Abstract 13767: A Novel Pharmacological Inhibitor of Type 5 Adenylyl Cyclase Inhibitor Enhances Exercise Capacity and Protects Against Glucose Intolerance and Myocardial Ischemia

Abstract

Disruption of adenylyl cyclase 5 (AC5 KO) is a healthful longevity model; not only do the AC5 KO mice live a third longer than wild type (WT) mice, but are also protected against heart failure, obesity and diabetes and exercise intolerance. To translate to the clinics, we developed a new drug, C90, which inhibits AC5, and examined its effects on cardioprotection in pigs, exercise capacity and glucose tolerance in mice. C90 (30 mg/kg/day) or vehicle were chronically administered to age-matched C57/BL6 male mice via osmotic pump. After baseline exercise, the WT mice, all performing similarly, were divided into two groups; one that received C90 for 14 days and the other receiving vehicle for 14 days. After 14 days of C90 treatment, WT mice exhibited greater exercise capacity reflected by longer running distance (384 ± 27 m vs. 253 ± 16 m, p<0.05) and greater work to exhaustion (18.1 ± 1.5 J vs. 12.4 ± 0.7 J, p<0.05) than mice receiving vehicle. Sensitivity to glucose was measured using a glucose tolerance test in mice. Following 14-days treatment with C90 (30 mg/kg/day), the mice exhibited an overall improvement in glucose tolerance, measured as area under the curve (A.U.) for glucose levels following insulin injection, when compared to vehicle (6414 ± 890 A.U. vs. 9658 ± 1039 A.U., p<0.04). Furthermore, C90-treated mice had a lower fasting glucose level on a regular diet, when compared to vehicle (113 ± 6.5 mg/dl vs. 129 ± 4.2 mg/dl, p<0.05). The cardioprotective effects of C90 were previously demonstrated in mice. In the current study, we investigated the cardioprotective effects of C90 in a porcine model of ischemia/reperfusion (I/R). Ischemia was induced for 60 min coronary artery occlusion, followed by 3-hours reperfusion. C90 (1.2 mg/kg), infused 5 min following the start of the reperfusion led to a decreased infarct size/area at risk (INF/AAR) (21.6 ± 4.3% vs. 36.8 ± 2.9%, p<0.05) when compared to vehicle, with no difference between AAR/left ventricle between the C90 and vehicle groups. In view of its lower level of toxicity than other AC5 inhibitors, C90 is an excellent candidate for clinical development for pharmacological treatment of myocardial ischemia, glucose intolerance and exercise intolerance.