Journal of pharmacological sciences最新文献_第2页

Neuron-specific overexpression of human vasoactive intestinal peptide receptor 2 in mice causes cognitive dysfunction and abnormal dendritic morphology in the prefrontal cortex 人类血管活性肠肽受体2在小鼠神经元特异性过表达导致认知功能障碍和前额叶皮层树突形态异常

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI: 10.1016/j.jphs.2025.12.005

Ami Ono , Tatsunori Miyaoka , Daichi Koan , Zihao Jin , Lu Chen , Atsuko Hayata-Takano , Satoshi Asano , Rei Yokoyama , Kenji Ishimoto , Nobumasa Hino , Akihiro Harada , Takanobu Nakazawa , Hitoshi Hashimoto , James A. Waschek , Shinsaku Nakagawa , Kotaro Tanimoto , Yukio Ago

{"title":"Neuron-specific overexpression of human vasoactive intestinal peptide receptor 2 in mice causes cognitive dysfunction and abnormal dendritic morphology in the prefrontal cortex","authors":"Ami Ono , Tatsunori Miyaoka , Daichi Koan , Zihao Jin , Lu Chen , Atsuko Hayata-Takano , Satoshi Asano , Rei Yokoyama , Kenji Ishimoto , Nobumasa Hino , Akihiro Harada , Takanobu Nakazawa , Hitoshi Hashimoto , James A. Waschek , Shinsaku Nakagawa , Kotaro Tanimoto , Yukio Ago","doi":"10.1016/j.jphs.2025.12.005","DOIUrl":"10.1016/j.jphs.2025.12.005","url":null,"abstract":"<div><div>Accumulating evidence suggests that microduplications of the <em>VIPR2</em> gene are strongly associated with schizophrenia. <em>VIPR2</em> encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of VPAC2 overexpression with respect to schizophrenia remain unclear. Therefore, we aimed to determine the effects of human VPAC2 overexpression in neurons on cognition-related behaviors and prefrontal cortex dendritic morphology in mice. We crossed a Tau-Cre mouse line, which targets neuronal recombinase activity, with a newly generated double transgenic mouse line containing tetracycline-responsive element-human VPAC2-IRES-mCherry and ROSA:LNL:tTA. Immunohistochemical and Western blot analyses revealed that VPAC2 was overexpressed in neurons throughout the brain. Mice that overexpressed VPAC2 showed impaired performance in the novel object recognition test. Furthermore, VPAC2-overexpressing mice exhibited significant reductions in brain weight and the length, branch number, and complexity of arborization of prefrontal cortex pyramidal neuron dendrites. RNA sequencing analysis revealed that VPAC2 overexpression may affect signaling pathways involved in regulating stem cell pluripotency, cell cycle, and actin cytoskeleton. Quantitative PCR analysis also confirmed increased expression of the X-linked lymphocyte-regulated 3B gene, which regulates dendritic morphogenesis and spine assembly. These results suggest that VPAC2 overexpression in neurons has a detrimental effect on brain development, which leads to impaired neural circuitry and cognitive function.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 111-121"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines 人乳腺癌细胞系中ifn γ-诱导的PD-L1表达的src依赖性调节

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI: 10.1016/j.jphs.2025.12.004

Chihiro Hayashi , Yuto Mizuno , Yu Iida , Akane Nagasako , Michiko Endo , Wakana Fukae , Eriko Yamashita , Yoshihiro Ishikawa , Masanari Umemura

{"title":"Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines","authors":"Chihiro Hayashi , Yuto Mizuno , Yu Iida , Akane Nagasako , Michiko Endo , Wakana Fukae , Eriko Yamashita , Yoshihiro Ishikawa , Masanari Umemura","doi":"10.1016/j.jphs.2025.12.004","DOIUrl":"10.1016/j.jphs.2025.12.004","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ–induced PD-L1 mRNA and protein expression, as well as activation of PD-L1–related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8<sup>+</sup> T-cells, TNBC cells were more susceptible to T-cell–mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ–mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 132-141"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Delayed response of the median raphe serotonin neurons projecting to the ventral hippocampus to aversive stimuli 中缝正中5 -羟色胺神经元投射到腹侧海马对厌恶刺激的延迟反应

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-02-01 Epub Date: 2025-12-08 DOI: 10.1016/j.jphs.2025.12.003

Hinako Morishita , Harune Hori , Hiroyuki Kawai , Hisashi Shirakawa , Hitoshi Hashimoto , Kazuki Nagayasu

引用次数: 0

SGLT2 inhibitor-induced glycosuria improves steatotic liver disease in parallel with enhanced ureagenesis in ob/ob mice 在ob/ob小鼠中，SGLT2抑制剂诱导的糖尿可改善脂肪变性肝病，同时增强尿原性

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-02-01 Epub Date: 2025-12-24 DOI: 10.1016/j.jphs.2025.12.006

Satoshi Kidoguchi , Kento Kitada , Asahiro Morishita , Yudai Tsuji , Hiroyuki Ohsaki , Daisuke Yamazaki , Takashi Morikawa , Yoshio Konishi , Hideki Kobara , Takashi Yokoo , Jens Titze , Kazuo Takahashi , Akira Nishiyama

{"title":"SGLT2 inhibitor-induced glycosuria improves steatotic liver disease in parallel with enhanced ureagenesis in ob/ob mice","authors":"Satoshi Kidoguchi , Kento Kitada , Asahiro Morishita , Yudai Tsuji , Hiroyuki Ohsaki , Daisuke Yamazaki , Takashi Morikawa , Yoshio Konishi , Hideki Kobara , Takashi Yokoo , Jens Titze , Kazuo Takahashi , Akira Nishiyama","doi":"10.1016/j.jphs.2025.12.006","DOIUrl":"10.1016/j.jphs.2025.12.006","url":null,"abstract":"<div><h3>Purpose</h3><div>Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in hepatic ureagenesis for water conservation to the association between improvement of steatotic liver disease and the energy-consuming nature of hepatic ureagenesis.</div></div><div><h3>General methods</h3><div><em>ob/ob</em> mice fed a high-fat diet without carbohydrate restriction were administered luseogliflozin, an SGLT2 inhibitor, for eight weeks.</div></div><div><h3>Findings</h3><div>Luseogliflozin significantly decreased the liver weight, plasma aspartate aminotransferase and alanine aminotransferase levels, and fat content in mice with enhanced glycosuria (H-GlcV group). The ratio of urinary urea excretion decreased as a substitute for increased glucose excretion in the H-GlcV group. Luseogliflozin significantly increased liver urea content and tended to increase malate dehydrogenase (MDH)-1 activity. Liver MDH-1 activity was significantly positively correlated with liver urea content, suggesting that MDH-1-induced amino acid recruitment from the tricarboxylic acid cycle to the urea cycle may contribute to enhanced ureagenesis. In addition, liver weight was significantly negatively correlated with the liver urea content.</div></div><div><h3>Conclusions</h3><div>Our data suggest that enhanced hepatic ureagenesis as a compensatory water conservation mechanism for glycosuria-induced fluid loss may be associated with amelioration of steatotic liver disease in SGLT2 inhibitor-treated <em>ob/ob</em> mice.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 122-131"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Magnesium deficiency differentially modulates hippocampal and prefrontal oscillations and cardiac rhythms 镁缺乏对海马和前额叶振荡和心律的调节存在差异

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-02-01 Epub Date: 2025-12-09 DOI: 10.1016/j.jphs.2025.12.002

Sora Inoue , Yuji Ikegaya , Nobuyoshi Matsumoto , Tetsuhiko Kashima

{"title":"Magnesium deficiency differentially modulates hippocampal and prefrontal oscillations and cardiac rhythms","authors":"Sora Inoue , Yuji Ikegaya , Nobuyoshi Matsumoto , Tetsuhiko Kashima","doi":"10.1016/j.jphs.2025.12.002","DOIUrl":"10.1016/j.jphs.2025.12.002","url":null,"abstract":"<div><div>Magnesium (Mg) is an essential cation critical for neuronal and cardiac homeostasis, principally by modulating <em>N</em>-methyl-d-aspartate (NMDA) receptor function. While magnesium deficiency (MgD) is known to impair memory and autonomic function, the systemic interplay remains poorly understood.</div><div>As a preliminary step to investigating neural activity during memory tasks, this study investigated the effects of 3 weeks of MgD on neural activity patterns and cardiac function in rats. Simultaneous electrophysiological recordings from the dorsal hippocampus and medial prefrontal cortex, along with electrocardiogram and electromyogram (EMG) monitoring, revealed that MgD selectively altered neural oscillations without affecting cardiac function or sleep architecture. Notably, frequency-specific changes in local field potentials (LFPs) were most pronounced during quiet wakefulness under dark conditions. This excessive enhancement of gamma wave activity may contribute to memory impairment.</div><div>This 3-week deficiency was characterized by altered neural excitability, which could lead to cognitive impairment and partial cardiac arrhythmia.</div><div>Our findings demonstrate that spontaneous neural activity is altered even in the 3-week of MgD and support a model in which the deficiency progressively disrupts physiological regulation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 97-110"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery 朊病毒样蛋白的rna介导聚集机制及其在药物发现中的应用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-01-01 Epub Date: 2025-11-29 DOI: 10.1016/j.jphs.2025.11.006

Yasushi Yabuki , Norifumi Shioda

引用次数: 0

Acute and chronic effects of imeglimin on peripheral circadian clocks in mice 依米明对小鼠外周生物钟的急性和慢性影响

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-01-01 Epub Date: 2025-11-29 DOI: 10.1016/j.jphs.2025.11.005

Yifan Shi , Pingping Xu , Jun-ichi Morishige , Yunze Yang , Tomohiro Iba , Naoto Nagata , Takashi Hosono , Ryo Miyazaki , Naoki Sakane , Masanori Ono , Tomoko Fujiwara , Hiroshi Fujiwara , Hitoshi Ando

{"title":"Acute and chronic effects of imeglimin on peripheral circadian clocks in mice","authors":"Yifan Shi , Pingping Xu , Jun-ichi Morishige , Yunze Yang , Tomohiro Iba , Naoto Nagata , Takashi Hosono , Ryo Miyazaki , Naoki Sakane , Masanori Ono , Tomoko Fujiwara , Hiroshi Fujiwara , Hitoshi Ando","doi":"10.1016/j.jphs.2025.11.005","DOIUrl":"10.1016/j.jphs.2025.11.005","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle.</div></div><div><h3>Methods</h3><div>Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR.</div></div><div><h3>Results</h3><div>Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (<em>Nr1d1</em> and <em>Dbp</em> in skeletal muscle; <em>Per2</em> in liver), whereas dosing at ZT 0 decreased <em>Nr1d1</em> and <em>Dbp</em> in both tissues. In the chronic study, imeglimin decreased the peak expression of <em>Nr1d1</em> and <em>Dbp</em> in skeletal muscle, while liver rhythms remained unchanged. <em>Nampt</em> and <em>Sirt1</em> expression was unaffected in either tissue.</div></div><div><h3>Conclusion</h3><div>In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 51-58"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spinal dopamine D1/D2 receptor complex stimulates NGF release to activate astrocytes and promote neuropathic pain 脊髓多巴胺D1/D2受体复合物刺激NGF释放，激活星形胶质细胞，促进神经性疼痛

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.jphs.2025.10.005

Yi-Ni Bao , Zi-Meng Zhang , Han Jiang , Rui Wang , Shen Zhang , Dan-Li Zhou , Wen-Ling Dai , Ji-Hua Liu

{"title":"Spinal dopamine D1/D2 receptor complex stimulates NGF release to activate astrocytes and promote neuropathic pain","authors":"Yi-Ni Bao , Zi-Meng Zhang , Han Jiang , Rui Wang , Shen Zhang , Dan-Li Zhou , Wen-Ling Dai , Ji-Hua Liu","doi":"10.1016/j.jphs.2025.10.005","DOIUrl":"10.1016/j.jphs.2025.10.005","url":null,"abstract":"<div><h3>Aims</h3><div>Blocking peripheral nerve growth factor (NGF) obviously alleviated neuropathic pain, however, the effect and mechanism of spinal NGF in neuropathic pain are remain controversial. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.</div></div><div><h3>Methods</h3><div>Chronic constriction injury (CCI) of the sciatic nerve was used to instill neuropathic pain. Pain behaviors were assessed using Von Frey filaments and Hargreaves test. For <em>in vitro</em> studies, primary neurons and astrocytes were cultured. RT-PCR, immunofluorescence and Western blot were used to assess the cell signaling pathway.</div></div><div><h3>Results</h3><div>Blocking spinal NGF effectively reduced CCI-induced neuropathic pain and suppressed astrocyte activation both in vivo and <em>in vitro</em>. The trends of changes in spinal NGF and the astrocyte marker matched the trends of changes in pain thresholds in CCI. Moreover, NGF-induced hypersensitivity could be abolished by astrocyte inhibitor. NGF was found mainly expressed in spinal neurons, and that the NGF receptor tropomyosin receptor kinase A (TrkA) but not p75, was widely expressed in spinal astrocytes. Dopamine D1/D2 receptor complex could promote NGF expression in spinal neurons, which bind to TrkA to promote astrocytes activation via ASK1-JNK/NF-κB signaling.</div></div><div><h3>Conclusions</h3><div>These findings imply that D1/D2 receptor complex promotes NGF secretion in spinal neurons, which bind to TrkA to promote astrocyte activation and neuropathic pain via ASK1/JNK/NF-κB pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 12-22"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake 细胞外锌通过Zrt-和irt相关蛋白12依赖性摄取抑制小胶质细胞炎症转移

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-01-01 Epub Date: 2025-10-30 DOI: 10.1016/j.jphs.2025.10.006

Takaaki Aratake , Youichirou Higashi , Takahiro Shimizu , Satoshi Fukata , Motoaki Saito

{"title":"Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake","authors":"Takaaki Aratake , Youichirou Higashi , Takahiro Shimizu , Satoshi Fukata , Motoaki Saito","doi":"10.1016/j.jphs.2025.10.006","DOIUrl":"10.1016/j.jphs.2025.10.006","url":null,"abstract":"<div><div>Microglia exhibit phenotypic plasticity between anti-inflammatory M2 and pro-inflammatory M1 states, and the transition from M2 to M1 is implicated in the progression of acute brain injuries. However, the molecular mechanisms that regulate this phenotypic shift remain poorly understood. Zn<sup>2+</sup>, stored in presynaptic vesicles, is extracellularly released during pathological events, such as cerebral ischemia, and modulates microglial function. In this study, we aimed to investigate the role of extracellular Zn<sup>2+</sup> in the M2-to-M1 transition using BV2 microglial cells. Pretreatment with ZnCl<sub>2</sub> during M2 polarization significantly suppressed lipopolysaccharide-induced production of interleukin (IL)-6 and tumor necrosis factor-α following the phenotypic shift. Among the zinc transporters, Zrt- and Irt-related protein 12 (ZIP12) expression was markedly upregulated by IL-4 stimulation, and siRNA-mediated knockdown of ZIP12 abolished the Zn<sup>2+</sup>-mediated suppression of pro-inflammatory cytokine production. Furthermore, ZIP12 knockdown reduced intracellular Zn<sup>2+</sup> accumulation in IL-4-treated microglia, as revealed by FluoZin-3 fluorescence. These findings indicate that extracellular Zn<sup>2+</sup> is taken up via ZIP12 during M2 polarization and subsequently acts to suppress pro-inflammatory cytokine production, thereby restraining the shift toward an M1 phenotype.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 29-36"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels 可乐定诱导的豚鼠胸主动脉张力变化：α 1l肾上腺素受体、l型电压依赖性Ca2+通道和K+通道的作用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-01-01 Epub Date: 2025-11-10 DOI: 10.1016/j.jphs.2025.11.002

Keisuke Obara, Ryusei Ono, Daiki Kato, Minori Gohara, Qianghaodi Hong, Yusuke Matsuyama, Ayano Yashiro, Kento Yoshioka, Yoshio Tanaka

{"title":"Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels","authors":"Keisuke Obara, Ryusei Ono, Daiki Kato, Minori Gohara, Qianghaodi Hong, Yusuke Matsuyama, Ayano Yashiro, Kento Yoshioka, Yoshio Tanaka","doi":"10.1016/j.jphs.2025.11.002","DOIUrl":"10.1016/j.jphs.2025.11.002","url":null,"abstract":"<div><div>We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba<sup>2+</sup>, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba<sup>2+</sup>; this Ba<sup>2+</sup>-potentiated component was nearly abolished by verapamil. The Ba<sup>2+</sup>-enhanced clonidine-evoked contraction was insensitive to the α<sub>2</sub>-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α<sub>1</sub>-AR antagonists prazosin and tamsulosin, yielding p<em>A</em><sub>2</sub> values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a p<em>A</em><sub>2</sub> value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba<sup>2+</sup> but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α<sub>1L</sub>-ARs, promoting Ca<sup>2+</sup> influx through L-type voltage-dependent Ca<sup>2+</sup> channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba<sup>2+</sup>-sensitive K<sup>+</sup> channels. In addition, clonidine itself appears to directly or indirectly activate Ba<sup>2+</sup>-sensitive K<sup>+</sup> channels, thereby suppressing the α<sub>1L</sub>-AR–L-type VDCC functional coupling.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 41-50"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0