期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 301, 期 6, 页码 H2322-H2333出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00052.2011
关键词
isolated mouse heart; A(2B) knockout mice; ATP-sensitive K+ channel
资金
- National Heart, Lung, and Blood Institute [HL-027339, HL-09444, HL-071802, T32-HL-090610]
Sanjani MS, Teng B, Krahn T, Tilley S, Ledent C, Mustafa SJ. Contributions of A(2A) and A(2B) adenosine receptors in coronary flow responses in relation to the K-ATP channel using A(2B) and A(2A/2B) double-knockout 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 A(2B)AR and its relationship to the A(2A)AR in coronary flow (CF) changes using A(2B) single-knockout (KO) and A(2A/2B) double-KO (DKO) mice in a Langendorff setup. We used two approaches: 1) selective and nonselective AR agonists and antagonists and 2) A(2A)KO and A(2B)KO and A(2A/2B)DKO mice. BAY 60-6583 (a selective A(2B) agonist) had no effect on CF in A(2B)KO mice, whereas it significantly increased CF in wild-type (WT) mice (maximum of 23.3 +/- 9 ml.min(-1).g(-1)). 5'-N-ethylcarboxamido adenosine (NECA; a nonselective AR agonist) increased CF in A(2B)KO mice (maximum of 34.6 +/- 4.7 ml.min(-1).g(-1)) to a significantly higher degree compared with WT mice (maximum of 23.1 +/- 2.1 ml.min(-1).g(-1)). Also, CGS-21680 (a selective A(2A) agonist) increased CF in A(2B)KO mice (maximum of 29 +/- 1.9 ml.min(-1).g(-1)) to a significantly higher degree compared with WT mice (maximum of 25.1 +/- 2.3 ml.min(-1).g(-1)). SCH-58261 (an A(2A)-selective antagonist) inhibited the NECA-induced increase in CF to a significantly higher degree in A(2B)KO mice (19.3 +/- 1.6 vs. 0.5 +/- 0.4 ml.min(-1).g(-1)) compared with WT mice (19 +/- 3.5 vs. 3.6 +/- 0.5 ml.min(-1).g(-1)). NECA did not induce any increase in CF in A(2A/2B)DKO mice, whereas a significant increase was observed in WT mice (maximum of 23.1 +/- 2.1 ml.min(-1).g(-1)). Furthermore, the mitochondrial ATP-sensitive K+ (K-ATP) channel blocker 5-hydroxydecanoate had no effect on the NECA-induced increase in CF in WT mice, whereas the NECA-induced increase in CF in WT (17.6 +/- 2 ml.min(-1).g(-1)), A(2A)KO (12.5 +/- 2.3 ml.min(-1).g(-1)), and A(2B)KO (16.2 +/- 0.8 ml.min(-1).g(-1)) mice was significantly blunted by the K-ATP channel blocker glibenclamide (to 0.7 +/- 0.7, 2.3 +/- 1.1, and 0.9 +/- 0.4 ml.min(-1).g(-1), respectively). Also, the CGS-21680-induced (22 +/- 2.3 ml.min(-1).g(-1)) and BAY 60-6583-induced (16.4 +/- 1.60 ml.min(-1).g(-1)) increase in CF in WT mice was significantly blunted by glibenclamide (to 1.2 +/- 0.4 and 1.8 +/- 1.2 ml.min(-1).g(-1), respectively). In conclusion, this is the first evidence supporting the compensatory upregulation of A(2A)ARs in A(2B)KO mice and demonstrates that both A(2A)ARs and A(2B)ARs induce CF changes through K-ATP channels. These results identify AR-mediated CF responses that may lead to better therapeutic approaches for the treatment of cardiovascular disorders.
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