Abstract 113: Cytokines Expression in Hypothalamic Paraventricular Nucleus Account for Cardiovascular Deficits and Improved Functions after Training in Spontaneously Hypertensive Rats.

Abstract

Aim: To analyze the sequence of adaptive responses induced by training (T) on both hemodynamic profile and cytokines gene expression within the paraventricular nucleus (PVN). Methods: SHR submitted to T (treadmill, 55% maximal capacity, 1h/day, 5 d/week) or kept sedentary (S), were cannulated for measurement of pressure (BP), heart rate (HR) and baroreflex sensitivity (BrS) at rest on weeks 0, 1, 2, 4 and 8 of protocols. HR and BP variability (power spectral analysis) were also evaluated. After euthanasia, brains were removed for isolation of PVN. Total mRNA was extracted for quantification of TNFα and IL-6 expression by real time PCR (HPRT as the endogenous gene). WKY were used as time controls. One-way ANOVA, with Fisher post-hoc test and Pearson correlation were employed. Results: At the beginning of the protocols, SHR exhibited high mean BP and HR, decreased BrS, increased BP variability and decreased HR variability (170±3 mmHg, 356±7 b/min; 2.3±0.2 b/min/mmHg, 14±2 mmHg 2 and 14±2 ms 2 ) when compared to WKY (119±2 mmHg, 307±6 b/min; 3.6±0.3 b/min/mmHg, 6±1 mmHg 2 and 22±2 ms 2 , respectively). Pro-inflammatory cytokines expression in PVN are also elevated in SHR vs WKY (TNF-α= 1.9±0.3 vs 1.2±0.1, IL-6= 4.9±0.8 vs 1.1±0.3 UA). In the SHR, T caused significant increases on BrS (4.0±0.2 b/min/mmHg, T 2 -T 8 ), HR variability (21±1 ms 2 , with a 60% increase of HF component from T 4 -T 8 ) and prevented the increase on BP variability in the SHR (13±2 vs 20±3 mmHg 2 , T 8 vs S 8 , with 29% reduction of LF component at T 8 ). T caused a prompt normalization of TNFα and IL-6 mRNA expression within the PVN (1.3±0.2 and 0.9±2 UA at T 2 ), accompanied by HR reduction (338±4 b/min, T 4 -T 8 ) and mean BP fall (159±6 mmHg, T 8 ), with significant correlations between TNFα x HR variability (Y=-3.6x+24.3, r= -0.29; P=0.04), TNFα x BrS (Y=-0.7x+4.3, r=-0.35; P=0.01), TNFα x BP (Y=9x+140, r= 0.26; P=0.04) and TNFα x HR (Y=18x+309, r= 0.29; P=0.03). PVN IL-6 content was also correlated with HR variability (Y=-1.8x+21.5, r=-0.36; P=0.01), BrS (Y= -0.3x+4.2, r=-0.44; P<0.001) and HR (Y=7x+324, r=0.30; P=0.02). Conclusions: Data suggested the involvement of PVN pro-inflammatory cytokines in the mediation of cardiovascular deficits in the SHR and the efficacy of T to prompt normalize these deleterious effects.