Abstract
In a previous study we showed that simvastatin (SIM) therapy normalized sympathetic outflow and cardiovascular reflex regulation in chronic heart failure (CHF). However, the precise neural and cellular pathways for these effects are still unknown. Some studies indicate that statins are neuroprotective, in part, by a nitric oxide (NO)- dependent mechanism. It is also well known that NO is sympathoinhibitory. Therefore, we hypothesized that SIM exerts its beneficial effect on sympathetic outflow in CHF via upregulation of neuronal nNOS and eNOS mechanisms. The aims of this study were to determine the effects of SIM on the expression of nNOS and eNOS in a neuronal cell line (CATH.a) and the expression of nNOS in RVLM and PVN in normal rabbits. The results indicate that SIM (1 umol/L) upregulated nNOS expression (mRNA: 1.21±0.14 to 2.12±0.21; ratio of protein: 0.26±0.02 to 0.37±0.03 P<0.05) and eNOS expression (mRNA: 1.43±0.11 to 3.23±0.51, P<0.05) in CATHa cells by real time PCR and Western blotting. The upregulation the expression of nNOS and eNOS were depressed by AngII (100 nmol/L). We also found a similar effect in the RVLM and PVN in normal rabbits fed SIM (3.0 mg/kg/day) for 3 weeks. These data provide implications for the mechanism by which SIM (and probably other statins) normalize sympathetic outflow and cardiovascular reflex regulation in CHF and hypertension. Supported by NIH grant HL038690.
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