Schematic illustrating proposed mechanism of TLR4 activation and downstream signaling in the PVN hypertension. One of the mechanisms of sustained elevation of blood pressure in essential hypertension could be due to increased activation of TLR4 in the PVN and subsequent activation of NFκB pathway to produce inflammatory alterations, sympathoexcitation, and cardiac hypertrophy. Blockade of TLR4 in the PVN attenuates hypertensive response and prevents detrimental inflammatory changes associated with hypertension. Besides reduction in MAP in VIPER treated SHR rats, we also observed reduction in plasma NE levels. Therefore these beneficial effects might be also due to reduction in plasma NE and HMGB1 levels as observed in this study: HMGB1, high mobility group box 1; MAP, mean arterial pressure; NE, norepinephrine; NFĸB, nuclear factor-kappa B; PVN, paraventricular nucleus; SHR, spontaneously hypertensive rat; TLR4, Toll-like receptor 4; VIPER, viral inhibitory peptide of TLR4.