Key result
In isolated mouse hearts, hypercapnic acidosis increased coronary flow by 31.3% in wild-type mice, which was significantly decreased to 9.2% after NOS blockade with L-NAME.
In mouse hearts, NO production and K ATP-channel activation account for the hypercapnic flow response, with K ATP-channels compensating when eNOS activity is chronically absent.
Does not inform clinical coronary flow management; leaves open NO/KATP mediation of hypercapnic responses in humans.
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 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. CONCLUSION: 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.
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Heintz et al. (2007) studied Hypercapnic acidosis (n=105). NOS blockade (L-NAME) or eNOS deletion vs. Wild-type control was evaluated on Increase in coronary flow during hypercapnic acidosis. In isolated mouse hearts, hypercapnic acidosis increased coronary flow by 31.3% in wild-type mice, which was significantly decreased to 9.2% after NOS blockade with L-NAME.
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