The transcriptional factor, nuclear factor kappa B (NFkB) plays an important role in the regulation of cytokines. Among the cytokines, tumor necrosis factor-alpha (TNF) plays an important role in cardiovascular pathophysiology. This study was done to determine whether TNF-α blockade with etanercept (ETN) or NFkB blockade with dithiol pyrolidine thiocarbamate (PDTC) attenuate oxidative stress in the paraventricular nucleus (PVN) and contribute to neurohumoral excitation in spontaneously hypertensive rats.
Method:
Male 20 week old SHR rats were treated with ETN (1 mg/kg BW, sc) or PDTC (100mg/kg BW, ip) for 5 week period. Left ventricular function was measured at baseline (20 weeks) and at 25 weeks using echocardiography. Blood pressure was measured at weekly intervals throughout the study. At the end of the protocol rats were sacrificed the PVN was microdissected for the measurement of cytokines, oxidative stress markers using real time PCR (fold increase compared to WKY controls) and by immunohistochemistry. Superoxide, total reactive oxygen species and peroxynitrite were measured in the PVN and LV using electron paramagnetic resonance. Plasma norepinephrine and epinephrine an indicator of neurohumoral excitation was measured using HPLC-EC.
Results:
PVN data are tabulated. SHR animals had increased expression of protein and mRNA for cytokines and oxidative stress markers in the PVN and LV with increased MAP and cardiac hypertrophy when compared to WKY rats. Treatment with ETN and PDTC attenuated these increases with PDTC showing marked effect than ETN on hypertrophy and blood pressure responses.
Conclusion:
These findings suggest that cytokine activation in the PVN contributes to increased oxidative stress and neurohumoral excitation in hypertension.
Macrophage migration inhibitory factor in hypothalamic paraventricular nucleus neurons decreases blood pressure in spontaneously hypertensive rats
