title: Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment.
abstract: OBJECTIVE
  This study addressed the hypotheses that the hypercapnic flow response in wild-type (WT) mouse heart is mainly mediated by nitric oxide (NO) and, thus, severely blunted in endothelial nitric oxide synthase knockout (eNOS-KO) mice and in WT mice after continuous pharmacological block (2 weeks) of NOS enzymes (WT-LN).
  
  
  RESULTS
  Step changes of arterial pCO(2) were performed in isolated perfused hearts (n = 105). Contributions of NOS (L-NAME, TRIM), cyclooxygenase (indomethacin), epoxyeicosanotrienes (miconazole), adenosine A2A-receptors (SCH 58261), KV-channels (4-AP), KCa-channels (TEA), and K ATP-channels (glibenclamide) were studied in WT and eNOS-KO mouse hearts. Change of arterial pCO(2) increased coronary flow by 31.3 +/- 4% in WT, a response that was significantly decreased to 9.2 +/- 6% after L-NAME. Additional glibenclamide infusion (n = 5) completely abolished the steady-state flow increase during hypercapnic acidosis (-4.2 +/- 2.3%, P = 0.004 vs. control). Hearts from eNOS-KO mice as well as WT-LN showed a fully preserved flow response insensitive towards NOS-blockade. Whereas indomethacin, miconazole, TEA, and SCH 58261 were ineffective to reduce the flow response, glibenclamide blunted it in eNOS-KO hearts.
  
  
  CONCLUSIONS
  NO-production and K ATP-channel activation together may fully account for the steady-state hypercapnic flow response in mouse heart. However, chronic deletion of eNOS does not result in a reduced hypercapnic flow response. Enhanced activation of K ATP-channels and potentially Kv-channels contributes to the compensatory mechanisms involved in the hypercapnic flow response when eNOS activity is absent.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Medical Faculty Carl Gustav Carus, University Hospital Dresden, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Anke.Heintz@uniklinikum-dresden.de
authors.forename: Anke
authors.initials: A
authors.lastname: Heintz
authors.forename: Martin
authors.initials: M
authors.lastname: Damm
authors.forename: Markus
authors.initials: M
authors.lastname: Brand
authors.forename: Thea
authors.initials: T
authors.lastname: Koch
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
mesh_terms: D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D003326:Coronary Circulation; D006935:Hypercapnia / Q000503:physiopathology*; D054086:KATP Channels / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D043683:Receptors, Adenosine A2 / Q000502:physiology
chemical_list: D054086:KATP Channels; D024681:Potassium Channels, Calcium-Activated; D043683:Receptors, Adenosine A2; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester