Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
112 巻 , 2 号
選択された号の論文の17件中1~17を表示しています
Forum Minireview
  • Masayuki Takeda, Isao Araki, Tsutomu Mochizuki, Hiroshi Nakagomi, Hide ...
    2010 年 112 巻 2 号 p. 121-127
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M2/3) and in the relaxation of both urethral and prostatic smooth muscle by nitric oxide (NO). In addition, the rhabdosphincter relaxes by inhibition of the pudendal nucleus at the sacral portion. During the storage phase, increase in sympathetic activity relaxes the urinary bladder via activation of post-synaptic β3-receptors and in the contraction of both urethral and prostatic smooth muscles via α1-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture) and neurological disorders (central and peripheral). Theories of pharmacotherapy for voiding dysfunction are 1) increase detrusor contractility and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors and cholinesterase inhibitor; and the latter includes α1-adrenoceptor antagonists, NO donors, benzodiazepines, baclofen, dantrolene, and boturinum toxin.
  • Masaki Yoshida, Koichi Masunaga, Takashi Nagata, Makoto Yono, Yukio Ho ...
    2010 年 112 巻 2 号 p. 128-134
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    Overactive bladder (OAB) syndrome, which is characterized by a complex of storage symptoms (urinary urgency, frequency, nocturia, and urgency incontinence) is highly prevalent within the general population, causing major distress to patients in terms of their psychosocial and physical functioning. Muscarinic receptors of bladder smooth muscles are involved in both normal and disturbed bladder contraction. The muscarinic receptor functions may change in bladder disorders associated with OAB, implying that mechanisms, which normally have little clinical importance, may be up-regulated and contribute to the pathophysiology of OAB. In addition, several reports have suggested that various stimulations release many substances, including adenosine triphosphate, prostaglandins, nitric oxide, and acetylcholine, from bladder urothelium, which contribute to pathophysiology of the increased bladder sensation, OAB symptoms, and detrusor overactivity. Bladder urothelium possesses a non-neuronal cholinergic system and high density of muscarinic receptors. The roles and functions of the non-neuronal cholinergic system in OAB are now being evaluated. In the pharmacotherapy of OAB, antimuscarinic agents are the first choice drugs. Furthermore, new therapeutic targets at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain are proposed. In this review, the pathophysiology of OAB, especially the role of non-neuronal acetylcholine, is discussed. In addition, new drugs with new action mechanisms will be introduced.
  • Akiyoshi Ohtake, Shuichi Sato, Masao Sasamata, Keiji Miyata
    2010 年 112 巻 2 号 p. 135-141
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    Overactive bladder (OAB) syndrome is a common condition that is most often observed in the elderly. Pharmacological treatment with muscarinic receptor antagonists has been most widely used for OAB. An antimuscarinic agent, solifenacin, showed the highest affinity for the muscarinic M3 receptor, which mediates urinary bladder contraction. In preclinical studies, solifenacin exhibited a highly bladder-selective profile compared with other antimuscarinic agents. Solifenacin was also shown to increase bladder capacity without affecting residual urine in an OAB model of rats. Urgency is now considered to result from overactivation of afferent nerves from the urinary bladder. It has been reported that afferent nerves are located adjacent to the urothelium, and stimulation of muscarinic receptors expressed on the urothelium may contribute to the activation of afferent nerves via non-neuronal ATP release. Solifenacin produces its inhibitory effect on bladder afferent activity partly via the suppression of non-neuronal ATP release. Clinically, solifenacin ameliorates all symptoms in OAB patients; and in particular, it produces a significant decrease in urgency episodes, which is the principal symptom of OAB. The pharmacological profile of solifenacin is therefore considered to contribute to its beneficial effects of high efficacy against OAB symptoms with good tolerability.
  • Akira Yoshida, Tomomi Fujino, Shuji Maruyama, Yoshihiko Ito, Yuko Taki ...
    2010 年 112 巻 2 号 p. 142-150
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    We have reviewed the binding of antimuscarinic agents, used to treat urinary dysfunction in patients with overactive bladder, to muscarinic receptors in target and non-target tissues in vivo. Transdermal administration of oxybutynin in rats led to significant binding in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin showed significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M3 subtype. Oral tolterodine bound more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding activity of oral darifenacin in mice was shown to be pronounced and long-lasting in the bladder, submaxillary gland, and lung. In vivo quantitative autoradiography using (+)N-[11C]methyl-3-piperidyl benzilate in rats showed significant occupancy of brain muscarinic receptors on intravenous injection of oxybutynin, propiverine, solifenacin, and tolterodine. The estimated in vivo bladder selectivity compared to brain was significantly greater for solifenacin and tolterodine than oxybutynin. Darifenacin occupied few brain muscarinic receptors. Similar findings were also observed with positron emission tomography in conscious rhesus monkeys. The newer generation of antimuscarinic agents may be advantageous in the bladder selectivity after systemic administration.
  • Martin C. Michel
    2010 年 112 巻 2 号 p. 151-157
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    α1-Adrenoceptor antagonists are the mainstay of medical treatment of male voiding dysfunction which typically is attributed to benign prostatic hyperplasia. While original concepts have assumed that they relieve voiding dysfunction by relaxing prostatic smooth muscle, newer data indicate that their therapeutic effects at least partly occur independent of prostatic relaxation, perhaps involving direct effects on blood vessels, urothelium, afferent nerves, and/or smooth muscle of the urinary bladder. The adverse event profiles differ among α1-adrenoceptor antagonists, with tamsulosin having a particularly good cardiovascular tolerability. While this was originally attributed to its selectivity for α1A-adrenoceptors, it appears that alfuzosin which lacks subtype-selectivity, has a very similar tolerability. In contrast, doxazosin and terazosin, which are chemically and pharmacologically more closely related to alfuzosin than to tamsulosin, appear to have more side effects attributable to the cardiovascular system. More recent data indicate that tolerability differences between α1-adrenoceptor antagonists may at least partly relate to pharmacokinetic rather than to pharmacodynamic differences. Taken together, these data emphasize the idea that concepts about drug efficacy and tolerability despite being highly plausible may not necessarily be true and always require thorough experimental testing.
Full Papers
  • Na-Ra Jeon, Sushruta Koppula, Byung-Wook Kim, Su-Ho Park, Hyo-Won Lee, ...
    2010 年 112 巻 2 号 p. 158-166
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    The effects of MMHD [(S,E)-2-methyl-1-(2-methylthiazol-4-yl) hexa-1,5-dien-ol], a novel synthetic compound derived from epothilone, was investigated for its effects on the expression of proinflammatory mediators in lipopolysaccharide-stimulated BV-2 microglia. MMHD attenuated the expressions of inducible nitric oxide synthase and cyclooxygenase-2 mRNA and protein without affecting cell viability. Moreover, MMHD suppressed nuclear factor-κB (NF-κB) activation via the translocation of p65 into the nucleus. These results indicate that MMHD exerts anti-inflammatory properties by suppressing the transcription of proinflammatory cytokine genes through the NF-κB signaling pathway.
  • Shintaro Kato, Hideki Amano, Yoshiya Ito, Koji Eshima, Naoyoshi Aoyama ...
    2010 年 112 巻 2 号 p. 167-175
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    Erythropoietin (EPO) has been shown to enhance angiogenesis, but its precise mechanisms of enhancement during ischemia are not fully elucidated. We examined the effect of EPO on blood flow recovery from acute hind-limb ischemia induced by ligation of the femoral artery in male C57Bl/6 mice. The density of microvessels with platelet adhesion in ischemic tissues was assessed by intravital microscopy. Treatment with EPO (100 and 1000 IU/kg, i.p.) restored blood flow in a dose-dependent manner and increased plasma levels of soluble-P-selectin, vascular endothelial growth factor (VEGF), and stromal cell–derived factor (SDF-1). Flow cytometric analysis revealed increased P-selectin expression on platelets in EPO-treated mice compared to PBS-treated mice. Intravital microscopic studies showed that EPO increased density of microvessels with platelet adhesion selectively in the ischemic tissues. Neutralizing antibody against P-selectin reduced the density of microvessels with platelet adhesion enhanced with EPO and impaired blood flow recovery with reductions in VEGF and SDF-1 levels. These results suggest that EPO administration enhances recovery from hind-limb ischemia, and platelet adhesion to the microvessels is a key event to enhance the angiogenesis in the ischemic tissues.
  • Masashi Mukohda, Hideyuki Yamawaki, Muneyoshi Okada, Yukio Hara
    2010 年 112 巻 2 号 p. 176-183
    発行日: 2010年
    公開日: 2010/02/18
    ジャーナル フリー
    The concentration of methylglyoxal (MGO), a metabolite of glucose, increases in plasma of type II diabetic patients as well as in tissues of hypertensive rats. We have previously shown that MGO inhibited noradrenaline (NA)–induced smooth muscle contraction in rat aorta. However, the effect of MGO on relaxing responses in isolated blood vessel remains to be clarified. Thus, we examined if MGO affects acetylcholine (ACh)– or sodium nitroprusside (SNP)–induced vasodilation on NA (100 nM)–induced pre-contraction in rat thoracic aorta. Treatment of endothelium-intact aorta with MGO (420 μM, 30 min) did not change ACh (1 nM – 3 μM)–induced endothelium-dependent relaxation. In contrast, treatment of endothelium-denuded aorta with MGO shifted the concentration–response curve for SNP (0.1 – 300 nM) to the left. MGO increased reactive oxygen species (ROS) production in smooth muscle on analysis of protein carbonylation. Anti-oxidant agents such as tempol (10 μM), catalase (5000 U/mL), and nitric oxide synthase inhibitor, NG-nitro-L-arginine methylester (100 μM) had no effect on MGO-induced enhancement of SNP-induced relaxation. However, iberiotoxin (100 nM), a large-conductance Ca2+-activated K+ (BKCa)–channel inhibitor, significantly prevented the effect. The present study revealed that MGO enhanced SNP-induced relaxation in a ROS-independent manner via in part opening smooth muscle BKCa channels.
  • Satoko Suga, Shigemi Goto, Akifumi Togari
    2010 年 112 巻 2 号 p. 184-191
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/01/22
    ジャーナル フリー
    There is currently great interest in the bone metabolism induced by the sympathetic nerve system. Recently, direct neurite–osteoblastic cell communication was demonstrated using an in vitro co-culture model comprising neurite-sprouting murine superior cervical ganglia and MC3T3-E1 osteoblast-like cells. In the present study, we examined whether the direct nerve–osteoclastic cell communication was present in an in vitro co-culture model comprising cultured murine superior cervical ganglia and mouse osteoclast-like cells. RAW264.7 cells treated with receptor activator of NF-κB ligand were used as osteoclast-like cells. We found that the addition of scorpion venom (SV) elicited neurite activation via intracellular Ca2+ mobilization and, after a lag period, osteoclastic Ca2+ mobilization in the co-culture. SV did not have any direct effect on the osteoclastic cells in the absence of the neurites. The addition of an α1-adrenergic receptor (AR) antagonist, prazosin, concentration-dependently prevented the osteoclastic activation that resulted as a consequence of neural activation by SV. We also found that α1-adrenergic receptor agonists evoked transient Ca2+ mobilization and gene expression of interleukin-6 in osteoclastic cells. These results demonstrate that osteoclastic activation occurs via α1-AR in osteoclastic cells as a direct response to neuronal activation.
  • Go Takahashi, Hiroyuki Tanaka, Keiko Wakahara, Reishi Nasu, Mikiko Has ...
    2010 年 112 巻 2 号 p. 192-202
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/01/22
    ジャーナル フリー
    Recent research has focused on the effects of ambient particulate pollution and much evidence has indicated that particulate pollution is associated with the onset of asthma and allergy; however, the effect of diesel exhaust particles (DEP) on the development of allergen-induced airway remodeling has not been fully investigated in vivo. In the present study, we examined the effects of DEP on Dermatophagoides farinae allergens (Der f)–induced asthma-like phenotypes in mice. Mice were administered i.t. 8 times with Der f. DEP were injected i.t. with Der f 4 times throughout the experiment or twice at the sensitization period. In both cases, DEP aggravated Der f–induced increases in airway responsiveness to acetylcholine, the number of eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF), serum Der f–specific IgG1 levels, Th2 cytokines and transforming growth factor-β1 levels in BALF, and amount of hydroxyproline in the right lungs. Furthermore, goblet cell hyperplasia and subepithelial fibrosis were also markedly aggravated. These findings indicate that DEP can potentiate airway remodeling induced by repeated allergen challenge as well as Th2-drived airway hyperresponsiveness, eosinophilic inflammation, and IgG1 production and that DEP can exhibit adjuvant activity for airway remodeling, probably due to the enhancement of allergen sensitization and/or of Th2 polarizing pathways.
  • Masato Komai, Hiroyuki Tanaka, Koichi Nagao, Masayuki Ishizaki, Daisuk ...
    2010 年 112 巻 2 号 p. 203-213
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/02/04
    ジャーナル フリー
    CC-chemokine receptor 3 (CCR3) is a chemokine receptor for which major ligands, CC-chemokine ligand (CCL) 11, CCL24, and CCL26, are known to be involved in chemotaxis for eosinophils. In the present study, we evaluated the effect of a low molecular weight CCR3-receptor antagonist, Ki19003 (4-[[5-(2,4-dichlorobenzylureido)pentyl][1-(4-chlorophenyl)ethyl]amino]butanoic acid), on airway remodeling in a mouse model of allergic asthma. BALB/c mice were sensitized twice by intraperitoneal injection of ovalbumin (OA) and exposed daily to 1% OA for 3 weeks. Twenty-four hours after the final antigen challenge, bronchoalveolar lavage and histological examinations were carried out. Ki19003 clearly inhibited antigen-induced increase in the number of eosinophils in bronchoalveolar lavage fluid (BALF), but did not affect the number of other cell types examined in this study. Ki19003 also inhibited the increased production of transforming growth factor-β1 in BALF and the amount of hydroxyproline in the lungs in a dose-dependent manner. Furthermore, Ki19003 significantly attenuated allergen-induced subepithelial and peribronchial fibrosis. These findings indicate that CCR3 antagonism prevents not only the infiltration of eosinophils into the airways but also the development of allergen-induced subepithelial and peribronchial fibrosis. Therefore, a CCR3 antagonist may be useful in the treatment of airway remodeling, especially subepithelial and peribronchial fibrosis, in allergic asthma.
  • Haiping Zhao, Dan Lv, Wei Zhang, Wei Dong, Juan Feng, Zhiguang Xiang, ...
    2010 年 112 巻 2 号 p. 214-222
    発行日: 2010年
    公開日: 2010/02/18
    ジャーナル フリー
    Familial dilated cardiomyopathy (FDCM) is caused by defective genes and specific medicines are not currently available to treat this. Ginsenoside-Rb1 provides cardioprotection in the experimental models of myocardial ischemia–reperfusion injury. Here we investigate Rb1’s effect on DCM in cTnTR141W transgenic mouse. The transgene-positive mice aged 2 months were randomized into the model group and Rb1 [70 mg/(kg·day)] group; transgene-negative mice were used as a control. After 4-month treatment, cardiac function was assessed by echocardiography; cardiac tissues were prepared for histology and electron microscopy. Expression levels of molecular markers of cardiac hypertrophy, fibrosis, and intercalated disc proteins were detected by RT-PCR. Rb1 significantly decreased mortality, chamber dilation, and contractile dysfunction in cTnTR141W mice. Rb1 attenuated cardiac hypertrophy, interstitial fibrosis, ultrastructural degeneration, and intercalated disc remodeling in DCM hearts. Western blotting showed that Rb1 significantly decreased heparin-binding epidermal growth factor–like growth factor (HB-EGF) expression and signal transduction and activators of transcription 3 (STAT3) activation, which were gradually increased in DCM hearts. Our results showed that Rb1 clearly alleviated cardiac dysfunction and remodeling in the cTnTR141W transgenic mouse, indicating its potential utility in the treatment of FDCM.
  • Reijiro Okumura, Yoshiyuki Shibukawa, Takashi Muramatsu, Sadamitsu Has ...
    2010 年 112 巻 2 号 p. 223-230
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/01/30
    ジャーナル フリー
    Although the central role of ameloblasts in synthesis and resorption of enamel matrix proteins during amelogenesis is well documented, the Ca2+-transport/extrusion mechanism remains to be fully elucidated. To clarify Ca2+-transport in rat ameloblasts, we investigated expression and localization of Na+-Ca2+ exchanger (NCX) isoforms and the functional characteristics of their ion transporting/pharmacological properties. RT-PCR and immunohistochemical analyses revealed expression of NCX1 and NCX3 in ameloblasts, localized in the apical membrane. In patch-clamp recordings, Ca2+ efflux by Na+-Ca2+ exchange showed dependence on external Na+. Ca2+ influx by Na+-Ca2+ exchange, measured by fura-2 fluorescence, showed dependence on extracellular Ca2+ concentration, and it was blocked by NCX inhibitors KB-R7943, SEA0400, and SN-6. These results showed significant expression of NCX1 and NCX3 in ameloblasts, indicating their involvement in the directional Ca2+ extrusion pathway from cells to the enamel mineralizing front.
  • Ayako Hidaka, Yasu-Taka Azuma, Hidemitsu Nakajima, Tadayoshi Takeuchi
    2010 年 112 巻 2 号 p. 231-241
    発行日: 2010年
    公開日: 2010/02/18
    [早期公開] 公開日: 2010/01/30
    ジャーナル フリー
    The present study was designed to identify the inhibitory neurotransmitters mediating nonadrenergic noncholinergic relaxation in the longitudinal muscle of C57/BL mouse distal colon. Relaxation induced by electrical field stimulation (EFS) was recorded isotonically in the presence of atropine and guanethidine. Cyclic guanosine-3′,5′-monophosphate (cyclic GMP) content was measured by radioimmunoassay. EFS-induced relaxation was inhibited by nitro-L-arginine (L-NNA) and Sn (IV) protoporphyrin dichloride IX (SnPP-IX), a nitric oxide (NO) and carbon monoxide (CO) synthase inhibitor, respectively. A combination of both inhibitors produced an additive effect. ODQ, a soluble guanylate cyclase inhibitor, inhibited EFS-induced relaxation. NOR-1, a NO donor, and carbon monoxide-releasing molecule-2 (CORM-2), a CO donor, treatment relaxed the distal colon and increased cyclic GMP content. The effects of NOR-1 and CORM-2 were inhibited by ODQ. KT5823, a cyclic GMP–dependent protein kinase inhibitor, inhibited EFS-induced relaxation. EFS-induced relaxation in the presence of KT5823 was further inhibited by L-NNA, but not by SnPP-IX. In addition, KT5823 inhibited CORM-2–induced relaxation, but not NOR-1–induced relaxation. H89, a cyclic AMP–dependent protein kinase inhibitor, inhibited EFS-induced relaxation, and EFS-induced relaxation in the presence of H89 was further inhibited by L-NNA. These results suggested that NO and CO function as inhibitory neurotransmitters in the longitudinal muscle of C57BL mouse distal colon.
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