Abstract 19060: An Anti-Viral Drug with Properties of Selective Inhibition of Adenylyl Cyclase Type 5 Reduces Infarct Size More when Delivered after than Before Reperfusion

Abstract

There are at least two reasons why very few of the discoveries from genetically engineered mice have been translated to the clinics: 1.Most therapy requires delivery of a drug, since it is difficult to change a gene in patients; 2. Most cardioprotective agents require pretreatment before coronary artery (CA) reperfusion (R), but patients with myocardial infarction are rarely seen before CAR. We studied the drug 9-beta-D-arabinofuranosyladenine (Ara-Ade), previously used and FDA approved as an antiviral drug, because it has a structure resembling adenosine, but demonstrates selective adenylyl cyclase isoform type 5 (AC5) inhibition properties, i.e., it inhibits responses to beta-adrenergic receptor stimulation much greater in AC5 transgenic (Tg) mice than wild type, but not more in AC6 Tg and not at all in AC5 knockout, both in vitro and in vivo. We examined its ability to reduce infarct size (measured with TTC) after 30 min CA occlusion (CAO) and 24 hr CAR in mice. Surprisingly, infarct size, expressed as a fraction of the area at risk was lower, p<0.05, when the drug was delivered at CAR (16%), than when given before either CAO or CAR (21%) compared to vehicle (36%). p Ara-Ade also reduced infarct size in chronically instrumented conscious pigs, when delivered after CAR. In this model instantaneous measurements of coronary blood flow demonstrated that post reperfusion coronary hyperemia and reactive hyperemia, following a 15 sec CAO, were attenuated, consistent with isolated heart studies showing reduced coronary flow recovery after ischemia. Thus, a novel drug that inhibits AC5 induces even more cardioprotection when delivered after CAR than before, making it potentially more useful the clinical setting, where patients with myocardial infarction require CAR immediately after arriving at the hospital. It is conceivable that the mechanism, in part, involves protection of CAR damage, since the magnitude of coronary hyperemia after CAR has been related to CAR reperfusion damage.