The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 86, Issue 2
Displaying 1-18 of 18 articles from this issue
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Review
  • Estrogen and Cerebrovascular Physiology and Pathophysiology
    Dale A. Pelligrino, Elena Galea
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 137-158
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.137
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    Numerous studies have uncovered a wide variety of estrogen effects with apparent cardiovascular benefits, the most recognized ones being vasodilation, anti-atherogenesis, diminished post-ischemic inflammation and anti-oxidant effects. This article provides an overview of the influence of estrogen on the cerebral vasculature, under physiologic and pathophysiologic conditions, and covers both acute and chronic effects. The discussion is primarily focused on the vasodilatory and anti-inflammatory actions of estrogen, since those particular estrogen influences have received the greatest attention in studies published to date. With respect to vasodilation, although some consideration is given to the role of other vasodilating mechanisms and factors, the emphasis is mostly placed on the endothelial isoform of nitric oxide synthase, eNOS, which has emerged as a clear target of estrogen. Some consideration is given to recent findings that suggest that estrogen can stimulate eNOS activity by decreasing the expression of the eNOS inhibitor caveolin-1. With regard to the ability of estrogen to counteract inflammation, potential mechanisms by which estrogen limits the post-ischemic leukocyte adhesion, and the expression of the inducible NOS, are discussed.
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  • Adrenomedullin Inhibits the Pressor Effects and Decrease in Renal Blood Flow Induced by Norepinephrine or Angiotensin II in Anesthetized Rats
    Kouichiro Minami, Kayoko Segawa, Yasuhito Uezono, Yosuke Shiga, Munehi ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 159-164
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.159
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    Adrenomedullin (AM), a hypotensive peptide originally isolated from human pheochromocytoma, has been reported to regulate renal functions. In patients with glomerulonephritis, the serum levels of AM are elevated as well as hypertensive agents norepinephrine (NE) and angiotensin II (AII). The effects of AM on the NE- or AII-induced pressor effects and renal blood flow responses, however, are not well clarified. We examined the effects of AM on blood pressure and renal blood flow induced by NE or AII in anesthetized rats. Arterial blood pressure and renal blood flow were measured using a calibrated pressure transducer and a laser Doppler flowmeter, respectively. Drugs were injected into the tail vein with a syringe. Intravenous administration of AM (1 - 3 nmol/kg) decreased the arterial blood pressure in anesthetized rats in a dose-dependent manner, whereas it did not affect the renal blood flow. NE or AII administration in anesthetized rats caused both increases in blood pressure and decreases in renal blood flow. Simultaneous administration of AM with NE or AII prevented the increasing effects of blood pressure and inhibited the decreases in renal blood flow caused by NE or AII. These findings suggest that AM may have a protective role against the pressor effects and decrease in renal blood flow caused by NE or AII.
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  • Effect of TAK-637, a Tachykinin NK1-Receptor Antagonist, on Lower Urinary Tract Function in Cats
    Izumi Kamo, Takayuki Doi
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 165-169
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.165
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    The effect of TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H[1,4]diazocino[2,1g][1,7]naphthyridine-6,13-dione), a tachykinin NK1-receptor antagonist, on lower urinary tract function was investigated in cats. TAK-637 (0.1, 0.3, 1 and 3 mg/kg, i.v.) produced a dose-dependent increase in bladder capacity without any significant reduction in voiding efficiency in decerebrate cats. The maximal increase in bladder capacity was 94%. By contrast, oxybutynin at 1 and 3 mg/kg (i.v.) produced a 18% and 35% increase in bladder capacity, respectively, with a 47% and 45% reduction in voiding efficiency. TAK-637 (3 mg/kg, i.v.) did not inhibit the micturition reflex induced by electrical stimulation of the rostral brainstem near the locus coeruleus, indicating that it does not impair the well-organized micturition reflex (bladder contraction and urethral relaxation). These results suggest that TAK-637 increases bladder storage capability without inhibiting the voiding function of the lower urinary tract, presumably by inhibiting the afferent pathway of the micturition reflex, rather than the efferent pathway.
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  • Markedly Increased Nasal Blockage by Intranasal Leukotriene D4 in an Experimental Allergic Rhinitis Model: Contribution of Dilated Mucosal Blood Vessels
    Nobuaki Mizutani, Takeshi Nabe, Aki Imai, Hiromu Sakurai, Hiroshi Take ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 170-182
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.170
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    We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized – challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD4 (10 μl/nostril) at 10−10 to 10−6 M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dose-dependently suppressed by Nω-nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized – challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized – non-challenged group. The amount of NO2− and NO3− in nasal cavity lavage fluid after LTD4 instillation in the sensitized – challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.
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  • Long Term Effects of Toki-shakuyaku-san on Brain Dopamine and Nerve Growth Factor in Olfactory-Bulb-Lesioned Mice
    Qing-Hua Song, Kazuo Toriizuka, Guang-Bi Jin, Takeshi Yabe, Jong-Chol ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 183-188
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.183
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    We used olfactory-bulb-lesioned mice induced by intranasal irrigation with zinc sulfate as a model of dementia, to investigate the effects of Toki-shakuyaku-san (TSS) on monoamines and nerve growth factor (NGF) in brain regions. TSS was given daily through the drinking water for either 1, 2, 3, 4 or 8 weeks from the day after olfactory lesion. The administration of TSS significantly suppressed the decrease of 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in olfactory bulb of olfactory-lesioned mice at 1 week, and tended to suppress the decrease of DOPAC and HVA during the experimental session. However, the administration of TSS had no influence on dopamine contents. NGF contents in the olfactory bulb were increased after the irrigation, and the value returned to the same level as the control at 8 weeks after. Although the NGF contents in the olfactory bulb of TSS-treated mice were immediately increased at 1 and 2 weeks, the value returned to normal level within 3 weeks. These findings indicate that oral administration of TSS prevents the reduction of dopamine metabolites, DOPAC and HVA, and immediately increased NGF contents in the olfactory bulb. This suggested that TSS treatment promotes the NGF contents in olfactory nerves and rescue the neurons from damage.
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  • Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes
    Rika Yoshio, Takanobu Taniguchi, Harumi Itoh, Ikunobu Muramatsu
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 189-195
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.189
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    Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant α1-adrenoceptor subtypes (α1a-, α1b- and α1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (α1A-subtype), dog carotid artery (α1B-subtype) and rat thoracic aorta (α1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three α1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for NAN-190 (5-HT1A antagonist) in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, α1a(α1A)- or α1d(α1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed α1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the α1B-subtype was approximately 500-fold lower than that of affinity to the α1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to α1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.
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  • Involvement of Neuropeptides in the Allergic Nasal Obstruction in Guinea Pigs
    Toshihiko Kaise, Yukino Akamatsu, Toshihide Ikemura, Kenji Ohmori, Aki ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 196-202
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.196
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    The purposes of the present study were i) to determine whether neuropeptides induce the nasal obstruction in guinea pigs, and ii) to examine the possible involvement of neuropeptides in allergic nasal obstruction. The decrease in nasal cavity volume was determined by acoustic rhinometry as an index of nasal obstruction. In non-sensitized guinea pigs, substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) caused the nasal obstruction 10 to 30 min after their intranasal application. LY303870 (1 mg/kg), a tachykinin NK1-receptor antagonist; SR48968 (1 mg/kg), a tackykinin NK2-receptor antagonist; and CGRP(8 - 37) (50 nmol/kg), a CGRP1-receptor antagonist, administered intravenously before the intranasal application of the neuropeptides, inhibited the responses induced by SP, NKA and CGRP, respectively. In the guinea pigs sensitized with dinitrophenyl-coupled Ascaris suum allergenic extract, the intranasal antigen challenge caused nasal obstruction. The response was biphasic and consisted of the early phase response (EPR) and the late phase response (LPR), which developed 30 min and 6 h, respectively, after the antigen challenge. Intravenous administration of LY303870 (1 mg/kg) before the antigen challenge inhibited the EPR, while those of SR48968 (1 mg/kg) and CGRP(8 - 37) (50 nmol/kg) inhibited the LPR. The present results suggest that neuropeptides are involved in the allergic nasal obstruction.
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  • Possible Roles of Cardiac Chymase After Myocardial Infarction in Hamster Hearts
    Denan Jin, Shinji Takai, Mayumi Yamada, Masato Sakaguchi, Yulin Yao, M ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 203-214
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.203
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    The significance of cardiac chymase after myocardial infarction (MI) was evaluated using a hamster model of MI. At 1, 3, 7, 14, 28 and 56 days after MI, tissues were removed for measurements of angiotensin-converting enzyme (ACE) and chymase activities. The mean infarct size 3 days after left coronary artery ligation was 47.3 ± 5.9% of the left ventricle circumference. The ratio of left ventricle weight to body weight was significantly increased from 3 days after MI. The level of plasma renin activity in the MI hamsters was significantly increased at the early phase of MI (1 - 3 days), while no significant changes in plasma ACE activity were observed. The ACE activity in the infarcted left ventricle was significantly increased starting from 3 days after MI and this increase was sustained up to 28 days. The chymase activity in the infarcted left ventricle was significantly increased starting from 1 day after MI and this increase was sustained up to 56 days. The number of chymase-positive mast cells in the infarcted left ventricle was significantly higher than in the sham group 3 and 7 days after operation. Treatment with an angiotensin (Ang) II type 1 receptor antagonist (candesartan cilexetil, 10 mg/kg per day) starting 3 days before the induction of MI significantly reduced the mortality rate during 14 days of observation following MI, whereas treatment with an ACE inhibitor (lisinopril, 20 mg/kg per day) did not. A significant improvement in hemodynamics (maximal negative and positive rates of pressure development, left ventricular systolic pressure and end-diastolic pressure, mean arterial blood pressure) was observed by the treatment with candesartan cilexetil, but not with lisinopril, 3 and 14 days after MI. These results suggested that Ang II produced by chymase may participate in the pathophysiologic state after MI in hamsters.
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  • Enhancement of Phenylephrine-Induced Contraction in the Isolated Rat Aorta With Endothelium by H2O-Extract From an Oriental Medicinal Plant Leonuri herba
    Shanling Pang, Shizuko Tsuchiya, Syunji Horie, Masayuki Uchida, Toshih ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 215-222
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.215
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    Leonuri herba (I-mu-ts'ao, the Chinese motherwort) is an ancient Chinese traditional herb. Although the pharmacological effects of extracts of Leonuri herba have been shown in platelets and uteri, the effect on the vascular system has not been determined. In the present study, we investigated the effects of extracts of Leonuri herba on the contraction of the isolated rat aorta. Although the H2O-extract (0.3 - 3 mg/ml) by itself showed a limited effect, the extract enhanced phenylephrine-induced contraction of the aorta with endothelium, but not without endothelium. The H2O-extract, like NG-nitro-L-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), significantly inhibited the relaxation induced by acetylcholine in the aorta with endothelium. The inhibitory effect of H2O-extract on the relaxation decreased by co-addition with 1 mM L-arginine. The vasoconstrictive effect of H2O-extract was not due to leonurine, which is a constituent in Leonuri herba and shows uterotonic activity. Intravenous injection of the H2O-extract (1.5 mg/kg) to rats caused an increase in blood pressure for 5 min, like L-NAME (1.35 mg/kg). These findings suggest that there is a component(s) in Leonuri herba, which shows a vasoconstrictive activity in rat aorta in vitro and in vivo and has similar pharmacological profile to that of L-NAME.
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  • Structure-Activity Relationships of Triterpenoid Derivatives Extracted From Gymnema inodorum Leaves on Glucose Absorption
    Kazumasa Shimizu, Mie Ozeki, Akira Iino, Shinjiro Nakajyo, Norimoto Ur ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 223-229
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.223
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    The leaves of Gymnema inodorum (GI) have been known to be effective for some diseases including diabetes mellitus, rheumatic arthritis and gout. The crude saponin mixtures extracted from GI leaves inhibited glucose absorption in the isolated intestinal tract and suppressed the increased blood glucose in rats. In this study, we examined the relationship between chemical structure and pharmacological activity of the four components from GI leave extracts (GiA-1, GiA-2, GiA-5 and GiA-7). These components were the derivatives of (3β,4α,16β)-16,23,28-trihydroxyolean-12-en-3-yl-β-D-glucopyranosiduroic acid. GiA-2, GiA-5 and GiA-7 that have suppressive effects on the high K+-induced contraction, an increase in ΔPD and the increased blood glucose level in the glucose tolerance test have −H at the 21st position and −CH2OH at 4β of aglycon. On the other hand, GiA-1 that does not have any effects on the three parameters mentioned above has −H at the 21st position and −CH3 at 4β of aglycon. In conclusion, it is suggested that the inhibitory effect of triterpenoids in Gymnema leaves on glucose absorption from the intestinal tract relies on −CH2OH at 4β.
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  • NO-Flurbiprofen Attenuates Excitotoxin-Induced Brain Inflammation, and Releases Nitric Oxide in the Brain
    Costanza Prosperi, Carla Scali, Giancarlo Pepeu, Fiorella Casamenti
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 230-235
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.230
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    Brain inflammation underlies the pathogenesis of Alzheimer’s disease (AD) and nonsteroidal anti-inflammatory drug therapy may delay the onset of AD. We investigated, in vivo, the effects of NO-flurbiprofen on brain inflammation in rats injected with quisqualic acid into the nucleus basalis and on the release of nitric oxide from the drug in naive rat brains. We showed that the excitotoxin-induced microglia reaction, the expression of inducible nitric oxide synthase-positive cells and the production of interleukin-1β and prostaglandin-E2 in the injected area were attenuated by the NO-flurbiprofen (15 mg/kg, p.o.) treatment. An oral administration of NO-flurbiprofen (25, 50 and 100 mg/kg) to naive rats was followed by significant increases in cortical nitrite levels. This drug may have important therapeutic implications for the treatment of AD.
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  • Involvement of Nitric Oxide and Vasoactive Intestinal Peptide in the Nonadrenergic-Noncholinergic Relaxation of the Porcine Retractor Penis Muscle
    Junho La, Taewan Kim, Taesik Sung, Tongmook Kang, Janghern Lee, Ilsuk ...
    Subject area: Infomation Science
    2001 Volume 86 Issue 2 Pages 236-243
    Published: 2001
    Released on J-STAGE: August 13, 2001
    DOIhttps://doi.org/10.1254/jjp.86.236
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    Neurotransmitters mediating nonadrenergic-noncholinergic (NANC) relaxation were investigated in strips of porcine retractor penis muscle (RPM). Muscle tone was raised by phenylephrine (1 μM) in the presence of atropine (1 μM) and guanethidine (50 μM). Upon electrical field stimulation (1 ms, 80 V, 1 - 32 Hz for 10 s), the initial fast relaxation was followed by the slow relaxation. Although the fast and the slow relaxation were completely abolished by tetrodotoxin (1 μM), they showed different pharmacological sensitivities to the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 0.1 mM). The fast relaxation was markedly inhibited by L-NAME in an L-arginine reversible manner and by oxyhemoglobin (50 μM), while the slow relaxation was hardly blocked by L-NAME. L-NAME and α-chymotrypsin (α-CT, 3 U/ml) selectively inhibited the fast and the slow relaxation, respectively. α-CT abolished L-NAME-resistant slow relaxation, and L-NAME completely abolished the α-CT-resistant fast relaxation. α-CT-resistant relaxation was not significantly different from the digitally calculated L-NAME-sensitive component, and L-NAME-resistant relaxation was similar to the digitally calculated α-CT-sensitive component. Vasoactive intestinal peptide (VIP, 0.003 - 0.1 μM) relaxed porcine RPM in a concentration-dependent manner. The effect of a VIP was partially inhibited by a VIP receptor antagonist, VIP(10 - 28) (1 and 3 μM). L-NAME-resistant relaxation was also reduced by VIP(10 - 28) (3 μM) and by another putative antagonist, VIP(6 - 28) (1 μM), although the effects of the two antagonists were somewhat inconsistent. From the histochemical staining, it was verified that nerve bundles that showed VIP-like immunoreactivities were also positive for the NADPH diaphorase reaction. These results suggest that NO and peptide neurotransmitter(s) including VIP mediate the NANC relaxation in porcine RPM.
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