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-α (TNF-α), influence the subfornical organ (SFO) to modulate sympathetic activity and blood pressure. The pressor effects of TNF-α in the SFO are partially mediated by angiotensin II (ANG II) receptor type 1 (AT₁R), and TNF-α is known to potentiate ANG II-induced hypertension. However, the cellular mechanism of the interaction between TNF-α and ANG II/AT₁R 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-α 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 AT₁R signaling and extracellular Ca²⁺. We then tested the hypothesis that TNF-α may modulate the effects of ANG II on SFO neurons by examining the effects of TNF-α treatment on the ANG II-induced rise in intracellular Ca²⁺. We discovered that TNF-α potentiated the ANG II-induced rise in intracellular Ca²⁺, an effect that was dependent on the duration of TNF-α 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/AT₁R activity by TNF-α in SFO neurons results from the previously demonstrated ability of this cytokine to modulate the activation threshold of vgNa⁺ currents.