{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:24:36Z","timestamp":1784827476468,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,23]],"date-time":"2019-08-23T00:00:00Z","timestamp":1566518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The aim of this study was to investigate the hemodynamic effects of SKA-31, an activator of the small (KCa2.x) and intermediate (KCa3.1) conductance calcium-activated potassium channels, and to evaluate its influence on endothelium-derived hyperpolarization (EDH)-KCa2.3\/KCa3.1 type relaxation in isolated endothelium-intact small mesenteric arteries (sMAs) from spontaneously hypertensive rats (SHRs). Functional in vivo and in vitro experiments were performed on SHRs or their normotensive controls, Wistar-Kyoto rats (WKY). SKA-31 (1, 3 and 10 mg\/kg) caused a brief decrease in blood pressure and bradycardia in both SHR and WKY rats. In phenylephrine-pre-constricted sMAs of SHRs, SKA-31 (0.01\u201310 \u00b5M)-mediated relaxation was reduced and SKA-31 potentiated acetylcholine-evoked endothelium-dependent relaxation. Endothelium denudation and inhibition of nitric oxide synthase (eNOS) and cyclooxygenase (COX) by the respective inhibitors l-NAME or indomethacin, attenuated SKA-31-mediated vasorelaxation. The inhibition of KCa3.1, KCa2.3, KIR and Na+\/K+-ATPase by TRAM-34, UCL1684, Ba2+ and ouabain, respectively, reduced the potency and efficacy of the EDH-response evoked by SKA-31. The mRNA expression of eNOS, prostacyclin synthase, KCa2.3, KCa3.1 and KIR were decreased, while Na+\/K+-ATPase expression was increased. Collectively, SKA-31 promoted hypotension and vasodilatation, potentiated agonist-stimulated vasodilation, and maintained KCa2.3\/KCa3.1-EDH-response in sMAs of SHR with downstream signaling that involved KIR and Na+\/K+-ATPase channels. In view of the importance of the dysfunction of endothelium-mediated vasodilatation in the mechanism of hypertension, application of activators of KCa2.3\/KCa3.1 channels such as SKA-31 seem to be a promising avenue in pharmacotherapy of hypertension.<\/jats:p>","DOI":"10.3390\/ijms20174118","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T04:38:23Z","timestamp":1566794303000},"page":"4118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Modulation of Cardiovascular Function in Primary Hypertension in Rat by SKA-31, an Activator of KCa2.x and KCa3.1 Channels"],"prefix":"10.3390","volume":"20","author":[{"given":"Monika","family":"Kloza","sequence":"first","affiliation":[{"name":"Department of Experimental Physiology and Pathophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Baranowska-Kuczko","sequence":"additional","affiliation":[{"name":"Department of Experimental Physiology and Pathophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"},{"name":"Department of Clinical Pharmacy, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Toczek","sequence":"additional","affiliation":[{"name":"Department of Experimental Physiology and Pathophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Kusaczuk","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biochemistry, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Sadowska","sequence":"additional","affiliation":[{"name":"Department of Experimental Physiology and Pathophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2954-942X","authenticated-orcid":false,"given":"Irena","family":"Kasacka","sequence":"additional","affiliation":[{"name":"Department of Histology and Cytophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Koz\u0142owska","sequence":"additional","affiliation":[{"name":"Department of Experimental Physiology and Pathophysiology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/apha.12628","article-title":"Endothelium-dependent hyperpolarization: Age, gender and blood pressure, do they matter?","volume":"219","author":"Leung","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/apha.12649","article-title":"EDH: Endothelium-dependent hyperpolarization and microvascular signaling","volume":"219","author":"Garland","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1139\/y2012-075","article-title":"Endothelial calcium-activated potassium channels as therapeutic targets to enhance availability of nitric oxide","volume":"90","author":"Kerr","year":"2012","journal-title":"Can. 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