{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:06:00Z","timestamp":1784027160736,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["16580242"],"award-info":[{"award-number":["16580242"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The tree shrew (Tupaia belangeri) is increasingly recognized as an important experimental model for studying human diseases due to its close phylogenetic relationship with humans. Because the basilar artery\u2019s response to endogenous vasoactive mediators varies among species, we investigated the effects of vasoactive substances on isolated tupaia basilar arteries to determine whether this species is suitable as a human model. 5-Hydroxytryptamine (5-HT) and histamine (His) induced contraction, while bradykinin (BK) and acetylcholine (ACh) produced concentration-dependent relaxation. Pharmacological analysis revealed that contractions triggered by 5-HT were regulated through 5-H1 and 5-HT2 receptors, while His-induced responses were mediated by H1 receptors. BK-induced relaxation was inhibited by the B2 antagonist HOE140 and N\u03c9-nitro-L-arginine (L-NA), but not by B1 antagonists or indomethacin, suggesting a B2 receptor-mediated nitric oxide (NO) pathway. ACh-induced relaxation was markedly reduced in the presence of L-NA and the M3 antagonist pFHHSiD, indicating M3 receptor-mediated NO release. At basal tone, L-NA evoked a contractile response, while indomethacin led to relaxation, suggesting basal regulation by NO and prostanoids. These findings demonstrate that 5-HT1\/5-HT2 and H1 receptors mediate contraction, while B2 and M3 receptors mediate relaxation in the tupaia basilar artery. This study highlights species-specific cerebrovascular regulation and supports the tupaia as a relevant model for investigating human cerebrovascular physiology and pathophysiology.<\/jats:p>","DOI":"10.3390\/biology15141146","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:12:53Z","timestamp":1784023973000},"page":"1146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Characterization of Vasomotor Responses in the Tree Shrew (Tupaia belangeri) Basilar Artery: A Promising Model for Human Cerebrovascular Research"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4253-6711","authenticated-orcid":false,"given":"Md. Zahorul","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"},{"name":"Department of Pharmacology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4806-9843","authenticated-orcid":false,"given":"Mohammad Enamul Hoque","family":"Kayesh","sequence":"additional","affiliation":[{"name":"Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"},{"name":"Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"},{"name":"Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2130-5837","authenticated-orcid":false,"given":"Michinori","family":"Kohara","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-2018","authenticated-orcid":false,"given":"Kyoko","family":"Tsukiyama-Kohara","sequence":"additional","affiliation":[{"name":"Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"},{"name":"Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1980-2869","authenticated-orcid":false,"given":"Atsushi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s42826-022-00128-1","article-title":"Role of animal models in biomedical research: A review","volume":"38","author":"Mukherjee","year":"2022","journal-title":"Lab. Anim. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lange, S., and Inal, J.M. (2024). Animal Models of Human Disease 2.0. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413743"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/ilar\/ilx033","article-title":"Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges","volume":"58","author":"Harding","year":"2017","journal-title":"ILAR J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1034\/j.1600-0684.2003.00022.x","article-title":"The tree shrews: Adjuncts and alternatives to primates as models for biomedical research","volume":"32","author":"Cao","year":"2003","journal-title":"J. Med. Primatol."},{"key":"ref_5","first-page":"127","article-title":"Tree shrew (Tupaia belangeri) as a novel laboratory disease animal model","volume":"38","author":"Xiao","year":"2017","journal-title":"Zool. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1038\/ncomms2416","article-title":"Genome of the Chinese tree shrew","volume":"4","author":"Fan","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1126\/science.1147555","article-title":"Molecular and genomic data identify the closest living relative of primates","volume":"318","author":"Janecka","year":"2007","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1111\/j.1096-3642.1924.tb03328.x","article-title":"On the brain of the tree shrew (Tupaia minor)","volume":"94","year":"1924","journal-title":"Proc. Zool. Soc. Lond."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/cr.2016.156","article-title":"Long-term propagation of tree shrew spermatogonial stem cells in culture and successful generation of transgenic offspring","volume":"27","author":"Li","year":"2017","journal-title":"Cell Res."},{"key":"ref_10","unstructured":"Poole, T.B., English, P., and Universities Federation for Animal Welfare (1999). The UFAW Handbook on the Care and Management of Laboratory Animals, Blackwell Science. [7th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1126\/science.1067179","article-title":"Resolution of the early placental mammal radiation using Bayesian phylogenetics","volume":"294","author":"Murphy","year":"2001","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1128\/JVI.01448-09","article-title":"Pathogenesis of hepatitis C virus infection in Tupaia belangeri","volume":"84","author":"Amako","year":"2010","journal-title":"J. Virol."},{"key":"ref_13","first-page":"104","article-title":"Progress on establishment of tree shrew (Tupaia) chronic infection with HBV in vivo","volume":"32","author":"Li","year":"2011","journal-title":"Dong Wu Xue Yan Jiu"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3724\/SP.J.1141.2013.02059","article-title":"Tree shrews under the spotlight: Emerging model of human diseases","volume":"34","author":"Xu","year":"2013","journal-title":"Zool. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tamayo, A., and Siepmann, T. (2021). Regulation of Blood Flow in the Cerebral Posterior Circulation by Parasympathetic Nerve Fibers: Physiological Background and Possible Clinical Implications in Patients With Vertebrobasilar Stroke. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.660373"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1152\/physrev.1998.78.1.53","article-title":"Regulation of the cerebral circulation: Role of endothelium and potassium channels","volume":"78","author":"Faraci","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1152\/japplphysiol.00954.2005","article-title":"Perivascular nerves and the regulation of cerebrovascular tone","volume":"100","author":"Hamel","year":"2006","journal-title":"J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cmet.2008.03.010","article-title":"Hypertension and cerebrovascular dysfunction","volume":"7","author":"Iadecola","year":"2008","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.molmed.2008.09.003","article-title":"The role of oxidative stress and NADPH oxidase in cerebrovascular disease","volume":"14","author":"Chrissobolis","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1254\/jjp.44.228","article-title":"Endothelium-dependent vasocontraction in response to noradrenaline in the canine cerebral artery","volume":"44","author":"Usui","year":"1987","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0022-3565(25)21854-7","article-title":"Alpha adrenergic receptor subtypes in human, monkey and dog cerebral arteries","volume":"226","author":"Toda","year":"1983","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0014-2999(90)94176-X","article-title":"Isolated bovine cerebral arteries from rostral and caudal regions: Distinct responses to adrenoceptor agonists","volume":"191","author":"Ayajiki","year":"1990","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1254\/jjp.61.93","article-title":"Characterization of \u03b2-adrenoceptors in pig basilar artery from functional and radioligand binding studies","volume":"61","author":"Miyamoto","year":"1993","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1365-2885.2008.01037.x","article-title":"Characterization of bradykinin-induced endothelium-independent contraction in equine basilar artery","volume":"32","author":"Ueno","year":"2009","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109190","DOI":"10.1016\/j.cbpc.2021.109190","article-title":"Vasomotor effects of noradrenaline, 5-hydroxytryptamine, angiotensin II, bradykinin, histamine, and acetylcholine on the bat (Rhinolophus ferrumequinum) basilar artery","volume":"250","author":"Islam","year":"2021","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/sj.bjp.0702783","article-title":"Stimulation of bradykinin B2-receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro","volume":"128","author":"Miyamoto","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.cbpc.2007.05.007","article-title":"Vasomotor effects of noradrenaline, acetylcholine, histamine, 5-hydroxytryptamine and bradykinin on snake (Trimeresurus flavoviridis) basilar arteries","volume":"146","author":"Yoshinaga","year":"2007","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.3382\/ps.2011-01945","article-title":"Characterization of 5-hydroxytryptamine-induced contraction and acetylcholine-induced relaxation in isolated chicken basilar artery","volume":"91","author":"Matsumoto","year":"2012","journal-title":"Poult. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1292\/jvms.14-0223","article-title":"Vasomotor effects of acetylcholine, bradykinin, noradrenaline, 5-hydroxytryptamine, histamine and angiotensin II on the mouse basilar artery","volume":"76","author":"Islam","year":"2014","journal-title":"J. Vet. Med. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1292\/jvms.20-0351","article-title":"Vasomotor effects of 5-hydroxytryptamine, histamine, angiotensin II, acetylcholine, noradrenaline, and bradykinin on the cerebral artery of bottlenose dolphin (Tursiops truncatus)","volume":"82","author":"Islam","year":"2020","journal-title":"J. Vet. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Islam, M.Z., Wu, S., Ootawa, T., Smith, H., Nguyen, H.T.T., Harada, E., and Miyamoto, A. (2024). Characteristics of cerebrovascular response to intrinsic vasoactive substances in sika deer (Cervus nippon yesoensis) and the possible effects of gravity on adrenergic responses. Animals, 14.","DOI":"10.3390\/ani14233500"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/0165-6147(91)90630-B","article-title":"Mode of action of the anti-migraine drug sumatriptan","volume":"12","author":"Humphrey","year":"1991","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0140-6736(91)90005-A","article-title":"Migraine pain associated with middle cerebral artery dilation: Reversal by sumatriptan","volume":"338","author":"Friberg","year":"1991","journal-title":"Lancet"},{"key":"ref_34","first-page":"54","article-title":"Receptors involved in the 5-hydroxytryptamine-induced contraction of isolated cerebral arteries","volume":"552","author":"Young","year":"1986","journal-title":"Acta Physiol. Scand. Suppl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1472-8206.2007.00483.x","article-title":"Characterization of the human basilar artery contractile response to 5-HT and triptans","volume":"21","author":"Silva","year":"2007","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1203\/00006450-199811000-00016","article-title":"Responsiveness of human infant cerebral arteries to sympathetic nerve stimulation and vasoactive agents","volume":"44","author":"Bevan","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1476-5381.1989.tb11828.x","article-title":"Characterization of 5-HT receptors mediating contraction of canine and primate basilar artery by use of GR43175, a selective 5-HT1-like receptor agonist","volume":"96","author":"Connor","year":"1989","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","first-page":"356","article-title":"Reactivity of isolated human cerebral arteries to biogenic amines","volume":"14","author":"Shibata","year":"1977","journal-title":"Blood Vessel."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1748-1716.1988.tb08302.x","article-title":"Differential vasomotor action of noradrenaline, serotonin, and histamine in isolated basilar artery from rat and guinea-pig","volume":"132","author":"Chang","year":"1988","journal-title":"Acta Physiol. Scand."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"675","DOI":"10.2176\/nmc.33.675","article-title":"Characteristics of histamine receptors in human cerebral arteries","volume":"33","author":"Takagi","year":"1993","journal-title":"Neurol. Med. Chir."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1111\/j.1476-5381.1988.tb11602.x","article-title":"Characterization of histamine receptors in isolated human cerebral arteries","volume":"94","author":"Ottosson","year":"1988","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.tips.2011.01.003","article-title":"Histamine receptors in the CNS as targets for therapeutic intervention","volume":"32","author":"Passani","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.1991.71.1.1","article-title":"Histaminergic transmission in the mammalian brain","volume":"71","author":"Schwartz","year":"1991","journal-title":"Physiol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.tips.2004.10.003","article-title":"The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders","volume":"25","author":"Passani","year":"2004","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_45","unstructured":"Phillis, J.W. (1993). Effects of bradykinin in the cerebral microcirculation. The Regulation of Cerebral Blood Flow, CRC Press."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/BF00165559","article-title":"Analysis of the mechanism of action of bradykinin on human basilar artery in vitro","volume":"335","author":"Whalley","year":"1987","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1161\/01.HYP.35.6.1314","article-title":"Bradykinin-induced vasodilation of human forearm resistance vessels is primarily mediated by endothelium-dependent hyperpolarization","volume":"35","author":"Honing","year":"2000","journal-title":"Hypertension"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6463","DOI":"10.1113\/JP272450","article-title":"Parasympathetic innervation of vertebrobasilar arteries: Is this a potential clinical target?","volume":"594","author":"Roloff","year":"2016","journal-title":"J. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1046\/j.1468-2982.1985.0504217.x","article-title":"Anti-spasmogenic effects of bencianol (ZY15051) on human cerebral arteries in vitro","volume":"5","author":"Whalley","year":"1985","journal-title":"Cephalalgia"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:36:45Z","timestamp":1784025405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":49,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biology15141146"],"URL":"https:\/\/doi.org\/10.3390\/biology15141146","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}