Abstract 5839: The Reduction of Brain Sigma-1 Receptor Contributes to Sympathetic Hyperactivation in Heart Failure
Background: Recently, it has been reported that sigma-1 receptor contributes to the pathogenesis of depression. Bidirectional relationships between depression and heart failure are well known and both diseases have high sympathetic outflow. In the central nervous system, sigma-1 receptor modulates neuronal calcium mobilization and N-methyl-D-aspartate (NMDA)-mediated response. Therefore, we hypothesized that sigma-1 receptor modulates sympathetic activity and contributes to sympathetic hyperactivation in heart failure.
Methods and Results: In mice, we performed aortic banding to create pressure overload as a model of heart failure. Four weeks after the banding, we fed the mice with high salt diet for additional 4 weeks to accelerate cardiac dysfunction (AB-H). Sham operation was performed as control (Sham). AB-H had decreased percent fractional shortening [28±3 versus 46±4 (%), p<0.05, n=3], increased left ventricular diastolic/systolic dimension [37±4/26±3 versus 31±3/16±2 (mm), p<0.05, n=3] and augmented sympathetic activity [695±36 versus 317±20 (ng/day), p<0.05, n=5]. The expression of brain (circumventricular tissues) sigma-1 receptor was significantly lower in AB-H than in Sham. Intracerebroventricular infusion of selective sigma-1 receptor agonist (PRE 084 1mM, 1μL/min for 10 min) lowered heart rate (HR) in both groups. However changes in HR were significantly smaller in AB-H than in Sham [−45±9 versus −91±12 (bpm)]. Furthermore, sympathetic activity evaluated by power spectral analysis was decreased only in Sham.
Conclusions: The brain sigma-1 receptor modulates sympathetic activity. The decrease in sigma-1 receptor contributes to sympathetic hyperactivation in mice with heart failure.