{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:42:38Z","timestamp":1785519758910,"version":"3.56.0"},"reference-count":23,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T00:00:00Z","timestamp":1682985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Helga J\u00f3nsd\u00f3ttir and Sigurlidi Kristj\u00e1nsson Memorial Fund"},{"name":"University of Iceland Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It has been demonstrated previously that a variety of carbonic anhydrase inhibitors (CAIs) can induce vasodilation in pre-contracted retinal arteriolar segments although with different efficacy and potency. Since the CAIs tested so far are able to permeate cell membranes and inhibit both intracellular and extracellular isoforms of the enzyme, it is not clear whether extra- or intracellular isoforms or mechanisms are mediating their vasodilatory effects. By means of small wire myography, we have tested the effects of four new CAIs on wall tension in pre-contracted retinal arteriolar segments that demonstrably do not enter cell membranes but have high affinity to both cytosolic and membrane-bound isoforms of CA. At concentrations between 10\u22126 M to 10\u22123 M, none of the four membrane impermeant CAIs had any significant effect on arteriolar wall tension, while the membrane permeant CAI benzolamide (10\u22123 M) fully dilated all arteriolar segments tested. This suggests that CAI act as vasodilators through cellular mechanisms located in the cytoplasm of vascular cells.<\/jats:p>","DOI":"10.3390\/ijms24098140","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T01:36:38Z","timestamp":1683077798000},"page":"8140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Membrane Permeability Is Required for the Vasodilatory Effect of Carbonic Anhydrase Inhibitors in Porcine Retinal Arteries"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-5854","authenticated-orcid":false,"given":"Thor","family":"Eysteinsson","sequence":"first","affiliation":[{"name":"Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland, IS101 Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8137-1513","authenticated-orcid":false,"given":"Andrea","family":"Garc\u00eda-Llorca","sequence":"additional","affiliation":[{"name":"Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland, IS101 Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnar Oessur","family":"Hardarson","sequence":"additional","affiliation":[{"name":"Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland, IS101 Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Vullo","sequence":"additional","affiliation":[{"name":"Sezione di Scienze Farmaceutiche e Nutraceutiche, Neurofarba Department, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1141-6146","authenticated-orcid":false,"given":"Fabrizio","family":"Carta","sequence":"additional","affiliation":[{"name":"Sezione di Scienze Farmaceutiche e Nutraceutiche, Neurofarba Department, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Sezione di Scienze Farmaceutiche e Nutraceutiche, Neurofarba Department, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,2]]},"reference":[{"key":"ref_1","first-page":"349","article-title":"Glaucoma and the applications of carbonic anhydrase inhibitors","volume":"75","author":"Scozzafava","year":"2014","journal-title":"Carbon. Anhydrase"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1136\/bjophthalmol-2021-319530","article-title":"Topical carbonic anhydrase inhibitors and glaucoma in 2021: Where do we stand?","volume":"106","author":"Stoner","year":"2022","journal-title":"Br. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.preteyeres.2004.09.001","article-title":"Optic nerve oxygenation","volume":"24","author":"Stefansson","year":"2005","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.exer.2003.11.010","article-title":"Dorzolamide induces vasodilatation in isolated pre-contracted bovine retinal arteries","volume":"78","author":"Josefsson","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Eysteinsson, T., Gudmundsdottir, H., Hardarson, A.O., Berrino, E., Selleri, S., Supuran, C.T., and Carta, F. (2019). Carbonic Anhydrase Inhibitors of Different Structures Dilate Pre-Contracted Porcine Retinal Arteries. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030467"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1080\/02713683.2022.2126861","article-title":"Vasodilation of Pre-contracted Porcine Retinal Arteries by Carbonic Anhydrase Inhibitors with Enhanced Lipophilicity","volume":"47","author":"Eysteinsson","year":"2022","journal-title":"Curr. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.preteyeres.2008.02.002","article-title":"Regulation of retinal blood flow in health and disease","volume":"27","author":"Pournaras","year":"2008","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.preteyeres.2012.04.004","article-title":"Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease","volume":"31","author":"Kur","year":"2012","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1254\/jphs.13R03CP","article-title":"Neurovascular interactions in the retina: Physiological and pathological roles","volume":"123","author":"Nakahara","year":"2013","journal-title":"J. Pharmacol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1042\/CS20210040","article-title":"Emerging role of carbonic anhydrase inhibitors","volume":"135","author":"Supuran","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1167\/iovs.08-2435","article-title":"The vasodilating effect of acetazolamide and dorzolamide involves mechanisms other than carbonic anhydrase inhibition","volume":"50","author":"Torring","year":"2009","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.exer.2014.09.006","article-title":"Dorzolamide-induced relaxation of porcine retinal arterioles in vitro depends on nitric oxide but not on acidosis in vascular smooth muscle cells","volume":"128","author":"Aalkjaer","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1600-0420.2006.00709.x","article-title":"Optic nerve pH and PO2: The effects of carbonic anhydrase inhibition, and metabolic and respiratory acidosis","volume":"84","author":"Pedersen","year":"2006","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"L178","DOI":"10.1152\/ajplung.00205.2006","article-title":"Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition","volume":"292","author":"Hohne","year":"2007","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1080\/14756360410001689559","article-title":"Benzolamide is not a membrane-impermeant carbonic anhydrase inhibitor","volume":"19","author":"Supuran","year":"2004","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6661","DOI":"10.1113\/JP272533","article-title":"Sources of protons and a role for bicarbonate in inhibitory feedback from horizontal cells to cones in Ambystoma tigrinum retina","volume":"594","author":"Warren","year":"2016","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5973","DOI":"10.1016\/j.bmc.2013.07.044","article-title":"Carbonic anhydrase inhibitors: Synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety","volume":"19","author":"Sethi","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ejmech.2016.10.037","article-title":"New approach of delivering cytotoxic drugs towards CAIX expressing cells: A concept of dual-target drugs","volume":"127","author":"Parvathaneni","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/S0021-9258(18)62326-9","article-title":"The Carbon Dioxide Hydration Activity of Carbonic Anhydrase. I. Stop-Flow Kinetic Studies on the Native Human Isoenzymes B and C","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1021\/cr200176r","article-title":"Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms?","volume":"112","author":"Alterio","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1080\/17460441.2020.1743676","article-title":"Exploring the multiple binding modes of inhibitors to carbonic anhydrases for novel drug discovery","volume":"15","author":"Supuran","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1039\/C4CC07320G","article-title":"Out of the active site binding pocket for carbonic anhydrase inhibitors","volume":"51","author":"Carradori","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gungor, O., and Kose, M. (2022). Design, synthesis, biological evaluation and molecular docking of cyclic biguanidine compounds as cholinesterase inhibitors. J. Biomol. Struct. Dyn., 1\u201315.","DOI":"10.1080\/07391102.2022.2158945"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8140\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:28:10Z","timestamp":1760124490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8140"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,2]]},"references-count":23,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24098140"],"URL":"https:\/\/doi.org\/10.3390\/ijms24098140","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,2]]}}}