the low- and medium-dosage levels. These results indicate that heavy cigarette smoke causes changes in the enzyme histochemical properties with a reduced CSA of the SOL in SHR, but not in WKY.
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  • Antisense-Inhibition of Plasma Membrane Ca2+ Pump Induces Apoptosis in Vascular Smooth Muscle Cells
    Satoshi Sasamura, Ken-Ichi Furukawa, Miwa Shiratori, Shigeru Motomura, ...
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 164-172
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.164
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    The effect of antisense oligodeoxynucleotides (ODNs) of plasma membrane Ca2+-pumping ATPase (PMCA) on rat aortic vascular smooth muscle cells (VSMCs) in primary culture was examined. More than 80% of the PMCA expressed in cultured VSMCs was the PMCA-1B subtype. Exposed to antisense ODNs against PMCA-1, not only the expression of the PMCA protein but also mRNA of PMCA-1B was diminished in a concentration-dependent manner. Extracellular Na+-independent 45Ca2+ efflux catalyzed via PMCA was inhibited with antisense ODNs. Both the resting and ionomycin- or ATP-stimulated levels of intracellular Ca2+ were increased by antisense ODNs. Furthermore, prolonged treatment with antisense ODNs caused apoptosis in VSMCs. The occurrence of apoptosis was inhibited by FK506, a potent immunosuppressant. These results demonstrate that the PMCA was specifically inhibited by antisense ODNs and suggest that PMCA plays an important role in regulation of intracellular Ca2+ concentrations, especially at the resting condition to prevent an occurrence of apoptosis that may be induced through the activation of calcineurin.
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  • Effects of Minoxidil on Ischemia-Induced Mechanical and Metabolic Dysfunction in Dog Myocardium
    Atsuko Yamamoto, Kumi Satoh, Kenichi Ichinosawa, Shigeru Kaneta, Seiic ...
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 173-180
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.173
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    Effects of minoxidil on ischemia-induced myocardial mechanical and metabolic dysfunction were examined in anesthetized open-chest dogs. A regional portion of the left ventricle was made ischemic for 20 min by ligating the left anterior descending coronary artery, and then reperfused for 120 min. Dimethylsulfoxide or minoxidil (0.3, or 1.0 mg/kg) was injected intravenously 10 min before ligation. Ischemia decreased regional myocardial contraction, and reperfusion recovered it but incompletely. Myocardial metabolic derangement was observed during ischemia, such as decreases in the myocardial levels of ATP and creatine phosphate. These metabolic changes caused by ischemia were restored by reperfusion. Minoxidil injection at 0.3 and 1.0 mg/kg significantly decreased blood pressures but increased coronary flow. Pretreatment with minoxidil significantly enhanced the recovery of myocardial contraction during reperfusion after ischemia. The levels of ATP and creatine phosphate in the ischemic myocardium were significantly preserved by minoxidil at 0.3 mg/kg. No significant effect of minoxidil on the metabolism was observed in the 120 min reperfused myocardium. In conclusion, minoxidil improved the mechanical dysfunction in the reperfused heart and the drug at low dose preserved high-energy phosphates during ischemia.
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  • Effects of Radical Scavengers, TA248 and TA276, on Stunned Myocardium in Dogs: Involvement of KATP Channels
    Tetsuro Kosugi, Kumi Satoh, Shigeru Kaneta, Yasuo Aoki, Hidetsugu Taka ...
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 181-188
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.181
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    TA248 (7-(β-D-glucopyranosyloxy)-4-hydroxy-3-octyloxy-2H-1-benzopyran-2-one) and TA276 (sodium 7-hydroxy-3-octyloxy-2H-1-benzopyran-2-one-4-oxide) were newly developed as radical scavengers. In vitro, TA276 scavenged both superoxide anions (· O2−) and hydroxyl radicals (· OH). TA248 also trapped · O2−, but had less activity on · OH. In vivo, left ventricular contractile functions were determined in pentobarbital-anesthetized open-chest dogs. A regional portion of the left ventricular wall was made ischemic for 20 min by ligating the left anterior descending coronary artery and then reperfused for 60 min. TA248 (3 mg/kg) and TA276 (3 mg/kg) injected i.v. 10 min before occlusion significantly improved myocardial stunning that is contractile dysfunction observed after reperfusion following brief ischemia. Glibenclamide (1 mg/kg) injected i.v. 20 min before occlusion significantly worsened the myocardial stunning. Pretreatment with glibenclamide completely abolished the beneficial effect of TA276 on myocardial stunning, whereas it only partially attenuated that of TA248, showing some improvement even in the presence of glibenclamide. Because of the incomplete scavenging activity of TA248, residual · OH may play some roles in improvement of myocardial stunning with TA248 in the presence of glibenclamide. We speculate that the · OH may eject glibenclamide from its binding site on KATP channels, leading to opening of the channels.
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Short Communications
  • Administration of Folium mori Extract Decreases Nitric Oxide Synthase Expression in the Hypothalamus of Streptozotocin-Induced Diabetic Rats
    Mi-Hyeon Jang, Hong Kim, Min-Chul Shin, Baek-Vin Lim, Taeck-Hyun Lee, ...
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 189-192
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.189
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    Folium mori, the leaves of Morus alba L., has traditionally been used for the treatment of diabetic hyperglycemia. It has been shown to induce enhanced NOS expression in the hypothalamus of rats with streptozotocin (STZ)-induced diabetes. In the present study, the effect of Folium mori on the expression of nitric oxide synthase (NOS) in the hypothalamus of STZ-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Enhanced NAPDH-d expression was detected in the paraventricular nucleus, ventromedial hypothalamic nucleus, and lateral hypothalamic area of the hypothalamus in the STZ-induced diabetes group. Administration of the aqueous extract of Folium mori to rats with STZ-induced diabetes resulted in decreased NADPH-d positivity. These results suggest that Folium mori treatment is effective in curbing the desire for food under diabetic conditions via modulation of NO expression in the hypothalamus.
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  • Effects of Naltrexone on Spontaneous Itch-Associated Responses in NC Mice With Chronic Dermatitis
    Tatsuya Maekawa, Tomomi Yamaguchi-Miyamoto, Hiroshi Nojima, Yasushi Ku ...
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 193-196
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.193
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    The effects of the opioid antagonist naltrexone on spontaneous itch-associated behaviors and cutaneous nerve activities were examined to determine whether it inhibits pruritus through peripheral action in NC mice with chronic dermatitis. Their rostral-back scratching and caudal-back biting were 19 and 3.4 times more, respectively, than those of control mice. The activities of cutaneous nerves innervating the rostral and caudal back were 9.5 and 5.4 times more, respectively, in affected mice than in control mice. Subcutaneous injections of naltrexone significantly inhibited the scratching and biting, without effects on the nerve activities. The results suggest that the peripheral action does not play a central role in inhibiting chronic itch-associated behaviors.
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  • Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model
    Hiromi Takeuchi, Shin-ichi Yatsugi, Tokio Yamaguchi
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 197-200
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.197
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    YM992 ((S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a novel antidepressant with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT2A receptor antagonistic activity. The effects of YM992 and two selective 5-HT re-uptake inhibitors (SSRIs) were studied in a marble-burying behavior test as a model of an obsessive-compulsive disorder (OCD) in mice at doses of 5, 10 and 15 mg/kg, i.p. YM992 and fluoxetine significantly inhibited marble-burying behavior at a dose of 15 mg/kg (i.p.) without affecting spontaneous locomotor activities. Citalopram also significantly inhibited the behavior at doses of 5, 10 and 15 mg/kg (i.p.) without affecting spontaneous locomotor activities. These results suggest that YM992, as well as SSRIs, may exhibit anti-OCD activity in addition to an antidepressive effect in clinical use.
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  • Time-Dependent Effect of Glutamate on Long-Term Potentiation in the Suprachiasmatic Nucleus of Rats
    Yukiko Nisikawa, Takao Shimazoe, Shigenobu Shibata, Shigenori Watanabe
    Subject area: Infomation Science
    2002 Volume 90 Issue 2 Pages 201-204
    Published: 2002
    Released on J-STAGE: October 20, 2002
    DOIhttps://doi.org/10.1254/jjp.90.201
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    The effect of glutamate on optic nerve stimulation-evoked field potentials in rat suprachiasmatic nucleus (SCN) was examined in vitro. Glutamate application for 20 min induced long-term potentiation (LTP) of the field potentials in the SCN at nighttime, whereas that induced a weak LTP at daytime. On the other hand, application for 40 min induced LTP in the SCN during the daytime, whereas it induced a weak one at nighttime. These results indicate that the effect of glutamate is dependent on the application time and that the effect is influenced by the duration of glutamate exposure.
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