Τετάρτη 21 Ιουνίου 2017

The pro-inflammatory cytokine tumor necrosis factor alpha excites subfornical organ neurons

Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNFα-/- mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNFα into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNFα, while direct administration of TNFα into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNFα. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNFα on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNFα depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration-dependent. Interestingly, following 24 hour incubation with TNFα, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNFα elevates SFO neuron excitability. This effect was likely mediated the transient sodium current, as TNFα both increased the magnitude of the current, and lowered its activation threshold. In contrast, TNFα did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNFα exposure elevates SFO neuron activity, providing a basis for TNFα's hypertensive and sympathetic effects.



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