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Adenosine-mediated coronary vasodilation is a critical cardioprotective mechanism during ischemia; however, whether this response is impaired by increased Aldo is unclear. We hypothesized that chronic Aldo impairs coronary adenosine-mediated vasodilation via downregulation of vascular K<jats:sup>+<\/jats:sup> channels. Male C57BL\/6J mice were treated with vehicle (Con) or subpressor Aldo for 4 wk. Coronary artery function, assessed by wire myography, revealed Aldo-induced reductions in vasodilation to adenosine and the endothelium-dependent vasodilator acetylcholine but not to the nitric oxide donor sodium nitroprusside. Coronary vasoconstriction to endothelin-1 and the thromboxane A<jats:sub>2<\/jats:sub> mimetic U-46619 was unchanged by Aldo. Additional mechanistic studies revealed impaired adenosine A<jats:sub>2A<\/jats:sub>, not A<jats:sub>2B<\/jats:sub>, receptor-dependent vasodilation by Aldo with a tendency for Aldo-induced reduction of coronary A<jats:sub>2A<\/jats:sub> gene expression. Adenylate cyclase inhibition attenuated coronary adenosine dilation but did not eliminate group differences, and adenosine-stimulated vascular cAMP production was similar between Con and Aldo mice. Similarly, blockade of inward rectifier K<jats:sup>+<\/jats:sup> channels reduced but did not eliminate group differences in adenosine dilation whereas group differences were eliminated by blockade of Ca<jats:sup>2+<\/jats:sup>-activated K<jats:sup>+<\/jats:sup> (K<jats:sub>Ca<\/jats:sub>) channels that blunted and abrogated adenosine and A<jats:sub>2A<\/jats:sub>-dependent dilation, respectively. Gene expression of several coronary K<jats:sub>Ca<\/jats:sub> channels was reduced by Aldo. Together, these data demonstrate Aldo-induced impairment of adenosine-mediated coronary vasodilation involving blunted A<jats:sub>2A<\/jats:sub>-K<jats:sub>Ca<\/jats:sub>-dependent vasodilation, independent of blood pressure, providing important insights into the link between plasma Aldo and cardiac mortality and rationale for aldosterone antagonist use to preserve coronary microvascular function. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY Increased plasma aldosterone levels are associated with worsened cardiac outcomes in diverse patient groups by unclear mechanisms. We identified that, in male mice, elevated aldosterone impairs coronary adenosine-mediated vasodilation, an important cardioprotective mechanism. This aldosterone-induced impairment involves reduced adenosine A<jats:sub>2A<\/jats:sub>, not A<jats:sub>2B<\/jats:sub>, receptor-dependent vasodilation associated with downregulation of coronary K<jats:sub>Ca<\/jats:sub> channels and does not involve altered adenylate cyclase\/cAMP signaling. Importantly, this effect of aldosterone occurred independent of changes in coronary vasoconstrictor responsiveness and blood pressure. <\/jats:p><jats:p> Listen to this article\u2019s corresponding podcast at https:\/\/ajpheart.podbean.com\/e\/attenuation-of-coronary-adenosine-dilation-by-aldosterone\/ . <\/jats:p>","DOI":"10.1152\/ajpheart.00081.2019","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T09:53:51Z","timestamp":1560506031000},"page":"H357-H363","source":"Crossref","is-referenced-by-count":8,"title":["Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca<sup>2+<\/sup>-activated K<sup>+<\/sup> channels"],"prefix":"10.1152","volume":"317","author":[{"given":"Maloree","family":"Khan","sequence":"first","affiliation":[{"name":"Biomedical Sciences, University of Missouri, Columbia, Missouri"},{"name":"Research Service, Harry S. 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