Chronically Increased Aldosterone In Vivo Attenuates Coronary Vasodilation to Adenosine

Adenosine‐induced coronary vasodilation is an important cardioprotective mechanism during cardiac hypoxia and ischemia and is utilized clinically for the determination of coronary flow reserve (CFR), an independent predictor of cardiac mortality. Impaired coronary vasodilation to adenosine is more common in diseases associated with inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS) and recent evidence indicates that systemic blockade of mineralocorticoid receptors (MR) improves CFR in patients with diabetes. The mechanisms underlying RAAS‐dependent attenuation of coronary adenosine‐induced vasodilation, however, remain unclear. Therefore, we hypothesized that chronic infusion of the MR agonist aldosterone would blunt coronary adenosine‐mediated vasodilation and that this would involve reduced adenosine type 2A (A 2A ) receptor‐dependent vasodilation. Studies were performed using 13–15 week old male C57BL/6J mice infused with either vehicle (95% EtOH in saline) or a subpressor dose of aldosterone (250 μg/kg/d) chronically for 4 weeks via osmotic minipump. After infusion, left ventricular coronary arteries were dissected and function was assessed by wire myography. Chronic infusion of aldosterone raised circulating aldosterone concentrations but did not increase heart weight. Aldosterone infusion blunted coronary vasodilation to adenosine, particularly within the range of adenosine concentrations relevant to those in vivo during cardiac hypoxia (1–10 μM), but did not reduce maximal adenosine‐induced vasodilation. Coronary vasodilation to the endothelium‐dependent vasodilator acetylcholine was also blunted by aldosterone infusion. Additional studies revealed that coronary adenosine‐induced vasodilation in the mouse is entirely dependent on activation of K + channels and that selective activation of adenosine type 2B (A 2B ) receptors with BAY 60–6583 induces greater vasodilation that activation of A 2A receptors with CGS‐21680. Chronic aldosterone infusion blunted coronary vasodilation in response to selective A 2A , but not selective A 2B , activation. RT‐PCR revealed no difference in aortic A 2A and A 2B gene expression. Taken together, our data demonstrate that chronic elevations of aldosterone blunt coronary vasodilation to adenosine via impaired A 2A ‐dependent vasodilation. This aldosterone‐dependent blunting of adenosine‐mediated vasodilation has implications for cardiac injury in response to hypoxia in states associated with inappropriate RAAS activation such as obesity and diabetes. Support or Funding Information Funded by VHA BLR&D BX002030 (SBB) and a STRIDE Undergraduate Summer Research Fellowship (MK) supported by the American Physiological Society and NIH NHLBI R25 HL115473‐01. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .