Time-dependent effects of training on cardiovascular control in spontaneously hypertensive rats: role for brain oxidative stress and inflammation and baroreflex sensitivity

PLoS One. 2014 May 1;9(5):e94927. doi: 10.1371/journal.pone.0094927. eCollection 2014.

Abstract

Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (-13%) at the 4th week, and, by reduced vasomotor component of pressure variability (-28%) and decreased mean arterial pressure (-7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baroreflex
  • Blood Pressure
  • Disease Models, Animal
  • Heart Rate
  • Hemodynamics
  • Hypertension / metabolism*
  • Hypertension / physiopathology*
  • Inflammation
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • NADPH Oxidases / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Physical Conditioning, Animal*
  • Rats
  • Rats, Inbred SHR
  • Reactive Oxygen Species / metabolism

Substances

  • NF-kappa B
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Mitogen-Activated Protein Kinases

Grants and funding

This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, research grant 09/54299-1), Conselho Nacional de Pesquisa (CNPq, research Grant 304060/2011-9) and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, fellowship to GSM). L.C. Michelini is a research fellow from CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.