Abstract 1375: The Role of Nitric Oxide Synthase Uncoupling in Right Ventricular Hypertrophy and Failure
Right ventricular failure (RVF) is the leading cause of death in patients with severe pulmonary hypertension (PH). Despite its profound clinical consequences, little is known about right ventricular (RV) adaptation and failure within the context of PH. NOS uncoupling has been identified as a potential cause of LV failure. In this study, we hypothesized that NOS uncoupling plays an important early role in the RVH/RVF. We studied the mechanisms of RV failure in Dahl Salt-Sensitive (SS) rats using a RV pressure overload model produced by banding the main pulmonary artery (PAB). 11 days following PAB there was marked RV hypertrophy (0.24 vs 0.36) with marked reduction of both systolic and diastolic functions (RVESP 48 vs 22 mmHg, dP/dt IP 46 vs 80, Tau 29.7 vs 19.4 ms). Analysis of NOS activity and dimerization demonstrated that NOS uncoupling (shift from dimer to monomeric NOS with a concomitant drop in NOS activity) occurred within 4 days of PAB and persisted through day 11. To test the hypothesis that NOS uncoupling is secondary to BH4 oxidation, thus limiting NOS cofactor availability, we treated rats with supplemental BH4 (36 mg/kg/d po). We observed that NOS coupling was improved by BH4 treatment 4 days after PAB. Interestingly, we also observed that treatment with the phosphodiesterase 5 inhibitor sildenafil (100 mg/kg/d po) preserved NOS coupling at day 4 and the improvement persisted. Sildenafil treatment also resulted in a marked reduction in luminal chemiluminescence suggesting reduced ROS signaling and there was also a concomitant improvement in RV systolic (dP/dt/IP 74 vs 46) and diastolic (Tau 14.5 vs 29.7 ms) function and a reduction in cardiac hypertrophy (RV/(LV+septum) 0.28 vs 0.36). These data provide the first evidence that RV hypertrophy and failure are associated with NOS uncoupling that can be prevented by BH4 supplementation. Moreover, these data also provide the first evidence that NOS coupling can be prevented in the RV with sildenafil. These data suggest that sildenafil (likely via cGMP/PKG signaling) modulates NOS coupling, possibly via ROS reduction and preventing BH4 oxidation, or that BH4 synthesis itself is regulated by PKG signaling.