title: Impact of heme and heme degradation products on vascular diameter in mouse visual cortex.
abstract: BACKGROUND
  Delayed cerebral vasospasm is the most common cause of mortality and severe neurological impairment in patients who survive subarachnoid hemorrhage. Despite improvements in the field of diagnostic imaging, options for prevention and medical treatment-primarily with the calcium channel antagonist nimodipine or hemodynamic manipulations-are insufficient. Previous studies have suggested that heme and bilirubin oxidation end products, originating from degraded hemoglobin around ruptured blood vessels, are involved in the development of vasospasm by inhibiting large conductance BKC a potassium channels in vascular smooth muscle cells. In this study, we identify individual heme degradation products regulating arteriolar diameter in dependence of BKC a channel activity.
  
  
  RESULTS
  Using differential interference contrast video microscopy in acute brain slices, we determined diameter changes of intracerebral arterioles in mouse visual cortex. In preconstricted vessels, the specific BKC a channel blockers paxilline and iberiotoxin as well as iron-containing hemin caused vasoconstriction. In addition, the bilirubin oxidation end product Z-BOX A showed a stronger vasoconstrictive potency than its regio-isomer Z-BOX B. Importantly, Z-BOX A had the same vasoconstrictive effect, independent of its origin from oxidative degradation or chemical synthesis. Finally, in slices of Slo1-deficient knockout mice, paxilline and Z-BOX A remained ineffective in changing arteriole diameter.
  
  
  CONCLUSIONS
  We identified individual components of the oxidative bilirubin degradation that led to vasoconstriction of cerebral arterioles. The vasoconstrictive effect of Z-BOX A and Z-BOX B was mediated by BKC a channel activity that might represent a signaling pathway in the occurrence of delayed cerebral vasospasm in subarachnoid hemorrhage patients.
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Joerk
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany (R.A.S., M.K., M.K., G.P., M.W.) Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany (R.A.S.).
authors.forename: Raphael Andreas
authors.initials: RA
authors.lastname: Seidel
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Sebastian Gottfried
authors.initials: SG
authors.lastname: Walter
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Anne
authors.initials: A
authors.lastname: Wiegand
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany (R.A.S., M.K., M.K., G.P., M.W.).
authors.forename: Marcel
authors.initials: M
authors.lastname: Kahnes
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany (R.A.S., M.K., M.K., G.P., M.W.).
authors.forename: Maurice
authors.initials: M
authors.lastname: Klopfleisch
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Knut
authors.initials: K
authors.lastname: Kirmse
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany (R.A.S., M.K., M.K., G.P., M.W.).
authors.forename: Georg
authors.initials: G
authors.lastname: Pohnert
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany (R.A.S., M.K., M.K., G.P., M.W.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Westerhausen
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Otto Wilhelm
authors.initials: OW
authors.lastname: Witte
authors.affiliation: Hans-Berger Department of Neurology, University Hospital Jena, Germany (A.J., S.G.W., A.W., K.K., O.W.W., K.H.).
authors.forename: Knut
authors.initials: K
authors.lastname: Holthoff
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000473:pathology; D001663:Bilirubin / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors; D051379:Mice; D008857:Microscopy, Interference; D010455:Peptides / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D011758:Pyrroles; D013345:Subarachnoid Hemorrhage / Q000150:complications; D014661:Vasoconstriction / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000209:etiology; D014793:Visual Cortex / Q000098:blood supply* / Q000187:drug effects
chemical_list: C586359:(Z)-2-(3-ethenyl-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)ethanamide; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D011758:Pyrroles; C048220:paxilline; D006418:Heme; D006427:Hemin; C064719:iberiotoxin; D001663:Bilirubin
keywords: bilirubin oxidation end products; cerebral vasospasm; potassium ion channels; subarachnoid hemorrhage