Tumor necrosis factor-α potentiates the effects of angiotensin II on subfornical organ neurons

Inflammation is thought to play a fundamental role in the pathophysiology of hypertension and heart failure, although the mechanisms for this remain unclear. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), influence the subfornical organ (SFO) to modulate sympathetic activity and blood pressure. The pressor effects of TNF-alpha in the SFO are partially mediated by angiotensin II (ANG II) receptor type 1 (AT(1)R), and TNF-alpha is known to potentiate ANG II-induced hypertension. However, the cellular mechanism of the interaction between TNF-alpha and ANG II/AT(1)R signaling remains unknown. In the present study, we performed Ca2+ imaging on dissociated SFO neurons in vitro from male Sprague-Dawley rats to determine whether TNF-alpha modulates ANG II-induced increases in intracellular Ca2+ in SFO neurons. We first established that a proportion of SFO neurons respond to ANG II, an effect that required AT(1)R signaling and extracellular Ca2+. We then tested the hypothesis that TNF-alpha may modulate the effects of ANG II on SFO neurons by examining the effects of TNF-alpha treatment on the ANG II-induced rise in intracellular Ca2+. We discovered that TNF-alpha potentiated the ANG II-induced rise in intracellular Ca2+, an effect that was dependent on the duration of TNF-alpha treatment. Finally, we determined that this potentiation of ANG II-induced Ca2+ activity relied on tetrodotoxin-sensitive voltage-gated Na+ (vgNa(+)) channels. These data suggest that the potentiation of ANG II/AT(1)R activity by TNF-alpha in SFO neurons results from the previously demonstrated ability of this cytokine to modulate the activation threshold of vgNa(+) currents.