{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:17:05Z","timestamp":1791346625084,"version":"4.3.1"},"reference-count":45,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:p>In sickle cell disease, nitric oxide (NO) depletion by cell-free plasma hemoglobin and\/or oxygen radicals is associated with arginine deficiency, impaired NO bioavailability, and chronic oxidative stress. In transgenic-knockout sickle (BERK) mice that express exclusively human \u03b1- and \u03b2<jats:sup>S<\/jats:sup>-globins, reduced NO bioavailability is associated with induction of non-NO vasodilator enzyme, cyclooxygenase (COX)-2, and impaired NO-mediated vascular reactivity. We hypothesized that enhanced NO bioavailability in sickle mice will abate activity of non-NO vasodilators, improve vascular reactivity, decrease hemolysis, and reduce oxidative stress. Arginine treatment of BERK mice (5% arginine in mouse chow for 15 days) significantly reduced expression of non-NO vasodilators COX-2 and heme oxygenase-1. The decreased COX-2 expression resulted in reduced prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>) levels. The reduced expression of non-NO vasodilators was associated with significantly decreased arteriolar dilation and markedly improved NO-mediated vascular reactivity. Arginine markedly decreased hemolysis and oxidative stress and enhanced NO bioavailability. Importantly, arteriolar diameter response to a NO donor (sodium nitroprusside) was strongly correlated with hemolytic rate (and nitrotyrosine formation), suggesting that the improved microvascular function was a response to reduced hemolysis. These results provide a strong rationale for therapeutic use of arginine in sickle cell disease and other hemolytic diseases.<\/jats:p>","DOI":"10.1152\/ajpheart.00162.2008","type":"journal-article","created":{"date-parts":[[2008,5,4]],"date-time":"2008-05-04T02:05:55Z","timestamp":1209866755000},"page":"H39-H47","source":"Crossref","is-referenced-by-count":67,"title":["Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress"],"prefix":"10.1152","volume":"295","author":[{"given":"Dhananjay K.","family":"Kaul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Dasgupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Fabry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221292098"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/0026-2862(73)90054-X"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.6.1584"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118537"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.08.025"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2006.03.008"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.10387"},{"key":"R8","unstructured":"Enwonwu CO.Increased metabolic demand for arginine in sickle cell anemia.Med Sci Res17: 997\u2013998, 1989."},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.2.410"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Gladwin MT, Kato GJ.Cardiopulmonary complications of sickle cell disease: role of nitric oxide and hemolytic anemia.Hematology Am Soc Hematol Educ Program51\u201357, 2005.","DOI":"10.1182\/asheducation-2005.1.51"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000044943.12533.A8"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA.Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis.Blood92: 2551\u20132555, 1998.","DOI":"10.1182\/blood.V92.7.2551"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110724"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1080\/10739680490278402"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(03)00441-6"},{"key":"R16","doi-asserted-by":"crossref","unstructured":"Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, Schimel DM, Cochard AE, Wang X, Schechter AN, Noguchi CT, Gladwin MT.Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability.Blood109: 3088\u20133098, 2007.","DOI":"10.1182\/blood-2006-08-039438"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118355"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9225"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200421633"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.6.H1799"},{"key":"R21","doi-asserted-by":"crossref","unstructured":"Kruckeberg WC, Doorenbos DI, Brown PO.Genetic differences in hemoglobin influence on erythrocyte oxidative stress hemolysis.Blood70: 909\u2013914, 1987.","DOI":"10.1182\/blood.V70.4.909.909"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.277.2.H676"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.11.4651"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.26.15069"},{"key":"R25","unstructured":"Lonsdorfer J, Bogui P, Otayeck A, Bursaux E, Poyart C, Cabannes R.Cardiorespiratory adjustments in chronic sickle cell anemia.Bull Eur Physiopathol Respir19: 339\u2013344, 1983."},{"key":"R26","unstructured":"Moncada S, Palmer RM, Higgs EA.Nitric oxide: physiology, pathophysiology, pharmacology.Pharmacol Rev43: 109\u2013142, 1991."},{"key":"R27","unstructured":"Morris CA, Suh J, Vichinsky EP, Klings ES, Steinberg M, Shigenaga M, Ames BN, Gladwin MT, Kato GJ.Oral arginine increases erythrocyte glutathione levels in sickle cell disease: implications for pulmonary hypertension. 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