Cardiovascular Research Advance Access originally published online on September 19, 2007
Cardiovascular Research 2008 77(1):188-196; doi:10.1093/cvr/cvm014
Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment
1 Department of Anesthesiology and Intensive Care Medicine, Medical Faculty Carl Gustav Carus, University Hospital Dresden, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
2 Institute of Physiology, Medical Faculty Carl Gustav Carus, University Hospital Dresden, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
* Corresponding author. Tel: +49-3514586006; fax: +49-3514586301. E-mail address: Anke.Heintz{at}uniklinikum-dresden.de
These authors contributed equally to this work.
Aims: 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).
Methods and results: Step changes of arterial pCO2 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 KATP-channels (glibenclamide) were studied in WT and eNOS-KO mouse hearts. Change of arterial pCO2 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.
Conclusion: NO-production and KATP-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 KATP-channels and potentially Kv-channels contributes to the compensatory mechanisms involved in the hypercapnic flow response when eNOS activity is absent.
KEYWORDS hypercapnia; acidosis; coronary circulation; Nitric oxide; Potassium channels
Time for primary review: 22 days
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