Findings from our laboratory indicate that proinflammatory
cytokines and their
transcription factor,
nuclear factor-kappaB (NF-κB), are increased in the hypothalamic paraventricular nucleus (PVN) and contribute towards the progression of
heart failure. In this study, we determined whether NF-κB activation within the PVN contributes to sympathoexcitation via interaction with
neurotransmitters in the PVN during the pathogenesis of
heart failure.
Heart failure was induced in rats by left anterior descending coronary artery
ligation.
Sham-operated control (
SHAM) or
heart failure rats were treated for 4 weeks through bilateral PVN infusion with SN50, SN50M or vehicle via osmotic minipump. Rats with
heart failure treated with PVN vehicle or SN50M (inactive
peptide for SN50) had increased levels of
glutamate,
norepinephrine (NE),
tyrosine hydroxylase (TH),
superoxide, gp91(
phox) (a subunit of
NAD(P)H oxidase), phosphorylated IKKβ and NF-κB p65 activity, and lower levels of
gamma-aminobutyric acid (
GABA) and the 67-kDa
isoform of
glutamate decarboxylase (GAD67) in the PVN compared with those of
SHAM rats. Plasma levels of
cytokines,
norepinephrine,
epinephrine and
angiotensin II, and renal sympathetic nerve activity (RSNA) were increased in
heart failure rats. Bilateral PVN infusion of SN50 prevented the decreases in PVN
GABA and GAD67, and the increases in RSNA and PVN
glutamate,
norepinephrine, TH,
superoxide, gp91(
phox), phosphorylated IKKβ and NF-κB p65 activity observed in vehicle or SN50M-treated
heart failure rats. A same dose of SN50 given intraperitoneally did not affect
neurotransmitters concentration in the PVN and was similar to vehicle-treated
heart failure rats. These findings suggest that NF-κB activation in the PVN modulates
neurotransmitters and contributes to sympathoexcitation in rats with
ischemia-induced
heart failure.