In renovascular hypertension, TNF- type-1 receptors in the area postrema mediate increases in cardiac and renal sympathetic nerve activity and blood pressure

Aims Neuroinflammation is a common feature in renovascular, obesity-related, and angiotensin II mediated hypertension. There is evidence that increased release of the pro-inflammatory cytokine tumour necrosis factor- (TNF-) contributes to the development of the hypertension, but the underlying neural mechanisms are unclear. Here, we investigated whether TNF- stimulates neurons in the area postrema (AP), a circumventricular organ, to elicit sympathetic excitation, and increases in blood pressure (BP). Methods and results In rats with renovascular hypertension, AP neurons that expressed TNF- type-1 receptor (TNFR1) remained constantly activated (expressed c-Fos) and injection of TNFR1 neutralizing antibody into the AP returned BP (systolic: approximate to 151mmHg) to normotensive levels (systolic: approximate to 108mmHg). Nanoinjection of TNF- (100pg/50 nL) into the AP of anaesthetized normotensive rats increased BP (approximate to 16mmHg) and sympathetic nerve activity, predominantly to the heart (approximate to 53%), but also to the kidneys (approximate to 35%). These responses were abolished by prior injection of a TNFR1 neutralizing antibody (1ng/50 nL) within the same site. TNFR1 were expressed in the somata of neurons activated by TNF- that were retrogradely labelled from the rostral ventrolateral medulla (RVLM). Conclusion These findings indicate that in renovascular hypertension, blocking TNFR1 receptors in the AP significantly reduces BP, while activation of TNFR1 expressing neurons in the AP by TNF- increases BP in normotensive rats. This is mediated, in part, by projections to the RVLM and an increase in both cardiac and renal sympathetic nerve activity. These findings support the notion that proinflammatory cytokines and neuroinflammation are important pathological mechanisms in the development and maintenance of hypertension.