研究者詳細 - 座間味　義人

論文 - 座間味　義人

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Long-term treatment with losartan augments vasodilator CGRPergic nerve activity in Spontaneously Hypertensive Rats 査読

Yoshito Zamami, Shingo Takatori, Narumi Hashikawa, Hiroko Ishikawa, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 198P - 198P 2012年

Hyperinsulinemia induces hypertension associated with neurogenic vascular dysfunction resulting from abnormal perivascular innervations in rat mesenteric resistance arteries 査読

Yoshito Zamami, Shingo Takatori, Narumi Hobara, Nana Yabumae, Panot Tangsucharit, Xin Jin, Naoya Hashikawa, Yoshihisa Kitamura, Kenji Sasaki, Hiromu Kawasaki

HYPERTENSION RESEARCH 34 ( 11 ) 1190 - 1196 2011年11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：NATURE PUBLISHING GROUP

We previously reported that chronic hyperinsulinemia and insulin resistance induced by fructose-drinking loading elicited hypertension associated with abnormal neuronal regulation of vascular tone in an in vivo study using pithed rats. Therefore, to further clarify the detailed mechanisms of perivascular nervous system malfunction induced by chronic hyperinsulinemia, we investigated the neurogenic vascular responses and distribution of perivascular nerves using mesenteric vascular beds isolated from fructose-loaded rats with hyperinsulinemia. Male Wistar rats (6 weeks old) received 15% fructose solution as drinking fluid for 10 weeks (fructose-drinking rats, FDR), which resulted in significant increases in plasma levels of insulin, the glucose-insulin index, blood norepinephrine (NE) levels and systolic blood pressure, but not blood glucose levels, when compared with normal water-drinking rats (control rats). In perfused mesenteric vascular beds of FDR, enhanced adrenergic nerve-mediated vasoconstriction with no effect on NE-induced vasoconstriction and decreased calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation with no effect on CGRP-induced vasodilation were observed. Immunohistochemistry studies showed increased density of neuropeptide Y immunopositive adrenergic fibers and reduced density of CGRP immunopositive fibers in mesenteric arteries of FDR. Furthermore, FDR showed decreased CGRP content in dorsal root ganglia. These findings suggest that dysfunction of the neuronal vascular control system resulting from abnormal innervation of mesenteric perivascular nerves induced by the hyperinsulinemic state is responsible for the development of hypertension in FDR. Hypertension Research (2011) 34, 1190-1196; doi:10.1038/hr.2011.97; published online 28 July 2011

DOI： 10.1038/hr.2011.97

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice 査読

Narumi Hashikawa-Hobara, Naoya Hashikawa, Chikao Yutani, Yoshito Zamami, Xin Jin, Shingo Takatori, Mitsunobu Mio, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 338 ( 2 ) 694 - 700 2011年8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

Apolipoprotein E (apo)-deficient [apoE(-/-)] mice have peripheral sensory nerve defects and a reduced and delayed response to noxious thermal stimuli. However, to date, no report has focused on the influence of apoE deficiency on calcitonin gene-related peptide (CGRP)-containing nerve fiber extensions. We have shown that the density of CGRP-containing nerve fibers decreases in mesenteric arteries of apoE(-/-) mice compared with wild-type mice. Here, we investigated whether apoE deficiency is involved in nerve growth factor (NGF)-induced CGRP-containing nerve regeneration using apoE(-/-) mice. NGF-mediated CGRP-like immunoreactivity (LI)-neurite outgrowth in apoE(-/-) cultured dorsal root ganglia (DRG) cells was significantly lower than that in wild-type cultures. However, the level of NGF receptor mRNA in apoE(-/-) DRG cells was similar to that in wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-nitric oxide (NO)-cGMP pathway. Expression of phosphorylated Akt was significantly reduced in apoE(-/-) DRG. The NO donor, sodium nitroprusside or S-nitroso-N-acetylpenicillamine, did not affect NGF-mediated neurite outgrowth in apoE(-/-) cultured DRG cells. However, 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt n-hydrate, a cGMP analog, induced NGF-mediated nerve facilitation similar to wild-type NGF-mediated neurite outgrowth levels. Furthermore, in apoE(-/-) DRG, soluble guanylate cyclase expression was significantly lower than that in wild-type DRG. These results suggest that in apoE(-/-) mice the Akt-NO-cGMP pathway is impaired, which may be caused by NGF-mediated CGRP-LI-neurite outgrowth defects.

DOI： 10.1124/jpet.111.181487

New Molecular Mechanisms for Cardiovascular Disease: Contribution of Endothelium-Derived Hyperpolarizing Factor in the Regulation of Vasoconstriction in Peripheral Resistance Arteries 査読

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Shingo Takatori, Narumi Hashikawa-Hobara, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 116 ( 4 ) 332 - 336 2011年8月

記述言語：英語出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

Endothelium regulates vascular tone via release of endothelium-derived relaxing factors (EDRF) including nitric oxide (NO), prostaglandin I(2) (PGI(2)), and endothelium-derived hyperpolarizing factor (EDHF). The mesenteric vascular bed produces vascular resistance to develop blood pressure and regulate tissue blood flow that plays an important role in maintenance of systemic blood pressure. There is now strong evidence that in these small resistance arteries, EDHF plays a major role in the response to vasoactive substances and regulation of vascular tone. Pharmacological analysis to investigate the role of the vascular endothelium in the regulation of alpha(1)-adrenoceptor agonist (methoxamine)-induced vasoconstriction in rat mesenteric vascular beds showed that vasoconstriction induced by continuous perfusion of methoxamine (7 mu M), but not high KCl (60 mM), time-dependently decreased to 20% of the initial constriction. The time-dependent reduction of methoxamine-induced vasoconstriction was inhibited by endothelium removal, inhibitor of EDHF (30 mM KCl, K(+)-channel blockers), and gap-junction inhibitor, but not NO synthase inhibitor and cyclooxygenase inhibitor and ageing. These results suggest that vascular endothelium counteracts to normalize excess vasoconstriction of the mesenteric resistance arteries by releasing EDHF, which is associated with activation of multiple K(+)-channels and gap junction involvement and markedly decreases with ageing.

DOI： 10.1254/jphs.10R30FM

Quercetin Diacylglycoside Analogues Showing Dual Inhibition of DNA Gyrase and Topoisomerase IV as Novel Antibacterial Agents 査読

Abugafar M. L. Hossion, Yoshito Zamami, Rafiya K. Kandahary, Tomofusa Tsuchiya, Wakano Ogawa, Akimasa Iwado, Kenji Sasaki

JOURNAL OF MEDICINAL CHEMISTRY 54 ( 11 ) 3686 - 3703 2011年6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 CHEMICAL SOC

A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6 ''-acylgalactoside, and quercetin 2 '',6 ''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 mu g/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.

DOI： 10.1021/jm200010x

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

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

Role of Angiontensin Receptors on Remodeling Perivascular Nerves 査読

Narumi Hobara, Mitsuhiro Goda, Naoya Hashikawa, Xin Jin, Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 130 ( 11 ) 1421 - 1425 2010年11月

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

The aim of this study was to investigate age-related changes in the density of calcitonin gene-related peptide (CGRP) -containing nerve fibers in spontaneously hypertensive rats (SHR) and the effects of long-term inhibition of the renin-angiotensin system on these changes. An age-related decrease in the density of CGRP-like immunoreactive (LI) -containing nerve fibers but not neuropeptide Y (NPY) -LI-containing sympathetic nerve fibers was found in the mesenteric artery of SHR but not Wistar-Kyoto rats (WKY). The density of NPY-LI-containing nerve fibers was significantly greater in SHR than in WKY. SHR were treated for 7 weeks with angiotensin-converting enzyme inhibitor (0.005% temocapril), angiotensin 11 type-1 (AT1) receptor antagonist (0.025% losartan), or vasodilator (0.01% hydralazine) in their drinking water. Each drug treatment significantly lowered the systolic blood pressure measured using the tail-cuff method. Long-term treatment of SHR with temocapril and losartan significantly increased the density of CGRP-LI-containing nerve fibers in mesenteric arteries. Furthermore, to clarify the effect of the angiontensin II type-2 (AT2) receptor in the restoration of perivascular nerve innervation, we used the phenol-injured rat model, in which the perivascular nerves are markedly reduced by the topical application of phenol. Activation of AT2R significantly restored CGRP-LI innervation in phenol-injured rats. These results suggest that selective stimulation of AT2 receptors facilitates reinnervation of mesenteric perivascular CGRP-containing nerves.

DOI： 10.1248/yakushi.130.1421

Design, synthesis, and biological evaluation of a novel series of quercetin diacylglucosides as potent anti-MRSA and anti-VRE agents 査読

Abugafar M. L. Hossion, Nao Otsuka, Rafiya K. Kandahary, Tomofusa Tsuchiya, Wakano Ogawa, Akimasa Iwado, Yoshito Zamami, Kenji Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 20 ( 17 ) 5349 - 5352 2010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：PERGAMON-ELSEVIER SCIENCE LTD

A series of novel quercetin diacylglucosides were designed and first synthesized by Steglich esterification on the basis of MRSA strains inhibiting natural compound A. The in vitro inhibition of different multidrug resistant bacterial strains and Escherichia coli DNA gyrase B was investigated. In the series, compound 10h was up to 128-fold more potent against vancomycin-resistant enterococci and more effective than A, which represents a promising new candidate as a potent anti-MRSA and anti-VRE agent. (C) 2010 Published by Elsevier Ltd.

DOI： 10.1016/j.bmcl.2010.02.060

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

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

Ameliorative effect of Eucommia ulmoides Oliv. leaves extract (ELE) on insulin resistance and abnormal perivascular innervation in fructose-drinking rats 査読

Xin Jin, Keisuke Amitani, Yoshito Zamami, Shingo Takatori, Narumi Hobara, Naomi Kawamura, Tetsuya Hirata, Atsunori Wada, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF ETHNOPHARMACOLOGY 128 ( 3 ) 672 - 678 2010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 IRELAND LTD

Aim of the study: Eucommia ulmoides Oliv, leaf is a traditional Chinese medicine that exhibits an antidiabetic action. This study was designed to investigate whether long-term administration of Eucommia ulmoides Oliv. leaves extract (ELE) ameliorates pre-diabetic state of insulin resistance and abnormal perivascular innervation in the hyperinsulinemic state.
Materials and methods: ELE at doses of 500 and 1000 mg/kg was administered orally once daily for 4 weeks in fructose-drinking rats (FDRs). Plasma levels of insulin, blood glucose levels, and perivascular innervation were assessed using biochemical and immunohistochemical methods.
Results: FDR showed significant increase in plasma levels of insulin, an index for insulin resistance (Homeostasis Model Assessment ratio-HOMA-IR) and systolic blood pressure (SBP), but not blood glucose levels, as compared with control rats. Immunohistochemical study showed significantly greater density of tyrosine hydroxylase (TH)-like immunoreactivity MO-containing nerves and significantly lower density of calcitonin gene-related peptide (CGRP)-LI-containing nerves in mesenteric arteries of FDR than those in control. A 4-week treatment with ELE (500 and 1000 mg/kg, p.o.) significantly decreased plasma levels of insulin and HOMA-IR without affecting blood glucose levels and significantly lowered SBP in FOR. ELE treatment in FDR resulted in significant increase in CGRP-LI never fiber density and significant decrease in TH-LI never fiber density in mesenteric arteries of FDR.
Conclusions: These results suggest that long-term ELE treatment effectively prevents insulin resistance development and ameliorates abnormal perivascular innervation in FOR. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jep.2010.02.019

ラット腸間膜動脈におけるヒスタミン誘発血管弛緩反応に及ぼす塩酸レボカバスチンおよび塩酸オロパタジンの影響

小山敏広, 楢原由生未, 孫鵬遠, 李思敏, 金きょう, 座間味義人, 高取慎吾, 北村佳久, 川崎博巳

アレルギー・免疫 17 ( 4 ) 662 - 670 2010年3月

記述言語：日本語出版者・発行元：(株)医薬ジャーナル社

ヒスタミン誘発血管弛緩反応に対するヒスタミンH1受容体拮抗薬レボカバスチンとオロパタジンの効果についてラット腸間膜動脈灌流標本を用いて比較検討した。灌流圧を上昇させた標本において、ヒスタミン(10^-8-10^-4M)による濃度依存性の血管弛緩反応は、レボカバスチン(10μM)およびオロパタジン(10μM)によって抑制されたが、レボカバスチンの抑制率がオロパタジンの抑制率に比較して有意に大であった。H2およびH3受容体拮抗薬が共存するとオロパタジンの抑制作用はレボカバスチンの作用と同程度となった。これらの結果から、レボカバスチンはオロパタジンに比べて、強いH2、H3受容体への拮抗作用を有することが拮抗作用の要因と考えられる。(著者抄録)

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

Functional Alteration of Nervous System in Renovascular Hypertension 査読

Toshihiro Koyama, Yukako Hatanaka, Mitsuhiro Goda, Yoshito Zamami, Narumi Hobara, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 129 ( 2 ) 185 - 189 2009年2月

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

The role of nitric oxide (NO)-containing nerves in adrenergic neurotransmission in hypertension was studied in mesenteric resistance arteries without endothelium in 2-kidney-1-clip renal hypertensive rats (2K-1C RHR) and sham-operated normotensive rats (Sham-R). Mesenteric vascular beds isolated from 2K-1C RHR and Sham-R were perfused with Krebs solution and changes in perfusion pressure were measured with a pressure transducer. Perfusion of a NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS) without affecting vasoconstriction induced by exogenously injected noradrenaline. L-NAME significantly increased the neurogenic release of NA evoked by PNS in both 2K-1C RHR and Sham-R preparations. The facilitatory effect Of L-NAME based on the inhibition of NO production in 2K-1C RHR was less than that in Sham-R. These results Suggest that the function of NO-containing nerves, which presynaptically inhibit adrenergic neurotransmission, is decreased in the renovascular hypertensive model rat.

DOI： 10.1248/yakushi.129.185

Changes in neuronal regulation of vascular tone and its pathophysiological role in diabetic state 査読

Yoshito Zamami, Shingo Takatori, Yukiko Iwatani, Xin Jin, Toshihiro Koyama, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 109 25P - 25P 2009年

Cardiovascular responses and drug evaluation using the pithed rat model 査読

Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

Folia Pharmacologica Japonica 133 ( 1 ) 22 - 26 2009年

PIOGLITAZONE OPPOSES NEUROGENIC VASCULAR DYSFUNCTION VIA ABNORMAL INNERVATION OF MESENTERIC PERIVASCULAR NERVES INDUCED BY HYPERINSULINEMIA 査読

Yoshito Zamami, Keisuke Amitani, Miho Hosoda, Xin Jin, Narumi Hobara, Shingo Takatori, Yoshihisa Kitamura, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF VASCULAR RESEARCH 46 130 - 130 2009年

Royal jelly ameliorates insulin resistance in fructose-drinking rats. 査読

Yoshito Zamami, Shingo Takatori, Mitsuhiro Goda, Toshihiro Koyama, Yukiko Iwatani, Xin Jin, Shima Takai-Doi, Hiromu Kawasaki

Biological & pharmaceutical bulletin 31 ( 11 ) 2103 - 7 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Royal jelly (RJ) is known to contain excellent nutrition and a variety of biological activities. The present study was designed to investigate the effects of RJ on insulin resistance (hyperinsulinemia) in fructose-drinking rats (FDR; insulin resistance animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin and triglyceride, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), and systolic blood pressure, but not blood glucose levels, when compared with control rats. RJ (100, 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma levels of insulin and triglyceride, HOMA-R, without affecting blood glucose or total cholesterol levels and tended to lower systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, RJ treatment resulted in a significant reduction in sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction or CGRP-induced vasodilation. These results suggest that RJ could be an effective functional food to prevent insulin resistance associated with the development of hypertension.

DOI： 10.1248/bpb.31.2103

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