A recent study published in Hypertension demonstrates that cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α acting at the level of the subfornical organ induce the expression of inflammatory and excitatory mediators that subsequently drive sympathetic nervous system activation.
The subfornical organ (SFO), a highly vascularized structure is a circumventricular organ that lacks a blood–brain barrier. Previous research indicates this brain structure is a crucial ‘sensor’ for peripheral inflammation, mediating the central effects of certain pro-inflammatory cytokines, and thus, contributing to an increase in autonomic and neuro-hormonal output.
In the Hypertension study Shun-Guang Wei and colleagues from the University of Iowa Carver College of Medicine, Iowa City, IA examined potential mechanisms in the subfornical organ, and downstream in the PVN, that might mediate cardiovascular and autonomic responses to circulating PICs.
The investigators report that (1) localized microinjections of TNF-α and IL-1βinto the SFO increase BP, HR, and RSNA, closely mimicking the effects of systemically administered TNF-α and IL-1β; (2) pretreating the SFO with microinjections of agents that counter RAS and COX-2 activity attenuates the cardiovascular and sympathetic responses to SFO microinjections of PICs; (3) TNF-α and IL-1β receptor immunoreactivity is colocalized with AT1R-like, ACE, COX-2, and EP3 receptor immunoreactivity on subfornical organ neurons; and (4) subfornical organ microinjections of TNF-α and IL-1β upregulate mRNA for key components of the RAS (ACE and AT1R) and mediators of central inflammation (TNF-α and IL-1β, their receptors and COX-2) in both SFO and PVN.
These findings suggest that the SFO-mediated acute sympathoexcitatory response to PICs depends on the ambient level of RAS and COX-2 activity and that PICs act within the subfornical organ to increase RAS and COX-2 activity.
The authors provide evidence that IL-1β and TNF-α up-regulate mediators and mechanisms that increase the brain renin–angiotensin system (RAS) activity or prostaglandin E2production in the SFO of male Sprague–Dawley rats.
This study provides new insights into the central mechanisms driving neurohumoral excitation in cardiovascular disorders like HF and hypertension.
The SFO is directly exposed to blood-borne signals and peripheral cytokines, and it projects straight to the cardiovascular autonomic nuclei.
The authors suggest that through the above mentioned effects and mechanisms, peripheral pro-inflammatory cytokines are able to drive a chronic and sustained hyperactivity of the sympathetic nervous system observed in pathologic states such as heart failure or some forms of hypertension.
In addition, according to the authors, these mechanisms and pathogenic loops can be amplified by other excitatory mediators, like angiotensin II and aldosterone that circulate in chronic states like heart failure and hypertension.