Abstract 18: Improvement of Autonomic Control in Spontaneously Hypertensive Rats

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Abstract

Aim: Previous studies suggested that down-regulation of brain RAS and normalization of pro-inflammatory cytokines (PICs) expression contributed to reverse cardiovascular deficits in trained SHR. We investigate possible mechanisms involved and the sequence of their appearance within the paraventricular nucleus (PVN)

Methods: SHR, submitted to treadmill training (T) or kept sedentary (S), were chronically instrumented for pressure (AP), heart rate (HR) and baroreflex sensitivity (BrS) recordings on weeks 0, 1, 2, 4 and 8 of protocols. After euthanasia fresh brains were removed and PVN dissected to quantify NADPH oxidase and PICs gene expression (real time PCR), DHE oxidation (HPLC), MAPKs phosphorylation (Western Blotting) and NF-kB activity (electrophoretic mobility shift assay); fixed brains were used for PVN PICs immunofluorescence (if). WKY served as time controls. One- or two-way ANOVA (Fisher as post-hoc test) were used

Results: SHR-S vs WKY-S exhibited higher MAP and HR and decreased BrS (170±3 mmHg, 356±7 b/min; 2.31±0.19 b/min/mmHg, corresponding to +43%, +17% and -36%, respectively). SHR-S showed within the PVN increased expression of either p47 NADPH oxidase (2.3±0.2 vs 1.2±0.4 AU), DHE oxidation products (1267±122 vs 300±55 EOH/DHE/μg protein), NFkB binding to the DNA (100 vs 56±20%), TNFα and IL-6 gene & protein expression (1.9±0.3 vs 1.2±0.1 and 4.9±0.8 vs 1.1±0.3 AU, respectively), but normal phospho/total MAPKs. In the SHR, T normalized BrS (4.0±0.2 b/min/mmHg, T2-T8) simultaneously with normalization of both p47phox expression and superoxide content and a marked reduction of phospho/total ERK1/2 expression and NFkB activity. PICs (mRNA & if) were also normalized in SHR-T (T2-T8). These changes preceded a marked decrease on resting HR (T4-T8, with increased HF component of HR variability) and MAP fall simultaneously with reduced LF component of pressure variability, observed only at T8

Conclusions: Data indicate that normalization of oxidative stress and pro-inflammatory profile and reduced ERK1/2 signaling within the PVN are important mechanisms to correct BrS in the trained SHR even in the presence of hypertension. Improvement of baroreflex allows a better vagal control of the heart and abrogates sympathetic vasomotor drive

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