title: Role of heme oxygenase-2 in pial arteriolar response to acetylcholine in mice with and without transfusion of cell-free hemoglobin polymers.
abstract: Carbon monoxide derived from heme oxygenase (HO) may participate in cerebrovascular regulation under specific circumstances. Previous work has shown that HO contributes to feline pial arteriolar dilation to acetylcholine after transfusion of a cell-free polymeric hemoglobin oxygen carrier. The role of constitutive HO2 in the pial arteriolar dilatory response to acetylcholine was determined by using 1) HO2-null mice (HO2-/-), 2) the HO inhibitor tin protoporphyrin IX (SnPPIX), and 3) 4,5,6,7-tetrabromobenzotriazole (TBB), an inhibitor of casein kinase-2 (CK2)-dependent phosphorylation of HO2. In anesthetized mice, superfusion of a cranial window with SnPPIX decreased arteriolar dilation produced by 10 microM acetylcholine by 51%. After partial polymeric hemoglobin exchange transfusion, the acetylcholine response was normal but was reduced 72% by SnPPIX and 95% by TBB. In HO2-/- mice, the acetylcholine response was modestly reduced by 14% compared with control mice and was unaffected by SnPPIX. After hemoglobin transfusion in HO2-/- mice, acetylcholine responses were also unaffected by SnPPIX and TBB. In contrast, nitric oxide synthase inhibition completely blocked the acetylcholine responses in hemoglobin-transfused HO2-/- mice. We conclude 1) that HO2 activity partially contributes to acetylcholine-induced pial arteriolar dilation in mice, 2) that this contribution is augmented in the presence of a plasma-based hemoglobin polymer and appears to depend on a CK2 kinase mechanism, 3) that nitric oxide synthase activity rather than HO1 activity contributes to the acetylcholine reactivity in HO2-/- mice, and 4) that plasma-based polymeric hemoglobin does not scavenge all of the nitric oxide generated by cerebrovascular acetylcholine stimulation.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, 600 North Wolfe St., Blalock 1404, Baltimore, MD 21205, USA.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Qin
authors.forename: Herman
authors.initials: H
authors.lastname: Kwansa
authors.forename: Enrico
authors.initials: E
authors.lastname: Bucci
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
authors.forename: Darren
authors.initials: D
authors.lastname: Boehning
authors.forename: David
authors.initials: D
authors.lastname: Shugar
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology; D016913:Blood Component Transfusion; D001802:Blood Substitutes / Q000008:administration & dosage*; D002245:Carbon Dioxide / Q000097:blood; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D054022:Cerebrum / Q000098:blood supply*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000008:administration & dosage*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; D001802:Blood Substitutes; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D008665:Metalloporphyrins; D011524:Protoporphyrins; D014230:Triazoles; D014665:Vasodilator Agents; C079129:hemoglobin polymer; D002245:Carbon Dioxide; D019335:Nitroarginine; D009569:Nitric Oxide; C032628:tin protoporphyrin IX; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D047390:Casein Kinase II; D000109:Acetylcholine