{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T11:25:19Z","timestamp":1769426719752,"version":"3.49.0"},"reference-count":91,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association (AHA)","doi-asserted-by":"publisher","award":["15PRE25090219"],"award-info":[{"award-number":["15PRE25090219"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2018,4,1]]},"abstract":"<jats:p>DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional \u03b1<jats:sub>2<\/jats:sub>-adrenergic receptors (\u03b1<jats:sub>2<\/jats:sub>ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca<jats:sup>2+<\/jats:sup>channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired \u03b1<jats:sub>2<\/jats:sub>AR signaling; however, the mechanisms involved are unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages impair \u03b1<jats:sub>2<\/jats:sub>AR-mediated inhibition of Ca<jats:sup>2+<\/jats:sup>channels in SMCG neurons from DOCA-salt and high-fat diet (HFD)-induced hypertensive rats. Whole cell patch-clamp methods were used to record Ca<jats:sup>2+<\/jats:sup>currents from SMCG neurons maintained in primary culture. We found that DOCA-salt, but not HFD-induced, hypertension caused macrophage accumulation in mesenteric arteries, increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-\u03b1, and impaired \u03b1<jats:sub>2<\/jats:sub>AR-mediated inhibition of Ca<jats:sup>2+<\/jats:sup>currents in SMCG neurons. \u03b1<jats:sub>2<\/jats:sub>AR dysfunction did not involve changes in \u03b1<jats:sub>2<\/jats:sub>AR expression, desensitization, or downstream signaling factors. Oxidative stress impaired \u03b1<jats:sub>2<\/jats:sub>AR-mediated inhibition of Ca<jats:sup>2+<\/jats:sup>currents in SMCG neurons and resulted in receptor internalization in human embryonic kidney-293T cells. Systemic clodronate-induced macrophage depletion preserved \u03b1<jats:sub>2<\/jats:sub>AR function and lowered blood pressure in DOCA-salt rats. HFD caused hypertension without obesity in Sprague-Dawley rats and hypertension with obesity in Dahl salt-sensitive rats. HFD-induced hypertension was not associated with inflammation in SMCG and mesenteric arteries or \u03b1<jats:sub>2<\/jats:sub>AR dysfunction in SMCG neurons. These results suggest that macrophage-mediated \u03b1<jats:sub>2<\/jats:sub>AR dysfunction in the mesenteric circulation may only be relevant to mineralocorticoid-salt excess.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY Here, we identify a contribution of macrophages to hypertension development through impaired \u03b1<jats:sub>2<\/jats:sub>-adrenergic receptor (\u03b1<jats:sub>2<\/jats:sub>AR)-mediated inhibition of sympathetic nerve terminal Ca<jats:sup>2+<\/jats:sup>channels in DOCA-salt hypertensive rats. Impaired \u03b1<jats:sub>2<\/jats:sub>AR function may involve oxidative stress-induced receptor internalization. \u03b1<jats:sub>2<\/jats:sub>AR dysfunction may be unique to mineralocorticoid-salt excess, as it does not occur in obesity-related hypertension.<\/jats:p>","DOI":"10.1152\/ajpheart.00536.2017","type":"journal-article","created":{"date-parts":[[2018,1,6]],"date-time":"2018-01-06T14:45:54Z","timestamp":1515249954000},"page":"H863-H877","source":"Crossref","is-referenced-by-count":17,"title":["Macrophage-dependent impairment of \u03b1<sub>2<\/sub>-adrenergic autoreceptor inhibition of Ca<sup>2+<\/sup>channels in sympathetic neurons from DOCA-salt but not high-fat diet-induced hypertensive rats"],"prefix":"10.1152","volume":"314","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-0993","authenticated-orcid":false,"given":"Ryan K.","family":"Mui","sequence":"first","affiliation":[{"name":"Department of Physiology, Michigan State University, East Lansing, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxanne N.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah G.","family":"Garver","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nico","family":"Van Rooijen","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James J.","family":"Galligan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan"},{"name":"Neuroscience Program, Michigan State University, East Lansing, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1159\/000443885"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.08.018"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142883"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.07850"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00929.x"},{"key":"B6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0022-3565(24)39104-9","volume":"294","author":"Brink CB","year":"2000","journal-title":"J Pharmacol Exp Ther"},{"key":"B7","first-page":"285","volume":"5","author":"Burns DL","year":"1988","journal-title":"Microbiol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.36.3.360"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.201251"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00059-014-4072-7"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M500294-JLR200"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5258"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00052.2005"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2877"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2010.03.061"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.108.110353"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/406960"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.4.1009"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2337\/diab.46.12.2040"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.23.11178"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-7061(00)00225-9"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.1.464"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.00474"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.182923"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.091009"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfm409"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.08.010"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.303604"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.1.38"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00672"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2016.02.044"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119532"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/46040"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-200204000-00010"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/380255a0"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.6.H1928"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000126924.23467.A3"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0864"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2174\/157340310793566109"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00086.2011"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-200306000-00019"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.090696"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.23.1_Suppl.I16"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1291\/hypres.31.2075"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.1.9"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-199816030-00006"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104651"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.21.6.916"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-015-0118-6"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2009.11.00"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-013-0356-1"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2011.0177"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00592.2003"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nm1553"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/0895-7061(94)00211-S"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1080\/10641960902825487"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.824730"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64857-2"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000022880.45113.C9"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0860"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.134338"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2008.05.020"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-200205000-00031"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.18.5129"},{"key":"B65","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1038\/nm.4422","volume":"23","author":"Pirzgalska RM","year":"2017","journal-title":"Nat Med"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2006.05.015"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2014.11.013"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118623"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.18.5.630"},{"key":"B70","doi-asserted-by":"crossref","first-page":"3894","DOI":"10.1016\/S0021-9258(17)35731-9","volume":"261","author":"Regan JW","year":"1986","journal-title":"J Biol Chem"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01096.2001"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2010.264"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.215525"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4103\/2230-8210.100665"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/1056-8719(92)90036-Z"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.187021"},{"key":"B77","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0022-3565(24)36765-5","volume":"282","author":"Schwartz DD","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"B78","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.4049\/jimmunol.145.5.1430","volume":"145","author":"Spengler RN","year":"1990","journal-title":"J Immunol"},{"key":"B79","first-page":"64","volume":"62","author":"Stadtman ER","year":"1992","journal-title":"EXS"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64454-9"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00283.2015"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(94)90012-4"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000034738.79310.06"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.160671"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0306-8"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1042\/bj3210721"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-212"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03777"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.81.1.1"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2008.046334"},{"key":"B91","first-page":"1632","volume":"34","author":"Zhang Q","year":"2014","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00536.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T12:07:50Z","timestamp":1751198870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00536.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,1]]},"references-count":91,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,4,1]]}},"alternative-id":["10.1152\/ajpheart.00536.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00536.2017","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,1]]}}}