PT - JOURNAL ARTICLE AU - Claudio A. Bravo AU - Dorothy E. Vatner AU - Ronald Pachon AU - Jie Zhang AU - Stephen F. Vatner TI - A Food and Drug Administration–Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion AID - 10.1124/jpet.116.232538 DP - 2016 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 331--336 VI - 357 IP - 2 4099 - http://jpet.aspetjournals.org/content/357/2/331.short 4100 - http://jpet.aspetjournals.org/content/357/2/331.full SO - J Pharmacol Exp Ther2016 May 01; 357 AB - A Food and Drug Administration–approved antiviral agent, known as vidarabine or adenine 9-β-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal–regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation.