研究者詳細 - 小山　敏広

論文 - 小山　敏広

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Evaluation of pharmaceutical lifesaving skills training oriented pharmaceutical intervention. 査読国際誌

Zamami Y, Imai T, Imanishi M, Takechi K, Shiraishi N, Koyama T, Sagara H, Shiino Y, Sendo T, Ishizawa K

Journal of pharmaceutical health care and sciences 2 ( 1 ) 21 - 21 2016年

Risk factor of acute renal failure induced by edaravone in patients with cerebrovascular disorder 査読

座間味義人, 相良英憲, 萱野由佳, 小山敏広, 白石奈緒子, 江角悟, 川豊世武, 千堂年昭, 氏家良人, 名倉弘哲

日本臨床救急医学会雑誌 Vol.19 ( No.3 ) 461 - 465 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）

エダラボンを用いた治療は患者の神経学的予後を改善する一方，急性腎障害発現のリスクがあると報告されている．本研究はエダラボン投与による急性腎障害発現を予防するために，エダラボン投与時の患者背景から危険因子を解析することを目的とした．岡山大学病院においてエダラボンが投与された患者を対象に，患者基本情報およびエダラボン投与情報，血液検査結果を電子カルテより遡及的に調査した．調査データから単変量解析を実施し，抽出した因子を用いて二項ロジスティック回帰分析を行った結果，感染症の併発が，エダラボンによる急性腎障害発現の有意な危険因子(予測因子)であることが示唆された．したがって，感染症の所見がある患者にエダラボンを投与する際は，急性腎障害発現に留意する必要がある．

DOI： 10.11240/jsem.19.461

Exploring autistic-like traits relating to empathic attitude and psychological distress in hospital pharmacists 査読

Yuji Higuchi, Yosuke Uchitomi, Maiko Fujimori, Toshihiro Koyama, Hitomi Kataoka, Yoshihisa Kitamura, Toshiaki Sendo, Masatoshi Inagaki

INTERNATIONAL JOURNAL OF CLINICAL PHARMACY 37 ( 6 ) 1258 - 1266 2015年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Background Pharmacists are expected to play a key role in modern cancer care. Research suggests that an empathic approach and attitude in medical staff improves the quality of patient care. An empathic attitude and psychological distress are thought to be associated with autistic-like traits, but little is known about such traits. Objective In this study, we aimed to clarify the associations among autistic-like traits, empathic attitude in a medical context, and psychological health in hospital pharmacists. Setting Eligibility criteria for inclusion were certified pharmacists working at hospitals for patient care who returned their questionnaires. Method Eight hundred and twenty-three hospital pharmacists completed a number of self-administered questionnaires anonymously by mail. Main outcome measures Scores were obtained on the Autism-Spectrum Quotient, the Jefferson Scale of Empathy, the General Health Questionnaire-12, and subscales of the Interpersonal Reactivity Index (Perspective Taking, IRI-Empathic Concern, IRIPersonal Distress). We performed correlation and mediation analyses to confirm that the empathy and general health questionnaires were associated with autism-spectrum quotient scores, and with each IRI subscale. Results Complete responses were obtained from 379 pharmacists comprising 151 males (39.8 %) with a mean age of 37.7 +/- A 10.8 years (missing data, n = 13) and a median of 11 years after qualification as a pharmacist. Autism-Spectrum Quotient scores were inversely correlated with empathy (r = -0.22, p < 0.001) and positively correlated with general health scores (r = 0.40, p < 0.001). In the models with mediation, the inverse correlation between autism-spectrum quotient and empathy scores was mediated indirectly by IRI-Perspective Taking and IRI-Empathic Concern, and the positive correlation between autism-spectrum quotient and general health was mediated indirectly by IRI-Personal Distress. There were also direct effects, with significant effects of autism-spectrum quotient on empathy and general health scores. Conclusion Our findings suggest that autistic-like traits affect both empathic attitude in a medical context and the psychological health of pharmacists. We recommend that to improve empathy in those with high levels of autistic-like traits, we may need to develop specialized interventions, such as improving communication skills training.

DOI： 10.1007/s11096-015-0204-2

The Effectiveness of Team-based Learning (TBL) as a New Teaching Approach for Pharmaceutical Care Education 査読

Manabu Suno, Toshiko Yoshida, Toshihiro Koyama, Yoshito Zamami, Tomoko Miyoshi, Takaaki Mizushima, Mitsune Tanimotoa

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 133 ( 10 ) 1127 - 1134 2013年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The concept of Team-Based Learning (TBL) was developed in the late 1970s by Larry Michaelsen, who wanted students to enjoy the benefits of small group learning within large classes in the business school environment. In contrast to problem-based learning (PBL), which is student centered, TBL is typically instructor centered. Recently, TBL is being used as a teaching method in over 60 health science professional schools in the US and other countries. In the present study, the impact of adopting TBL in teaching pharmaceutical care practices to students was evaluated. Students were required to answer a set of multiple-choice questions individually in individual readiness assessment test (IRAT) before the TBL sessions to assess their level of preparation. The same set of questions was then reattempted by the group readiness assessment test (GRAT) during TBL. Comparing the scores obtained in the GRAT and IRAT before the first TBL session, the scores from the GRAT were always higher than those of the IRAT, indicating that TBL has encouraged active learning. In addition, students were surveyed about their level of satisfaction with TBL and written comments about TBL were solicited. The results of the questionnaire showed that 87.3 +/- 9.3% of the students were satisfied. Moreover, no student commented that TBL was in any way inferior to the PBL. Implementation of a TBL approach was successfully integrated into the pharmaceutical care education course. In order to further improve the usefulness of TBL in teaching pharmaceutical care, a hybrid teaching approach that also comprises PBL and a lecture-based course is desirable.

DOI： 10.1248/yakushi.12-00254

The mechanisms of electroconvulsive stimuli in BrdU-positive cells of the dentate gyrus in ACTH-treated rats 査読

Keiko Kuwatsuka, Hiromi Hayashi, Yuka Onoue, Ikuko Miyazaki, Toshihiro Koyama, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

Journal of Pharmacological Sciences 122 ( 1 ) 34 - 41 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）

In clinical studies, electroconvulsive stimuli have been associated with improvements in both depression and treatment-resistant depression. In a previous study, treatment with adrenocorticotropic hormone (ACTH) for 14 days decreased adult hippocampal cell proliferation. Furthermore, electroconvulsive stimuli significantly decreased the duration of immobility following repeated administration of ACTH for 14 days in rats. The present study was undertaken to further characterize the mechanism of treatment-resistant antidepressant effects of electroconvulsive stimuli by measuring cell proliferation, brain-derived neurotrophic factor (BDNF) levels, and phosphorylated and total cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB/CREB) levels in the hippocampus of ACTH-treated rats. Electroconvulsive stimuli increased cell proliferation in both saline-treated and ACTH-treated rats. Mature-BDNF protein levels showed a tendency to decrease in ACTH-treated rats. Electroconvulsive stimuli treatment increased mature-BDNF protein levels in the hippocampus of both saline-treated and ACTH-treated rats. Furthermore, electroconvulsive stimuli increased phospho-Ser133-CREB (pCREB) levels and the ratio of pCREB/CREB in both saline-treated and ACTH-treated rats. These findings suggest that the treatment-resistant antidepressant effects of electroconvulsive stimuli may be attributed, at least in part, to an enhancement of hippocampal cell proliferation. © The Japanese Pharmacological Society.

DOI： 10.1254/jphs.13015FP

Influence of doxorubicin and cyclophosphamide on psychological behavior in rats 査読

Kitamura Yoshihisa, Hattori Sayo, Miyake Ayaka, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 121 143P 2013年

Effect of the 5-HT1A receptor function on antidepressive effect and neurogenesis in ACTH treated rats 査読

Miyake Ayaka, Kitamura Yoshihisa, Hattori Sayo, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 121 144P 2013年

Adrenergic Stimulation-Released Histamine Taken-up in Adrenergic Nerves Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries 査読

Yuto Haruki, Shingo Takatori, Sayo Hattori, Yoshito Zamami, Toshihiro Koyama, Panot Tangsucharit, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 ( 4 ) 537 - 542 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

The present study investigated whether histamine was taken up by perivascular adrenergic nerves and released by periarterial nerve stimulation (PNS) to induce vascular responses. In rat mesenteric vascular beds treated with capsaicin to eliminate calcitonin gene related peptide (CGRP)ergic vasodilation and with active tone, PNS (1 - 4 Hz) induced only adrenergic nerve-mediated vasoconstriction. Histamine treatment for 20 min induced PNS-induced vasoconstriction followed by vasodilation without affecting CGRP-induced vasodilation. Chlorpheniramine, guanethidine, combination of histamine and desipramine, and endothelium-removal abolished PNS-induced vasodilation in histamine-treated preparations. These results suggest that histamine taken up by and released from adrenergic nerves by PNS causes endothelium-dependent vasodilation in rat mesenteric arteries.

DOI： 10.1254/jphs.12012SC

Involvement of perivascular nerves and transient receptor potential vanilloid 1 (TRPV1) in vascular responses to histamine in rat mesenteric resistance arteries 査読

Honghua Jin, Pengyuan Sun, Shingo Takatori, Toshihiro Koyama, Yoshito Zamami, Panot Tangsucharit, Yoshihisa Kitamura, Hiromu Kawasaki

EUROPEAN JOURNAL OF PHARMACOLOGY 680 ( 1-3 ) 73 - 80 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

A previous report showed that histamine in denuded mesenteric vascular beds produced a triphasic response; an initial small histamine H-2 receptor-mediated vasodilation, a transient histamine H-1 receptor-mediated vasoconstriction, and finally a long-lasting vasodilation. We further investigated the vascular effect of histamine in mesenteric preparations without an endothelium to clarify the possible involvement of perivascular nerves. Male Wistar rat mesenteric vascular beds without an endothelium were perfused with Krebs solution containing methoxamine to produce active tone and lafutidine to block histamine H-2 receptor-mediated vasodilation. Histamine (1-100 mu M) was perfused for 1 min and perfusion pressure was measured with a pressure transducer. Histamine caused a biphasic vascular response; initial vasoconstriction followed vasodilation. Tetrodotoxin (a neurotoxin, 1 mu M) and procaine (a local anesthetic, 100 mu M) significantly inhibited the vasoconstriction and vasodilation. Ruthenium red (a transient receptor potential vanilloid 1 (TRPV1) antagonist, 1 mu M) also significantly inhibited both phases of the response. Pretreatment with capsaicin (a depletor of calcitonin gene-related peptide (CGRP)-containing nerves, 5 mu M) significantly inhibited the vasodilation without affecting the initial vasoconstriction. Both indomethacin (a cyclooxygenase inhibitor, 0.5 mu M) and seratrodast (a thromboxane A(2) receptor antagonist, 0.1 mu M) abolished the histamine-induced vasoconstriction and subsequent vasodilation. These results suggest that histamine-induced vasoconstriction and long-lasting vasodilation are mediated by activation of TRPV1 on capsaicin-sensitive and capsaicin-insensitive nerves. They also suggest that perivascular nerves and prostanoids, probably thromboxane A(2), are responsible for the vascular response to histamine. (C) 2012 Elsevier B. V. All rights reserved.

DOI： 10.1016/j.ejphar.2012.01.018

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats 査読

Hiromi Hayashi, Maho Doi, Yuka Onoue, Keiko Kuwatsuka, Ayaka Miyake, Toshihiro Koyama, Kazuaki Shinomiya, Ikuko Miyazaki, Masato Aasanuma, Yoshihisa Kitamura

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 132 ( 2 ) 173 - 178 2012年2月

記述言語：日本語出版者・発行元：PHARMACEUTICAL SOC JAPAN

We previously reported that adrenocorticotropic hormone (ACTH) -treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

DOI： 10.1248/yakushi.132.173

Effect of Pharmacist Management on Serum Hemoglobin Levels with Renal Anemia in Hemodialysis Outpatients 査読

Junko Ohnishi, Akiyo Miyake, Keiko Kuwatsuka, Yuka Onoue, Miyoshi Lee, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Yoshihisa Kitamura

BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 ( 10 ) 1609 - 1612 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The initiation of a pharmacist-implemented management program to ensure appropriate use of erythropoietin-stimulating agents at Mizushima Kyodo Hospital is described. In the present study, we examined the influence of having pharmacists actively manage hemoglobin levels on therapeutic outcome in a retrospective study of 84 outpatients receiving hemodialysis. We compiled in-hospital guidelines for the use of erythropoietin and iron for outpatients with renal anemia. Pharmacists made recommendations, particularly about changes in the dose of erythropoietin and administration of iron preparations, to physicians. Clinical test results were monitored for 12 months (between November 2007 and October 2008) with and without the participation of pharmacists (continuous 6 months). The counseling by pharmacists significantly decreased hemoglobin levels in the high group (>12 g/dl) and significantly increased them in low group (<10 g/dl). Furthermore, it increased hemoglobin levels in the optimal group, suggesting the management of our hospital guidelines. On the other hand, low levels of hemoglobin indicated low levels of albumin. It is suggested that no improvement in hemoglobin levels may indicate low levels of albumin. These findings suggest that the active participation of pharmacists in the management of renal anemia in hemodialysis patients had a great therapeutic impact.

DOI： 10.1248/bpb.34.1609

Histamine H-3 receptor-mediated modulation of perivascular nerve transmission in rat mesenteric arteries 査読

Pengyuan Sun, Shingo Takatori, Xin Jin, Toshihiro Koyama, Panot Tangsucharit, Simin Li, Yoshito Zamami, Yoshihisa Kitamura, Hiromu Kawasaki

EUROPEAN JOURNAL OF PHARMACOLOGY 655 ( 1-3 ) 67 - 73 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H-3 receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H-3 receptor agonist (R)-alpha-methylhistamine (alpha-methylhistamine; 10-100 nM) significantly reduced periarterial nerve stimulation (2-8 Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol). In preparations with active tone produced by methoxamine (2 mu M) and in the presence of guanethidine (5 mu M), the periarterial nerve stimulation (1, 2 Hz)-induced vasodilator response was inhibited by a-methylhistamine (0.1-1 mu M) perfusion without affecting vasodilation induced by exogenously injected CGRP (5 pmol). Clobenpropit (histamine H-3 receptor antagonist, 1 mu M) canceled the alpha-methylhistamine-induced decrease in the periarterial nerve stimulation-induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H-3 receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2011.01.020

Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats 査読

Yoshihisa Kitamura, Maho Doi, Keiko Kuwatsuka, Yuka Onoue, Ikuko Miyazaki, Kazuaki Shinomiya, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 ( 1 ) 77 - 81 2011年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

DOI： 10.1248/bpb.34.77

Paracrine control of mesenteric perivascular axo-axonal interaction. 査読

H Kawasaki, S Takatori, 座間味義人, T Koyama, M Goda, K Hirai, P Tangsucharit, X Jin, N Hobara, Y Kitamura

Acta Physiologica Vol.203 ( No.1 ) 3 - 11 2010年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Immunohistochemical study of rat mesenteric arteries showed dense innervation of adrenergic nerves, calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves), nitric oxide-containing nerves (nitrergic nerves). Double-immunostaining revealed that most CGRPergic or nitrergic nerves were in close contact with adrenergic nerves. CGRPergic and transient receptor potential vanilloid-1 (TRPV1)-immunopositive nerves appeared in the same neurone. In rat perfused mesenteric vascular beds without endothelium and with active tone, perfusion of nicotine, or bolus injection of capsaicin and acetylcholine and periarterial nerve stimulation (PNS) lowered pH levels of out flowed perfusate concomitant with vasodilation. Cold-storage denervation of preparations abolished pH lowering induced by nicotine and PNS. Guanethidine inhibited PNS- and nicotine-, but not acetylcholine- and capsaicin-, induced pH lowering. Pharmacological analysis showed that protons were released not only from adrenergic nerves but also from CGRPergic nerves. A study using a fluorescent pH indicator demonstrated that nicotine, acetylcholine and capsaicin applied outside small mesenteric artery lowered perivascular pH levels, which were not observed in Ca(2+) free medium. Exogenously injected hydrochloric acid in denuded preparations induced pH lowering and vasodilation, which was inhibited by denervation, TRPV1 antagonists and capsaicin without affecting pH lowering. These results suggest that excitement of adrenergic nerves releases protons to activate TRPV1 in CGRPergic nerves and thereby induce vasodilation. It is also suggested that CGRPergic nerves release protons with exocytosis to facilitate neurotransmission via a positive feedback mechanism.

DOI： 10.1111/j.1748-1716.2010.02197.x

Endothelial Modulation of Agonist-induced Vasoconstriction in Mesenteric Microcirculation 査読

Xin Jin, Yukiko Otonashi-Satoh, Yoshito Zamami, Toshihiro Koyama, Pengyuan Sun, Yoshihisa Kitamura, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 130 ( 5 ) 723 - 728 2010年5月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

It is widely accepted that vascular endothelium regulates vasoconstriction via release of endothelium-derived relaxing factors (EDRF). The mesenteric circulation, which is the largest vascular bed, influences regulation of systemic blood pressure. However, the role of EDRF in the modulation of vascular tone in peripheral mesenteric circulation has not been extensively studied. Therefore, our recent studies investigated the role of the vascular endothelium in the regulation of methoxamine (alpha(1)-adrenoceptor agonist)-induced vasoconstriction and their age-related changes in rat mesenteric vascular beds. In mesenteric vascular beds with intact endothelium isolated from 8 week-old rats, the initial maximum vasoconstriction induced by continuous perfusion of methoxamine was time-dependently decreased during 3 hour-perfusion. Neither nitric oxide synthase inhibitor nor cyclooxygenase inhibitor altered this time-dependent reduction of methoxamine-induced vasoconstriction. Endothelium removal, K+-channel inhibitors and gap junction inhibitor significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In the preparations with intact endothelium from 16 week-old rats, the time-dependent reduction of methoxamine-induced vasoconstriction disappeared. Furthermore, endothelium removal and treatment with cyclooxygenase inhibitor, thromboxane A(2) receptor antagonist or superoxide dismutase mimetic significantly reduced the methoxamine-induced vasoconstriction in the preparations from 16 week-old rats. These findings suggest that vascular endothelium acts to depress methoxamine-induced vasoconstriction by releasing endothelium-derived hyperpolarizing factor (EDHF), and dysfunction in this endothelial modulation develops with ageing.

DOI： 10.1248/yakushi.130.723

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats 査読

Toshihiro Koyama, Yukako Hatanaka, Xin Jin, Ayako Yokomizo, Hidetoshi Fujiwara, Mitsuhiro Goda, Narumi Hobara, Yoshito Zamami, Yoshihisa Kitamura, Hiromu Kawasaki

HYPERTENSION RESEARCH 33 ( 5 ) 485 - 491 2010年5月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Neuronal nitric oxide (NO) has been shown to modulate perivascular adrenergic neurotransmission by inhibiting noradrenaline release from terminals in rat mesenteric arteries. This study was conducted to investigate changes in the inhibitory function of NO-containing nerves (nitrergic nerves) in mesenteric vascular beds of 2-kidney, 1-clip renovascular hypertensive rats (2K1C-RHR). Rat mesenteric vascular beds without endothelium were perfused with Krebs solution and the perfusion pressure was measured. In preparations from sham-operated rats (control) and 2K1C-RHRs, vasoconstriction induced by periarterial nerve stimulation (PNS; 2-8 Hz), but not vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol), was markedly facilitated in the presence of a nonselective NO synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) (100 mu M). The facilitatory effect of L-NAME in preparations from 2K1C-RHR was smaller than that in control preparations. L-NAME augmented PNS-evoked noradrenaline release, which was smaller in 2K1C-RHRs than in controls. The expression of neuronal NO synthase (nNOS) measured by western blotting in mesenteric arteries from 2K1C-RHRs was significantly decreased compared with control arteries. Immunohistochemical staining of mesenteric arteries showed dense innervation of nNOS-immunopositive nerves that was significantly smaller in arteries from 2K1C-RHR than that in control arteries. Mesenteric arteries were densely innervated by tyrosine hydroxylase-immunopositive nerves, which coalesced with nNOS-immunopositive nerves. These results suggest that the inhibitory function of nitrergic nerves in adrenergic neurotransmission is significantly decreased in 2K1C-RHRs. This functional alteration based on the decrease in nNOS expression and nitrergic innervation leads to enhanced adrenergic neurotransmission and contributes to the initiation and development of renovascular hypertension. Hypertension Research (2010) 33, 485-491; doi: 10.1038/hr.2010.48; published online 9 April 2010

DOI： 10.1038/hr.2010.48

R-(-)-alpha-Methylhistamine, a Histamine H-3 Receptor Agonist, Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries 査読

Pengyuan Sun, Xin Jin, Toshihiro Koyama, Simin Li, Yoshihisa Kitamura, Hiromu Kawasaki

BIOLOGICAL & PHARMACEUTICAL BULLETIN 33 ( 1 ) 58 - 63 2010年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

A novel histamine receptor subtype, histamine H-3 receptor, mediates inhibition of peripheral autonomic neurotransmission. The present study was designed to examine vascular effects of histamine H-3 receptor by using a selective histamine H-3 receptor agonist, R-(-)-alpha methylhistamine (alpha-methylhistamine), in rat mesenteric resistance arteries. The isolated mesenteric vascular beds were perfused with Krebs solution and perfusion pressure was measured. Active tone was produced by perfusion of Krebs solution containing 7 mu M methoxamine. In preparations with intact endothelium, perfusion of alpha-methylhistamine (1-100 mu M) for 1 min produced a concentration-dependent vasodilation. The maximum vasodilation at the highest concentration was approximately 45%. This vasodilation was abolished by endothelium removal and attenuated by histamine H-3 receptor antagonists, thioperamide and clobenpropit, but not by chlorpheniramine (histamine H-1 receptor antagonist) and cimetidine (histamine H-2 receptor antagonist). N-omega-nitro-L-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor), indomethacin (cyclooxygenase inhibitor) and tetraethylammonium (nonselective K+-channel blocker) and high KCl (30 mM) significantly inhibited alpha-methylhistamine-induced endothelium-dependent vasodilation. These findings suggest that alpha-methylhistamine induces endothelium-dependent vasodilation mainly via endothelium histamine H-3 receptors. It is also suggested that activation of histamine H-3 receptors in the endothelium releases mainly NO and partially prostaglandin I-2 and endothelium-derived hyperpolarizing factors to induce endothelium-dependent vasodilation.

DOI： 10.1248/bpb.33.58

Chronic hyperinsulinemia induces hypertension resulted from abnormal innervation of perivascular nerves in rat mesenteric resistance arteries 査読

Yoshito Zamami, Shingo Takatori, Nana Yabumae, Miho Hosoda, Toshihiro Koyama, Xin Jin, Narumi Hobara, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 112 76P - 76P 2010年

Age-Related Disappearance of the Inhibitory Effect of Vascular Endothelium on Agonist-Induced Vasoconstriction in Rat Mesenteric Vascular Beds 査読

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Narumi Hobara, Toshihiro Koyama, Pengyuan Sun, Simin Li, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 111 ( 4 ) 372 - 380 2009年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

We previously reported that endothelium-derived hyperpolarizing factor (EDHF)mediated response time-dependently suppressed methoxamine-induced vasoconstriction in mesenteric vascular beds isolated from 8-week-old rats. We investigated age-related changes in endothelial regulation of methoxamine-induced vasoconstriction. Mesenteric vascular beds isolated from young (8-week-old) to adult (16-week-old) rats were perfused, and changes in perfusion pressure induced by continuous perfusion of methoxamine or high KCl (60 mM) were measured over 180 min. In young preparations with intact endothelium, methoxamine-induced vasoconstriction time-dependently decreased to 20% of the initial levels, while time-dependent reduction was not observed in adult preparations. High KCl-induced vasoconstriction in young and adult preparations did not show time-dependent reduction. Endothelium removal abolished time-dependent reduction of methoxamine-induced vasoconstriction in young preparations and significantly attenuated vasoconstriction in adult preparations. Indomethacin, seratrodast, or tempol but not catalase significantly reduced methoxamine-induced vasoconstriction in adult preparations with endothelium. A23187 (Ca(2+)-ionophore)-, but not acetylcholine-, induced endothelium-dependent vasodilation in the presence of N(G)-L-nitro arginine methyl ether in adult preparations was significantly smaller than that in young preparations. These findings suggest that the inhibitory effect of mesenteric vascular endothelium on methoxamine-induced vasoconstriction disappears with aging by reducing EDHF and increasing endothelium-derived contracting factors and reactive oxygen species.

DOI： 10.1254/jphs.09183FP

Proton Acts as a Neurotransmitter for Nicotine-Induced Adrenergic and Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in the Rat Mesenteric Artery 査読

Hiromu Kawasaki, Shinji Eguchi, Satoko Miyashita, Shu Chan, Kazuhiro Hirai, Narumi Hobara, Ayako Yokomizo, Hidetoshi Fujiwara, Yoshito Zamami, Toshihiro Koyama, Xin Jin, Yoshihisa Kitamura

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 330 ( 3 ) 745 - 755 2009年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Nicotine stimulates presynaptic nicotinic acetylcholine receptors in perivascular adrenergic nerves and releases unknown transmitter(s) that activate transient receptor potential vanilloid-1 (TRPV1) located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves, resulting in vasodilation. The present study investigated a potential transmitter transmitting between perivascular adrenergic nerves and CGRPergic nerves. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs' solution containing methoxamine, and the perfusion pressure and pH levels of the perfusate were measured. Nicotine perfusion for 1 min induced concentration-dependent vasodilation and lowered pH levels, which were abolished by cold-storage denervation of preparations, guanethidine (adrenergic neuron blocker), and mecamylamine (nicotinic alpha(3)beta(4)-acetylcholine receptor antagonist). Capsazepine (TRPV1 antagonist) blunted nicotine-induced vasodilation, but had no effect on the reduction of pH. Injection of hydrochloric acid (HCl) and perfusion of Krebs' solution at low pH (6.0-7.2) induced vasodilation. HCl-induced vasodilation was inhibited by cold-storage denervation, capsazepine, capsaicin (CGRP depletor), and CGRP(8 37) (CGRP receptor antagonist). Perfusion of adrenergic transmitter metabolites (normetanephrine and 3-methoxydopamine), but not of other metabolites, induced vasodilation, which was not inhibited by capsaicin treatment. Immunohistochemical staining of mesenteric arteries showed dense innervation of CGRP-and TRPV1-immunopositive nerves, with both immunostainings appearing in the same neuron. Mesenteric arteries were densely innervated by neuropeptide Y-immunopositive nerves, which coalesced with CGRP-immunopositive nerves. Scanning and immunoscanning electron microscopic images showed coalescence sites of different perivascular fibers before they intruded into smooth muscles. These results indicate that nicotine initially stimulates adrenergic nerves via nicotinic alpha(3)beta(4)-receptors to release protons and thereby induces CGRPergic nerve-mediated vasodilation via TRPV1.

DOI： 10.1124/jpet.108.149435

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