{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:31:38Z","timestamp":1790829098921,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,11,15]],"date-time":"2018-11-15T00:00:00Z","timestamp":1542240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000014","name":"Canadian Blood Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000014","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Transfusion"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Hemoglobin\u2010based oxygen carriers (HBOCs) are potential alternatives to red blood cells in transfusions. Clinical trials using early versions of HBOCs noted adverse effects that appeared to result from removal of the vasodilator nitric oxide (NO). Previous reports suggest that size\u2010enlarged HBOCs may avoid NO\u2010rich regions along the vasculature and therefore not cause vasoconstriction and hypertension.<\/jats:p><\/jats:sec><jats:sec><jats:title>STUDY DESIGN AND METHODS<\/jats:title><jats:p>Hemoglobin (Hb) bis\u2010tetramers (bis\u2010tetramers of hemoglobin that are prepared using CuAAC chemistry [BT\u2010Hb] and bis\u2010tetramers of hemoglobin that are specifically acetylated and prepared using CuAAC chemistry [BT\u2010acHb]) can be reliably produced by a bio\u2010orthogonal cyclo\u2010addition approach. We considered that an HBOC derived from chemical coupling of two Hbs would be sufficiently large to avoid NO scavenging and related side effects. The ability of intravenously infused BT\u2010Hb and BT\u2010acHb to remain in the circulation without causing hypertension were determined in wild\u2010type (WT) and diabetic (<jats:italic>db\/db<\/jats:italic>) mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In WT mice, the coupled oxygen\u2010carrying proteins retained their function over several hours after administration. No significant changes in systolic blood pressure from baseline were observed after intravenous infusion of BT\u2010Hb or BT\u2010acHb in awake WT and <jats:italic>db\/db<\/jats:italic> mice. In contrast, infusion of native Hb or cross\u2010linked Hb tetramers in both animal models induced systemic hypertension.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>The results of this study indicate that bis\u2010tetrameric HBOCs derived from the bio\u2010orthogonal cyclo\u2010addition process are likely to overcome clinical issues that arise from NO scavenging by Hb derivatives.<\/jats:p><\/jats:sec>","DOI":"10.1111\/trf.15003","type":"journal-article","created":{"date-parts":[[2018,11,16]],"date-time":"2018-11-16T06:48:39Z","timestamp":1542350919000},"page":"359-370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cross\u2010linked hemoglobin bis\u2010tetramers from bioorthogonal coupling do not induce vasoconstriction in the circulation"],"prefix":"10.1111","volume":"59","author":[{"given":"Aizhou","family":"Wang","sequence":"first","affiliation":[{"name":"Davenport Chemistry 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