title: Metoprolol reduces cerebral tissue oxygen tension after acute hemodilution in rats.
abstract: BACKGROUND
  Perioperative beta-blockade and anemia are independent predictors of increased stroke and mortality by undefined mechanisms. This study investigated the effect of beta-blockade on cerebral tissue oxygen delivery in an experimental model of blood loss and fluid resuscitation (hemodilution).
  
  
  METHODS
  Anesthetized rats were treated with metoprolol (3 mg x kg) or saline before undergoing hemodilution with pentastarch (1:1 blood volume exchange, 30 ml x kg). Outcomes included cardiac output, cerebral blood flow, and brain (PBrO2) and kidney (PKO2) tissue oxygen tension. Hypoxia inducible factor-1alpha (HIF-1alpha) protein levels were assessed by Western blot. Systemic catecholamines, erythropoietin, and angiotensin II levels were measured.
  
  
  RESULTS
  Hemodilution increased heart rate, stroke volume, cardiac output (60%), and cerebral blood flow (50%), thereby maintaining PBrO2 despite an approximately 50% reduction in blood oxygen content (P < 0.05 for all). By contrast, PKO2 decreased (50%) under the same conditions (P < 0.05). Beta-blockade reduced baseline heart rate (20%) and abolished the compensatory increase in cardiac output after hemodilution (P < 0.05). This attenuated the cerebral blood flow response and reduced PBrO2 (50%), without further decreasing PKO2. Cerebral HIF-1alpha protein levels were increased in beta-blocked hemodiluted rats relative to hemodiluted controls (P < 0.05). Systemic catecholamine and erythropoietin levels increased comparably after hemodilution in both groups, whereas angiotensin II levels increased only after beta-blockade and hemodilution.
  
  
  CONCLUSIONS
  Cerebral tissue oxygen tension is preferentially maintained during hemodilution, relative to the kidney, despite elevated systemic catecholamines. Acute beta-blockade impaired the compensatory cardiac output response to hemodilution, resulting in a reduction in cerebral tissue oxygen tension and increased expression of HIF-1alpha.
authors.affiliation: Department of Anesthesia, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tenille E
authors.initials: TE
authors.lastname: Ragoonanan
authors.forename: W Scott
authors.initials: WS
authors.lastname: Beattie
authors.forename: C David
authors.initials: CD
authors.lastname: Mazer
authors.forename: Albert K Y
authors.initials: AK
authors.lastname: Tsui
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: David F
authors.initials: DF
authors.lastname: Wilson
authors.forename: Gordon
authors.initials: G
authors.lastname: Tait
authors.forename: Julie
authors.initials: J
authors.lastname: Yu
authors.forename: Elaine
authors.initials: E
authors.lastname: Liu
authors.forename: Melissa
authors.initials: M
authors.lastname: Noronha
authors.forename: Neil D
authors.initials: ND
authors.lastname: Dattani
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsakakis
authors.forename: Gregory M T
authors.initials: GM
authors.lastname: Hare
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood; D006438:Hemodilution; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D008297:Male; D008790:Metoprolol / Q000009:adverse effects / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000209:etiology
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D000804:Angiotensin II; D008790:Metoprolol; D010100:Oxygen