Abstract 1673: Enhanced Coronary Reserve Mediated by Nitric Oxide in Adenylyl Cyclase Type 5 Knockout
The adenylyl cyclase type 5 knockout (AC5 KO) mouse is characterized by increased longevity (lifespan 1/3 longer than wild type, WT) and protection against cardiac stress; AC5 KO are resistant to development of heart failure following either chronic pressure overload or chronic catecholamine stress. Prior work in this model, and in other mouse models in response to cardiovascular stress, has concentrated on examining molecular signaling involved in apoptosis and hypertrophy and cardioprotection. A relatively unexplored, but important mechanism in understanding cardiomyopathy in patients involves the limitation in coronary reserve (CR) and also impaired nitric oxide (NO) regulation of the heart and coronary vessels. The goal of this study was to determine if the observed cardioprotection in the AC5 KO mice could be related to NO, which in turn might enhance CR. When the NO donor, sodium nitroprusside, was infused in conscious mice with chronically implanted aortic blood flow transducers (Transonic) and aortic pressure catheters, cardiac output rose significantly more (p < 0.05) in AC5 KO (24 ± 3%) than in WT (12 ± 2%), and total peripheral resistance fell significantly more (p < 0.05) in AC5 KO (−36 ± 3%) compared to WT (−20 ± 3%). CR was measured by determining coronary blood flow at baseline and during hyperemia (induced by adenosine, 160 microg/kg/min) using high resolution ultrasound (Vevo 770). CR was enhanced (p < 0.05) in AC5 KO (3.7 ± 0.4, n = 4) compared to WT (2.8 ± 0.2, n = 5). CR was no longer increased in AC5 KO (1.8 ± 0.2) after NO synthase blockade with N-Nitro-L-arginine (L-NAME). These results demonstrate that the AC5 KO mouse exhibits enhanced sensitivity to NO and an elevated CR compared to WT. Both of these mechanisms could contribute to the increased longevity and protection against cardiac stress observed in the AC5 KO mouse.