Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm014
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Coronary flow regulation in mouse heart during hypercapnic acidosis: Role of NO and its compensation during eNOS impairment
* Department of Anesthesiology and Intensive Care Medicine
Institute of Physiology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr.74, 01307 Dresden, Germany
Correspondence to Anke Heintz, MD, Dept. of Anesthesiology and Intensive Care Medicine, University Hospital Dresden, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany E-mail: Anke.Heintz{at}uniklinikum-dresden.de
Aims: This study addressed the hypotheses that the hypercapnic flow response in wild-type (WT) mouse heart is mainly mediated by nitric oxide and, thus, severely blunted in endothelial nitric oxide knockout (eNOS-KO) mice and in WT mice after continuous pharmacological block (2 weeks) of NOS enzymes (WT-LN).
Methods: 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.
Results: 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 toward NOS blockade. Whereas indomethacin, miconazole, TEA and SCH 58261 were ineffective to reduce the flow response, glibenclamide blunted it in eNOS-KO hearts.
Conclusion: Nitric oxide 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 nitric oxide; K-ATP channel; vasodilation; coronary circulation; acidosis/hypercapnia
Time for primary review: 22 days
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