Abstract 13192: “Adenosine Lite”; a Combination of Adenosine Agonist and Adenylyl Cyclase Type 5 Inhibition Reduces Infarct Size and Ameliorates Heart Failure Progression Even when Delivered After Coronary Reperfusion
Adenosine is the “gold standard” for cardioprotection, yet after hundreds of studies it is still not widely used clinically. Our hypothesis is that some other action of adenosine, e.g., its potent peripheral vasodilation, may offset some of adenosine’s positive cardioprotective effects, and also limit its ability to reduce infarct size when delivered after coronary artery (CA) reperfusion (R), which is essential in the clinical setting. One pharmacological candidate is 9-beta-D-arabinofuranosyladenine (Ara-Ade), previously used and FDA approved as an antiviral drug that demonstrates selective adenylyl cyclase isoform type 5 (AC5) inhibition properties in addition to having a structure resembling adenosine. In mice, both Ara-Ade and adenosine reduced infarct size similarly, assessed by TTC as a fraction of the area at risk, when delivered before 30 min CA occlusion (O), but only Ara-Ade still reduced infarct size (16±1.2%), p<0.05 as compared with either vehicle ( 37±0.7%) or adenosine (38±0.6%), when delivered after CAR. Heart failure developing 4 weeks later was also diminished, p<0.05 vs vehicle. Because of its structural similarity to adenosine, its effects on reduction of infarct size, when delivered after CAR, were not observed after blockade of adenosine type A1 or A2a receptors, but was preserved after adenosine receptor A2b blockade. A major difference between Ara-Ade and adenosine could be attributed to peripheral vasodilation: adenosine reduced mean arterial pressure (33±4%) and increased heart rate (9.5±2.2%), effects which were not observed with Ara-Ade. Ara-Ade also reduced infarct size in chronically instrumented conscious pigs, when delivered after CAR, and in this model also reduced, p<0.05, post-CAR coronary hyperemia, which could be a mechanism for reducing oxidative stress during CAR and consequently providing additional cardioprotection. Thus, it is conceivable that the superimposition of AC5 inhibition on adenosine, would make this combination of effects more favorable clinically than adenosine alone, particularly when the drug must be delivered after CAR.
- © 2013 by American Heart Association, Inc.