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Interactions between A(2A) adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia.

American journal of physiology. Heart and circulatory physiology (2013-03-26)
Maryam Sharifi-Sanjani, Xueping Zhou, Shinichi Asano, Stephen Tilley, Catherine Ledent, Bunyen Teng, Gregory M Dick, S Jamal Mustafa
ABSTRACT

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K(+) (K(ATP)) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A(2A) and A(2B) receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A(2A) receptors, hydrogen peroxide (H(2)O(2)), and KATP channels. We used A(2A) and A(2B) knockout (KO) and A(2A/2B) double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A(2A) KO and A(2A)/(2B) DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A(2B) KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A(2B) KO mice (90 ± 23% of WT) but not A(2A) KO or A(2A)/A(2B) DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H(2)O(2) activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H(2)O(2), attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% (P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A(2A) KO mice (98 ± 7%). Our findings suggest that adenosine A(2A) receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H(2)O(2) as a signaling intermediate.

MATERIALS
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