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An exaggerated arterial blood pressure (BP) response during exercise is associated with an elevated risk of cardiovascular events in individuals with PAD. However, the precise mechanisms leading to this exaggerated BP response are poorly elucidated. The P2X<jats:sub>3<\/jats:sub> signalling pathway, which plays a key role in modifying the exercise pressor reflex (EPR), is the focus of the present study. We determined the regulatory role of P2X<jats:sub>3<\/jats:sub> on the EPR in a rat model of hindlimb IR. In vivo and in vitro approaches were used to determine the expression and functions of P2X<jats:sub>3<\/jats:sub> in muscle afferent nerves and EPR in IR rats. We found that in IR rats there was (1) upregulation of P2X<jats:sub>3<\/jats:sub> protein expression in the L4\u20136 dorsal root ganglia (DRG); (2) amplified P2X currents in isolated isolectin B4 (IB4)\u2010positive muscle DRG neurons; and (3) amplification of the P2X\u2010mediated BP response. We further verified that both A\u2010317491 and siRNA knockdown of P2X<jats:sub>3<\/jats:sub> significantly decreased the activity of P2X currents in isolated muscle DRG neurons. Moreover, inhibition of muscle afferents\u2019 P2X<jats:sub>3<\/jats:sub> receptor using A\u2010317491 was observed to alleviate the exaggerated BP response induced by static muscle contraction and P2X\u2010induced BP response by \u03b1,\u03b2\u2010methylene ATP injection. P2X<jats:sub>3<\/jats:sub> signalling pathway activity is amplified in muscle afferent DRG neurons in regulating the EPR following hindlimb IR.<\/jats:p>","DOI":"10.1113\/ep091616","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T07:06:17Z","timestamp":1705043177000},"page":"524-534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Amplified P2X<sub>3<\/sub> pathway activity in muscle afferent dorsal root ganglion neurons and exercise pressor reflex regulation in hindlimb ischaemia\u2013reperfusion"],"prefix":"10.1113","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7305-0568","authenticated-orcid":false,"given":"Lu","family":"Qin","sequence":"first","affiliation":[{"name":"Heart and Vascular Institute Penn State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Li","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute Penn State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-3983","authenticated-orcid":false,"given":"Jianhua","family":"Li","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute Penn State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00576.2012"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/000331979905000502"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00317.2001"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00661"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/377428a0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/387505a0"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199707000-00005"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2008.05.032"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.1800811211"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2019.12.005"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1972.sp009979"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1999.00426.x"},{"key":"e_1_2_10_14_1","first-page":"739","article-title":"Arterial embolism with acute massive ischemic myopathy and myoglobinuria: Evaluation of a hitherto unreported syndrome with report of two cases","volume":"47","author":"Haimovici H.","year":"1960","journal-title":"Surgery"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00630.2014"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.1.6"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4377-2930-6.00017-3"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305715"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.252537299"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1984.57.3.644"},{"key":"e_1_2_10_21_1","first-page":"244","article-title":"Increased activity of oxygen free radicals during reperfusion in patients with peripheral arterial disease undergoing percutaneous peripheral artery balloon angioplasty","volume":"10","author":"Lau C. 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