Nitrosative Stress-Induced Disruption of Baroreflex Neural Circuits in a Rat Model of Hepatic Encephalopathy: A DTI Study

Abstract

The onset of hepatic encephalopathy (HE) in liver failure is associated with high mortality; the underlying mechanism is undecided. Here we report that in an acute liver failure model employing intraperitoneal administration of thioacetamide in Sprague-Dawley rats, diffusion weighted imaging revealed a progressive reduction in apparent diffusion coefficient in the brain stem. Diffusion tensor imaging further showed that the connectivity between nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in brain stem and rostral ventrolateral medulla (RVLM), the origin of sympathetic innervation of blood vessels, was progressively disrupted until its disappearance, coincidental with the irreversible cessation of baroreflex-mediated sympathetic vasomotor tone signifying clinically the occurrence of brain death. In addition, superoxide, nitric oxide, peroxynitrite and ammonia levels in the NTS or RVLM were elevated, alongside swelling of astroctytes. A scavenger of peroxynitrite, but not an antioxidant, delivered intracisternally reversed all these events. We conclude that nitrosative stress because of augmented peroxynitrite related to accumulation of ammonia and swelling of astrocytes in the NTS or RVLM, leading to cytotoxic edema in the brain stem and severance of the NTS-RVLM connectivity, underpins the defunct baroreflex-mediated sympathetic vasomotor tone that accounts for the high mortality associated with HE.

MRI findings in two West Highland White Terrier dogs with hepatic encephalopathy secondary to portosystemic shunt

“…As cells swell because of inward shift of water, there is a commensurate decrease in diffusion, identified as low signal on apparent diffusion coefficient (ADC) 5. This finding was observed in both dogs and it was previously reported in human patients with fulminant hepatic failure 15.…”

Baroreflex functionality in the eye of diffusion tensor imaging

“…) and rats (Tsai et al . b ), we rarely encountered (6 out of 112 observations in mice; 15 out of 88 observations in rats; P < 0.0001, Chi‐square analysis) the presence of functional connectivity between the NTS and CVLM under basal conditions or in animal models of diseases. To comply with statutory regulations on experiments using laboratory animals, mice were under isoflurane anaesthesia during the MRI procedures.…”

“…) and rats (Tsai et al . b ), this visualization is now feasible. More importantly, the degree of prevalence of traffic within the neural circuits of cardiac vagal baroreflex and baroreflex‐mediated sympathetic vasomotor tone has been shown to bear physiological, pathophysiological and pathological implications.…”

“…; Tsai et al . b ). However, the two arms of the baroreflex exhibit disparity both in mode of operation and time course (Fig.…”

“…By successfully imaging changes in functional connectivity between key brainstem nuclei involved in the baroreflex circuits of mice and rats, recent work, primarily from our group (Tsai et al . , , a , b ; Su et al . ), has offered some new and controversial insights on DTI in general, and functionality of the baroreflex in particular.…”