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APETx2 (an ASIC3 antagonist) was arterially injected into the hindlimb before static muscle contraction. The mean arterial pressure (MAP) and heart rate (HR) were recorded. ASIC3\u2010mediated MAP response was studied via intra\u2010arterially injected lactic acid (LA). Western blot and immunofluorescence were used to determine the ASIC3 expression and location in L4\u20136 dorsal root ganglion (DRG). Calcium imaging was applied to detect pH6.7\u2010induced Ca<jats:sup>2+<\/jats:sup> entry in the isolated muscle DRG neurons. IR amplified the peak MAP response to muscle contraction (sham vs. IR: <jats:italic>p<\/jats:italic>\u2009=\u20090.031), which was reduced by the blockage of ASIC3 with APETx2 (baseline vs. blockage: <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). The peak MAP responses to LA were increased in IR rats (sham vs. IR, 1\u2009\u03bcmol\/kg: <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; 2 and 4\u2009\u03bcmol\/kg: sham vs. IR, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and were reduced by APETx2 (baseline LA control vs. blockage: <jats:italic>p<\/jats:italic>\u2009=\u20090.013). ASIC3 protein expression was increased in IR L4\u20106 DRGs (sham vs. IR, <jats:italic>p<\/jats:italic>\u2009=\u20090.012). APETx2 attenuated the pH\u20096.7\u2010induced Ca<jats:sup>2+<\/jats:sup> entry (\u0394F340\/F380: sham vs. IR, <jats:italic>p<\/jats:italic>\u2009=\u20090.017; IR vs. IR\u2009+\u2009APETx2, <jats:italic>p<\/jats:italic>\u2009=\u20090.003). Increased ASIC3 signaling amplifies muscle afferent activity and exacerbates the EPR following IR.<\/jats:p>","DOI":"10.14814\/phy2.70457","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T06:55:01Z","timestamp":1752130501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Muscle afferent <scp>ASIC3<\/scp> upregulation mediates the exacerbated exercise pressor reflex in male rats following hindlimb ischemia\u2013reperfusion"],"prefix":"10.14814","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7305-0568","authenticated-orcid":false,"given":"Lu","family":"Qin","sequence":"first","affiliation":[{"name":"Heart and Vascular Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuexin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-3983","authenticated-orcid":false,"given":"Jianhua","family":"Li","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-6175.2004.03683.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318261"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313236"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01093.2016"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00274.2022"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpb.2019.110387"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.186247"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2023.04.033"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00565.2019"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12576-011-0172-9"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.14851"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/000331979905000404"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2235"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1972.32.3.304"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/35053509"},{"key":"e_1_2_9_17_1","first-page":"381","volume-title":"Handbook of physiology\u2014section\u00a012, exercise: Regulation and integration of multiple systems","author":"Kaufman M. 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