{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T18:28:24Z","timestamp":1776450504506,"version":"3.51.2"},"reference-count":37,"publisher":"Institute of Physiology of the Czech Academy of Sciences","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:p>The incidence of cerebrovascular diseases increases significantly with aging. This study aimed to test the hypothesis that aging may influence the protein kinase A (PKA)-dependent vasodilation via RyR\/BKCa pathway in the middle cerebral arteries (MCA). Male Sprague-Dawley rats were randomly divided into control (4-6 month-old) and aged (24-month-old) groups. The functions of MCA and ion channel activities in smooth muscle cells were examined using myograph system and patch-clamp. Aging decreased the isoproterenol\/forskolin-induced relaxation in the MCA. Large-conductance Ca2+-activated-K+ (BKCa) channel inhibitor, iberiotoxin,  significantly attenuated the forskolin-induced vasodilatation and hyperpolarization in the young group, but not in the aged group. The amplitude and frequency of spontaneous transient outward currents (STOCs) were significantly decreased in the aged group. Single channel recording revealed that the mean open time of BKCa channels were decreased, while an increased mean closed time of BKCa channels were found in the aged group. The Ca2+\/voltage sensitivity of the channels was decreased accompanied by reduced BKCa \u03b1 and \u03b21-subunit, the expression of RyR2, PKA-C\u03b1 and PKA-C\u03b2 subunits were also declined in the aged group. Aging induced down-regulation of PKA\/BKCa pathway in cerebral artery in rats. The results provides new information on further understanding in cerebrovascular diseases resulted from age-related cerebral vascular dysfunction.<\/jats:p>","DOI":"10.33549\/physiolres.934944","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T18:23:18Z","timestamp":1671474198000},"page":"811-823","source":"Crossref","is-referenced-by-count":7,"title":["Aging-induced down-regulation of Pka\/Bkca pathway in rat cerebral arteries"],"prefix":"10.33549","volume":"71","author":[{"given":"N","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute for Fetology, First Hospital of Soochow University, Suzhou, Jiangsu 215006, P. 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Eur Neurol. 2015;73(3-4):150-157. https:\/\/doi.org\/10.1159\/000367652","DOI":"10.1159\/000367652"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Kalaria RN. The role of cerebral ischemia in Alzheimer's disease. Neurobiol Aging. 2000;21(2):321-330. https:\/\/doi.org\/10.1016\/S0197-4580(00)00125-1","DOI":"10.1016\/S0197-4580(00)00125-1"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Nagata K, Yamazaki T, Takano D, Maeda T, Fujimaki Y, Nakase T, Sato Y. Cerebral circulation in aging. Ageing Res Rev. 2016;30:49-60. https:\/\/doi.org\/10.1016\/j.arr.2016.06.001","DOI":"10.1016\/j.arr.2016.06.001"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Toro L, Marijic J, Nishimaru K, Tanaka Y, Song M, Stefani E. Aging, ion channel expression, and vascular function. Vascul Pharmacol. 2002;38(1):73-80. https:\/\/doi.org\/10.1016\/S0306-3623(02)00128-3","DOI":"10.1016\/s0306-3623(02)00128-3"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res. 1990;66(1):8-17. https:\/\/doi.org\/10.1161\/01.RES.66.1.8","DOI":"10.1161\/01.res.66.1.8"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Foulquier S, Lartaud I, Dupuis F. Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR. PLoS One. 2014;9(10):e110766. https:\/\/doi.org\/10.1371\/journal.pone.0110766","DOI":"10.1371\/journal.pone.0110766"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Hu XQ, Zhang L. Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells. 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Br J Pharmacol. 2013;169(2):413-425. https:\/\/doi.org\/10.1111\/bph.12121","DOI":"10.1111\/bph.12121"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Zhang L, Bonev AD, Mawe GM, Nelson MT. Protein kinase A mediates activation of ATP-sensitive K+ currents by CGRP in gallbladder smooth muscle. Am J Physiol. 1994;267(3 Pt 1):G494-G499. https:\/\/doi.org\/10.1152\/ajpgi.1994.267.3.G494","DOI":"10.1152\/ajpgi.1994.267.3.g494"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Cole WC, Cl\u00e9ment-Chomienne O, Aiello EA. Regulation of 4-aminopyridine-sensitive, delayed rectifier K+ channels in vascular smooth muscle by phosphorylation. Biochem Cell Biol. 1996;74(4):439-447. https:\/\/doi.org\/10.1139\/o96-048","DOI":"10.1139\/o96-048"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Fan G, Cui Y, Gollasch M, Kassmann M. Elementary calcium signaling in arterial smooth muscle. Channels (Austin). 2019;13(1):505-519. https:\/\/doi.org\/10.1080\/19336950.2019.1688910","DOI":"10.1080\/19336950.2019.1688910"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Szteyn K, Singh H. BKCa Channels as Targets for Cardioprotection. Antioxidants (Basel). 2020;9(8):760. Published 2020 Aug 17. https:\/\/doi.org\/10.3390\/antiox9080760","DOI":"10.3390\/antiox9080760"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Nishimaru K, Eghbali M, Lu R, Marijic J, Stefani E, Toro L. Functional and molecular evidence of MaxiK channel beta1 subunit decrease with coronary artery ageing in the rat. J Physiol. 2004;559(Pt 3):849-862. https:\/\/doi.org\/10.1113\/jphysiol.2004.068676","DOI":"10.1113\/jphysiol.2004.068676"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Reed JT, Pareek T, Sriramula S, Pabbidi MR. Aging influences cerebrovascular myogenic reactivity and BK channel function in a sex-specific manner. 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