title: Rate of NO scavenging alters effects of recombinant hemoglobin solutions on pulmonary vasoreactivity.
abstract: Many hemoglobin-based oxygen carriers (HBOCs) produce systemic and pulmonary hypertension and may increase microvascular permeability as a consequence of nitric oxide (NO) scavenging. In this study, we examined the effects of two recombinant human hemoglobin solutions, rHb1.1 and rHb2.0 for injection (rHb2.0), with different rates of NO scavenging on vasoconstrictor reactivity and vascular permeability in isolated, saline-perfused rat lungs. We hypothesized that rHb1.1, a first-generation HBOC with an NO scavenging rate similar to that of native human hemoglobin, would exacerbate pulmonary vasoconstriction and permeability and that rHb2.0, a second-generation HBOC with an NO scavenging rate approximately 20- to 30-fold lower than that of rHb1.1, would minimally influence these responses. Consistent with this hypothesis, rHb1.1 enhanced pulmonary vasoconstrictor reactivity to both hypoxia and thromboxane mimetic U-46619 in a dose-dependent fashion. In contrast, rHb2.0 produced little or no change in reactivity to these stimuli. Furthermore, whereas rHb1.1 abrogated pulmonary vasodilation to the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP), dose-dependent responses to SNAP were preserved, albeit attenuated, in lungs treated with rHb2.0. Finally, the capillary filtration coefficient was unaltered by either rHb1.1 or rHb2.0. We conclude that pulmonary hemodynamic responses to rHb2.0 are greatly reduced compared with those observed with rHb1.1, consistent with rHb2.0 having a diminished capacity to scavenge NO. In addition, neither hemoglobin solution measurably altered microvascular permeability in this preparation.
authors.affiliation: Department of Cell Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218, USA. tresta@salud.umn.edu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Resta
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.forename: Mark R
authors.initials: MR
authors.lastname: Eichinger
authors.forename: Michael P
authors.initials: MP
authors.lastname: Doyle
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000378:metabolism*; D006454:Hemoglobins / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000033:anatomy & histology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009929:Organ Size; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012996:Solutions; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects*
chemical_list: D016166:Free Radical Scavengers; D006454:Hemoglobins; D020030:Nitric Oxide Donors; D011994:Recombinant Proteins; D012996:Solutions; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D026423:S-Nitroso-N-Acetylpenicillamine