Interaction Between AT1 Receptor and NF-κB in Hypothalamic Paraventricular Nucleus Contributes to Oxidative Stress and Sympathoexcitation by Modulating Neurotransmitters in Heart Failure

Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-kappa B) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-kappa B contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-kappa B in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10 mu g/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5 mu g/h), a NF-kappa B inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-kappa B p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKK beta and gp91(phox) (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91(phox), NF-kappa B activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-kappa B in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.