Sanjani MS, Teng B, Krahn T, Tilley S, Ledent C, Mustafa SJ. Contributions of A 2A and A2B adenosine receptors in coronary flow responses in relation to the KATP channel using A2B and A2A/2B doubleknockout mice. Am J Physiol Heart Circ Physiol 301: H2322-H2333, 2011. First published September 23, 2011 doi:10.1152/ajpheart.00052.2011.-Adenosine plays a role in physiological and pathological conditions, and A 2 adenosine receptor (AR) expression is modified in many cardiovascular disorders. In this study, we elucidated the role of the A2BAR and its relationship to the A2AAR in coronary flow (CF) changes using A2B single-knockout (KO) and A2A/2B double-KO (DKO) mice in a Langendorff setup. We used two approaches: 1) selective and nonselective AR agonists and antagonists and 2) A2AKO and A 2BKO and A2A/2BDKO mice. BAY 60-6583 (a selective A2B agonist) had no effect on CF in A2BKO mice, whereas it significantly increased CF in wild-type (WT) mice (maximum of 23.3 Ϯ 9 ml·min ). NECA did not induce any increase in CF in A2A/2BDKO mice, whereas a significant increase was observed in WT mice (maximum of 23.1 Ϯ 2.1 ml·min). Furthermore, the mitochondrial ATP-sensitive K ϩ (KATP) channel blocker 5-hydroxydecanoate had no effect on the NECAinduced increase in CF in WT mice, whereas the NECA-induced increase in CF in WT (17.6 Ϯ 2 ml·min Ϫ1 ·g Ϫ1 ), A2AKO (12.5 Ϯ 2.3 ml·min , respectively). In conclusion, this is the first evidence supporting the compensatory upregulation of A2AARs in A2BKO mice and demonstrates that both A2AARs and A2BARs induce CF changes through KATP channels. These results identify AR-mediated CF responses that may lead to better therapeutic approaches for the treatment of cardiovascular disorders. isolated mouse heart; A2B knockout mice; ATP-sensitive K ϩ channel ADENOSINE is an endogenous nucleoside that is released through the breakdown of adenine nucleotides. The cardiovascular effects of adenosine are mediated through the activation of its four subtypes of receptors (ARs), namely, A 1 , A 2A , A 2B , and A 3 . The activation of A 1 ARs results in negative chronotropic and ionotropic effects and a decrease in coronary flow (CF) (68), whereas other studies have suggested that the activation of both A 1 ARs or A 3 ARs before ischemia is cardioprotective (6, 30). However, adenosine has been shown to play a vasoregulatory role in human coronary arteries (16,17,62,63