Abstract 1597: Angiotensin II Type 1 Receptor Antagonism Reduces Sympatho-Excitatory Inflammatory Mediators in Paraventricular Nucleus of Hypothalamus in Rats with Heart Failure
Introduction: Activity of the brain renin-angiotensin system (RAS) is augmented in heart failure (HF). Angiotensin II (ANG II), the main active component of the RAS, can activate the transcription factor nuclear factor kappa B (NFκB), and by that mechanism may increase brain expression of cytokines and other inflammatory mediators that contribute to sympathetic nerve activity in HF.
Hypothesis: Angiotensin type 1 receptor (AT1R) antagonism with valsartan (VAL) may inhibit NFκB activity and prevent the expression of inflammatory mediators in the brain, thereby ameliorating the augmented sympathetic drive in HF rats.
Methods: Sprague Dawley rats underwent coronary ligation to induce HF (n=17), or sham surgery (SHAM, n=7). HF was confirmed by echocardiography. Eight HF rats received VAL (30 mg/kg/day orally) or vehicle (VEH, water) for 6 weeks. Interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) mRNA in brain were measured by real time PCR; NFκB p50 subunit precursor p105 and its inhibitor IκB mRNA were measured by multiplex PCR (data normalized to GAPDH). Cerebrospinal fluid prostaglandin E2 (CSF PGE2) and plasma norepinephrine (NE) levels were measured by ELISA.
Results: HF+VEH had increased (*P<0.05; **P<0.01, vs SHAM) mRNA expression of IL-1β (0.12±0.02* vs 0.05±0.01), TNF-α (0.13±0.02** vs 0.04±0.01) and COX-2 (0.09±0.01** vs 0.04±0.01) in paraventricular nucleus (PVN) of hypothalamus, and these increases were accompanied by elevated mRNA expression of NFκB p105 (0.43±0.04** vs 0.18±0.03) and reduction in its inhibitor IκB (0.36±0.04** vs 0.69±0.05). HF+VEH rats also had higher CSF PGE2 (1587±231* vs 553±63 pg/ml) and plasma NE (1119±132* vs 293±62 pg/ml) levels. HF+VAL had less (# P<0.05, vs HF+VEH) IL-1β (by 42%#), TNF-α (by 40%#), COX-2 mRNA (by 30%#) in PVN and lower CSF PGE2 (by 32%#) and plasma NE (by 37%#) levels. HF+VAL also had reduced NF-κB p105 mRNA (by 42%#) and increased IκB mRNA (by 39%#) in PVN.
Conclusion: In HF rats, the upregulated brain RAS activates NFκB to increase synthesis of inflammatory mediators. The effect of central AT1R antagonists to reduce the augmented sympathetic nerve activity in HF is due at least in part to reduced ANG II activation of NFκB.