Normalization of hemoglobin-based oxygen carrier-201 induced vasoconstriction: targeting nitric oxide and endothelin.
Hemoglobin-based oxygen carrier (HBOC)-201 is a cell-free modified hemoglobin solution potentially facilitating oxygen uptake and delivery in cardiovascular disorders and hemorrhagic shock. Clinical use has been hampered by vasoconstriction in the systemic and pulmonary beds. Therefore, we aimed to1) determine the possibility of counteracting HBOC-201-induced pressor effects with either adenosine (ADO) or nitroglycerin (NTG);2) assess the potential roles of nitric oxide (NO) scavenging, reactive oxygen species (ROS), and endothelin (ET) in mediating the observed vasoconstriction; and3) compare these effects in resting and exercising swine. Chronically instrumented swine were studied at rest and during exercise after administration of HBOC-201 alone or in combination with ADO. The role of NO was assessed by supplementation with NTG or administration of the eNOS inhibitorNω-nitro-l-arginine. Alternative vasoactive pathways were investigated via intravenous administration of the ETA/ETBreceptor blocker tezosentan or a mixture of ROS scavengers. The systemic and to a lesser extent the pulmonary pressor effects of HBOC-201 could be counteracted by ADO; however, dosage titration was very important to avoid systemic hypotension. Similarly, supplementation of NO with NTG negated the pressor effects but also required titration of the dose. The pressor response to HBOC-201 was reduced after eNOS inhibition and abolished by simultaneous ETA/ETBreceptor blockade, while ROS scavenging had no effect. In conclusion, the pressor response to HBOC-201 is mediated by vasoconstriction due to NO scavenging and production of ET. Further research should explore the effect of longer-acting ET receptor blockers to counteract the side effect of hemoglobin-based oxygen carriers.NEW & NOTEWORTHYHemoglobin-based oxygen carrier (HBOC)-201 can disrupt hemodynamic homeostasis, mimicking some aspects of endothelial dysfunction, resulting in elevated systemic and pulmonary blood pressures. HBOC-201-induced vasoconstriction is mediated by scavenging nitric oxide (NO) and by upregulating endothelin (ET) production. Pressor effects can be prevented by adjuvant treatment with NO donors or direct vasodilators, such as nitroglycerin or adenosine, but dosages must be carefully monitored to avoid hypotension. However, hemodynamic normalization is more easily achieved via administration of an ET receptor blocker.
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.|Department of Cardiothoracic Surgery, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Yannick J
YJ
Taverne
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Daphne
D
de Wijs-Meijler
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Maaike
M
Te Lintel Hekkert
Neurotrauma Department, Naval Medical Research Center, Silver Spring, Maryland; and.
Paula F
PF
Moon-Massat
OPK Biotech, LLC (former), Cambridge, Maryland.
Gregory P
GP
Dubé
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Dirk J
http://orcid.org/0000-0003-2836-2241
DJ
Duncker
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; d.merkus@erasmusmc.nl.
Daphne
http://orcid.org/0000-0002-4852-831X
D
Merkus
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000494:pharmacology*; D007022:Hypotension / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001802:Blood Substitutes; D016232:Endothelins; D006454:Hemoglobins; D017382:Reactive Oxygen Species; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; C096798:HBOC 201; D009569:Nitric Oxide; D005996:Nitroglycerin; D000241:Adenosine
animal study; critical care medicine; endothelin; hemoglobin-based oxygen carrier; hypertension; nitric oxide; reactive oxygen species; vasoconstriction