Central treatment of simvastatin normalizes sympathetic outflow in CHF rabbits by a nNOS mechanism

Abstract

In a previous study in CHF rabbits we demonstrated a suppressed RSNA by simvastatin (SIM) via inhibition of an AngII-ROS mechanism. However SIM also has been shown to affect NOS and NO, which has long been known to be involved in the regulation of SNA. The purpose of this experiment was to determine the effects of SIM on RSNA and the involved NO mechanisms in CHF rabbits and in a neuronal cell line. We found that, In CHF rabbits, icv infusion of SIM significantly suppressed basal RSNA (1st day 69.5 ± 8.9 % of Max; 7th day 26.0 ± 6.0 % of Max. P < 0.05) and enhanced arterial baroreflex function (Slope: 1st day −1.9 ± 0.8; 7th day, −6.8 ± 1.4. P < 0.01) starting from the 2nd day and lasting through the following 5 days; This treatment significantly up regulated nNOS protein expression in the RVLM (Control, 0.68 ± 0.25; SIM treated, 1.34 ± 0.31. P < 0.05, n = 4 each group); In CATH.a neurons, incubation with SIM significantly up regulated nNOS mRNA (Control 0.89 ± 0.32, SIM 2.63 ± 0.52, P < 0.05, n = 3), which was blocked by co-incubation with Mevalonate, FPP, or GGPP; Incubation with Y-27632, on the other hand, significantly up regulated nNOS mRNA expression in these neurons. These results suggest that central treatment of SIM decreased sympathetic outflow in CHF rabbits via up regulation of nNOS expression in RVLM, which probably is due to the inhibition of HMG-CoA reductase and a decrease in Rho Kinase by SIM.