Abstract 411: Cytokine Receptors in the Subfornical Organ Mediate Sympathetic and Hemodynamic Responses to Peripherally Administered TNF-α and IL-1β in Rat

Abstract

Introduction: Pro-inflammatory cytokines (PIC) play an important role in regulating autonomic and cardiovascular function in hypertension (HTN) and heart failure (HF). Peripherally administered PIC such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) act within the brain to increase blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA). These molecules are too big to cross blood brain barrier (BBB), and so the mechanisms by which they activate sympathetic drive to elicit hemodynamic responses remain quite a mystery. Our preliminary data indicate a dense distribution of TNF-α and IL-1β receptors in the subfornical organ (SFO), a forebrain which lacks a BBB and can be accessed readily by circulating PIC. The SFO projects to the hypothalamic paraventricular nucleus, which has been implicated as an important source of cardiovascular and autonomic dysfunction in HTN and HF. Hypothesis: SFO neurons sense circulating PIC and mediate their effects on sympathetic drive and hemodynamic responses. Methods: One week after an SFO lesion or a sham lesion (SHAM), urethane anesthetized male SD rats underwent an intracarotid artery (ICA) injection of TNF-α (200 ng) or IL-1β (200 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were recorded. Results: In SHAM rats (n=5), ICA TNF-α dramatically increased (* p<0.05 vs. baseline) the BP (23 ± 1.5*), HR (61 ± 5*) and RSNA (88.5 ± 4.3 %*) responses, which peaked ∼30 min after injection. These early excitatory responses to ICA TNF-α were absent in SFO-lesioned rats (n=5), though a moderate excitatory response occurred hours later. Similarly, ICA IL-1β elicited increases in BP (21.8 ± 2.1*), HR (62 ± 6*) and RSNA (116.5 ± 5.2*) in the SHAM rats (n=5). In the SFO-lesioned rats (n=5), the BP (8.6 ± 1.3 †), HR (24 ± 2 †) and RSNA (26.8 ± 1.6 †) responses to ICA IL-1β were significantly († <0.05 vs. SHAM) attenuated. Conclusion: These data suggest that the SFO plays an important role as a central nervous system sensor of the peripheral inflammatory state, mediating the effects of circulating PIC on sympathetic drive and cardiovascular function in inflammatory conditions such as HTN and HF. The later occurring excitatory responses to PIC are unexplained but may involve their known vascular effects.