Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia

Maryam Sharifi-Sanjani, Xueping Zhou, Shinichi Asano, Stephen Tilley, Catherine Ledent, Bunyen Teng, Gregory M. Dick, S. Jamal Mustafa

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K+ (KATP) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A2A and A2B receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A2A receptors, hydrogen peroxide (H2O2), and KATP channels. We used A2A and A2B knockout (KO) and A2A/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 A2A KO and A2A/2B DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A2B KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A2B KO mice (90 ± 23% of WT) but not A2A KO or A2A/A2B DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H2O2 activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H2O2, 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 A2A KO mice (98 ± 7%). Our findings suggest that adenosine A2A receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H2O2 as a signaling intermediate.

Original languageEnglish
Pages (from-to)H1294-H1301
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number10
DOIs
StatePublished - 2013

Keywords

  • Adenosine receptors
  • Coronary circulation
  • Ischemic vasodilatation
  • Reactive oxygen species

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