{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:47:24Z","timestamp":1791193644907,"version":"4.1.0"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,6,12]]},"abstract":"<jats:p>\n                    Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and \u03b1-2 adrenoceptors (\u03b1-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and \u03b1-2 adrenoceptors, partly inhibited\n                    <jats:sc>l<\/jats:sc>\n                    -arginine-initiated NO formation as measured by a Griess reaction. Rauwolscine, a highly specific antagonist of \u03b1-2 AR, at very low concentrations completely inhibited NO formation. Like\n                    <jats:sc>l<\/jats:sc>\n                    -arginine, agmatine (decarboxylated arginine) also activated NO synthesis, however, at much lower concentrations. We found that dexmedetomidine, a specific agonist of \u03b1-2 AR was very potent in activating cellular NO, thus indicating a possible role for \u03b1-2 AR in\n                    <jats:sc>l<\/jats:sc>\n                    -arginine-mediated NO synthesis.\n                    <jats:sc>d<\/jats:sc>\n                    -arginine also activated NO production and could be inhibited by imidazoline and \u03b1-2 AR antagonists, thus indicating nonsubstrate actions of arginine. Pertussis toxin, an inhibitor of G proteins, attenuated\n                    <jats:sc>l<\/jats:sc>\n                    -arginine-mediated NO synthesis, thus indicating mediation via G proteins.\n                    <jats:sc>l<\/jats:sc>\n                    -type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel blocker nifedipine and phospholipase C inhibitor U73122 inhibited NO formation and thus implicated participation of a second messenger pathway. Finally, in isolated rat gracilis vessels, rauwolscine completely inhibited the\n                    <jats:sc>l<\/jats:sc>\n                    -arginine-initiated vessel relaxation. Taken together, these data provide evidence for binding of arginine to membrane receptor(s), leading to the activation of endothelial NO synthase (eNOS) NO production through a second messenger pathway. These findings provide a previously unrecognized mechanistic explanation for the beneficial effects of\n                    <jats:sc>l<\/jats:sc>\n                    -arginine in the cardiovascular system and thus provide new potential avenues for therapeutic development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0506824104","type":"journal-article","created":{"date-parts":[[2007,5,29]],"date-time":"2007-05-29T21:34:08Z","timestamp":1180474448000},"page":"9982-9987","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells"],"prefix":"10.1073","volume":"104","author":[{"given":"Mahesh S.","family":"Joshi","sequence":"first","affiliation":[{"name":"Departments of *Surgery and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"T. Bruce","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Departments of *Surgery and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fruzsina K.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sampath","family":"Parthasarathy","sequence":"additional","affiliation":[{"name":"Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Jack R.","family":"Lancaster","sequence":"additional","affiliation":[{"name":"Departments of Anesthesiology, Physiology, and Biophysics and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35487"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,6,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.23.10480"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.23.6.1121"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)01686-0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.13.6448"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.41.25437"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(01)00781-X"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.50.31213"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.67.6.1301"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.83.3.1057"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1998.00803.x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5273(02)00413-8"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(97)00183-4"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2001.01521.x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1291\/hypres.25.197"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(95)00226-V"},{"key":"e_1_3_4_16_2","first-page":"51","volume":"109","author":"Morrissey JJ","year":"1997","unstructured":"JJ Morrissey, S Klahr Proc Assoc Am Phys 109, 51\u201357 (1997).","journal-title":"Proc Assoc Am Phys"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706682"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7906055"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1995.tb32416.x"},{"key":"e_1_3_4_20_2","first-page":"2355","volume":"45","author":"Angus JA","year":"1986","unstructured":"JA Angus, TM Cocks, K Satoh Fed Proc 45, 2355\u20132359 (1986).","journal-title":"Fed Proc"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00504374"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1995.tb32453.x"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.70.5.1018"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1989.sp017475"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(87)90166-X"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2140273"},{"key":"e_1_3_4_27_2","first-page":"94","volume":"336","author":"Des RC","year":"1987","unstructured":"RC Des, S Nees Naunyn Schmiedebergs Arch Pharmacol 336, 94\u201398 (1987).","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199605000-00017"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1685"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs0810695"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1996.144277.x"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0922-4106(93)90068-K"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)91561-4"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.93.1.85"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs0870303"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1992.tb00514.x"},{"key":"e_1_3_4_37_2","first-page":"1235","volume":"278","author":"Bockman CS","year":"1996","unstructured":"CS Bockman, I Gonzalez-Cabrera, PW Abel J Pharmacol Exp Ther 278, 1235\u20131243 (1996).","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_4_38_2","first-page":"1272","volume":"276","author":"Regunathan S","year":"1996","unstructured":"S Regunathan, C Youngson, W Raasch, H Wang, DJ Reis J Pharmacol Exp Ther 276, 1272\u20131282 (1996).","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.33549\/physiolres.930000.49.115","volume":"49","author":"Kysela S","year":"2000","unstructured":"S Kysela, J Torok Physiol Res 49, 115\u2013122 (2000).","journal-title":"Physiol Res"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1994.tb09820.x"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)36547-0"},{"key":"e_1_3_4_42_2","first-page":"124","volume":"268","author":"Feletou M","year":"1994","unstructured":"M Feletou, O Dellazuana, J Duhault J Pharmacol Exp Ther 268, 124\u2013132 (1994).","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1990.tb16880.x"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-004-1589-y"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.FPJ03036X"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1358\/dnp.2004.17.6.829028"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(94)05489-6"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/362801a0"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.1994.tb01081.x"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.83.2.652"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.83.3.1057"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1006\/niox.1997.0116"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1080\/10715760000300011"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103702200"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10131"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00624.2002"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0506824104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T14:14:46Z","timestamp":1737036886000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0506824104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6,12]]},"references-count":56,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2007,6,12]]}},"alternative-id":["10.1073\/pnas.0506824104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0506824104","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,6,12]]},"assertion":[{"value":"2005-08-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}