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Pharmacol."],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:p> Hypotensive influences of benzodiazepines and other GABA<jats:sub>A<\/jats:sub> receptor ligands, recognized in clinical practice, seem to stem from the existence of \u201cvascular\u201d GABA<jats:sub>A<\/jats:sub> receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABA<jats:sub>A<\/jats:sub> receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABA<jats:sub>A<\/jats:sub> \u03b32 and \u03b11-5 subunit proteins. To confirm the role of \u201cvascular\u201d GABA<jats:sub>A<\/jats:sub> receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for \u03b15\u03b23\u03b32 over other \u03b1 x\u03b23\u03b32 GABA<jats:sub>A<\/jats:sub> receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100\u00a0\u00b5mol\/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABA<jats:sub>A<\/jats:sub> receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators. <\/jats:p>","DOI":"10.1139\/cjpp-2023-0285","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:00:56Z","timestamp":1698822056000},"page":"206-217","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta"],"prefix":"10.1139","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8433-7808","authenticated-orcid":false,"given":"Milica Gaji\u0107","family":"Boji\u0107","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Center for Biomedical Research, University of Banja Luka","place":["Banja Luka, Bosnia and Herzegovina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Treven","sequence":"additional","affiliation":[{"name":"Neurology Department, Medical University of Vienna","place":["Vienna, Austria"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal P.","family":"Pandey","sequence":"additional","affiliation":[{"name":"Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee","place":["Milwaukee, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.V.N. 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