title: Simvastatin inhibits central sympathetic outflow in heart failure by a nitric-oxide synthase mechanism.
abstract: Our previous study demonstrated that oral treatment with simvastatin (SIM) suppressed renal sympathetic nerve activity (RSNA) in the rabbits with chronic heart failure (CHF). The purpose of this experiment was to determine the effects of direct application of SIM to the central nervous system on RSNA and its relevant mechanisms. Experiments were carried out on 21 male New Zealand White rabbits with pacing-induced CHF. The CHF rabbits received infusion of vehicle, SIM, or SIM + N(omega)-nitro-L-arginine methyl ester into the lateral cerebral ventricle via osmotic minipump for 7 days. We found that 1) in CHF rabbits, intracerebroventricular infusion of SIM significantly suppressed basal RSNA (1st day 69.5 +/- 8.9% maximum; 7th day 26.0 +/- 6.0% maximum; P < 0.05, n = 7) and enhanced arterial baroreflex function starting from the 2nd day and lasting through the following 5 days; 2) statin treatment significantly up-regulated neuronal nitric-oxide synthase (nNOS) protein expression in the rostral ventrolateral medulla (RVLM) (control, n = 6, 0.12 +/- 0.04; SIM-treated, n = 7, 0.31 +/- 0.05. P < 0.05); 3) in CATH.a neurons, incubation with SIM significantly up-regulated the nNOS mRNA expression, which was blocked by coincubation with mevalonate, farnesyl-pyrophosphate, or geranylgeranyl-pyrophosphate; and 4) incubation with Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] significantly up-regulated nNOS mRNA expression in these neurons. These results suggest that central treatment with SIM decreased sympathetic outflow in CHF rabbits via up-regulation of nNOS expression in RVLM, which may be due to the inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and a decrease in Rho kinase by SIM.
authors.affiliation: Department of Cellular and Integrative Physiology. University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA. lgao@unmc.edu
authors.forename: Lie
authors.initials: L
authors.lastname: Gao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Irving H
authors.initials: IH
authors.lastname: Zucker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D019821:Simvastatin; D019001:Nitric Oxide Synthase