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However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na+ channels, was shown to stimulate peak and late components of voltage-gated Na+ current (INa). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late INa directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca2+-activated K+ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late INa effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late INa along with a slowing of the inactivation time course of the current. However, telmisartan\u2019s presence can also suppress the erg-mediated K+ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K+ current and the M-type K+ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding.<\/jats:p>","DOI":"10.3390\/ijms241814007","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T21:34:12Z","timestamp":1694554452000},"page":"14007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Investigating the Impact of Selective Modulators on the Renin\u2013Angiotensin\u2013Aldosterone System: Unraveling Their Off-Target Perturbations of Transmembrane Ionic Currents"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-6004","authenticated-orcid":false,"given":"Te-Ling","family":"Lu","sequence":"first","affiliation":[{"name":"School of Pharmacy, China Medical University, Taichung 406040, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Research and Education, An Nan Hospital, China Medical University, Tainan 709040, Taiwan"},{"name":"School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.1532-5415.1989.tb02245.x","article-title":"The renin-angiotensin system. 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