Blunted responsiveness of the neuronal activation marker Fos in brainstem cardiovascular nuclei of cirrhotic rats

Abstract

Cardiovascular function in cirrhosis is deranged, with indirect evidence of abnormal central cardiovascular regulation. We aimed to elucidate the role of brainstem cardiovascular nuclei in hemodynamic regulation by examining the protein product, Fos, of the immediate-early gene c-fos, in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation (BDL) of 25-days duration, while controls underwent a sham operation. To examine the effects of jaundice per se in the absence of cirrhosis, a third group of 5-day BDL rats was also studied. All rats were anesthetized with pentobarbital, and catheters were inserted to measure baseline blood pressure and heart rate. Separate groups were then subjected to volume manipulation by a hypotensive hemorrhage or isotonic saline infusion, or no challenge. Ninety minutes after the volume manipulation, the animals were killed and the medulla sectioned and stained for Fos by immunohistochemisty. The nucleus tractus solitarius (NTS) of the sham-operated unchallenged rats showed scant Fos immunoreactivity (27.8 +/- 3.3 cells), but both hemorrhage and volume infusion significantly increased Fos staining (86.0 +/- 3.7 and 95.2 +/- 8.5, respectively). In contrast, the unchallenged cirrhotic rats showed markedly increased Fos in the NTS (154.6 +/- 27.0), but neither hemorrhage nor volume infusion significantly changed the amount of Fos staining. Fos staining in the ventrolateral medulla (VLM) followed a similar pattern with low staining in the unchallenged sham rats and increased staining in the other groups, but no differences between the unchallenged and the volume-manipulated cirrhotic groups. The 5-day BDL jaundiced rats showed no baseline increase in Fos staining, nor any significant increase after hemorrhage. These results showing baseline activation of central neuronal regions responsible for blood pressure homeostasis, but completely blunted responsiveness in cirrhotic rats, confirm a central origin of disordered cardiovascular regulation. The presence of jaundice may also contribute to the central cardiovascular hyporesponsiveness.

Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression

“…25 However, accumulating evidence suggests that central nervous regulatory mechanisms are abnormal in liver disease. [26][27][28] Our previous study showed that baseline Fos expression in the NTS and VLM were significantly increased, but neuronal activation responses to both hemorrhage and volume expansion were severely blunted in cirrhotic rats. 28 This finding implies that at least part of the vascular hyporesponsiveness to constrictor or dilator influences might be secondary to attenuated central cardiovascular control mechanisms.…”

Region‐Specific Changes in Transient Receptor Potential Vanilloid Channel Expression in the Vasopressin Magnocellular System in Hepatic Cirrhosis‐Induced Hyponatraemia

“…Chronic bile duct ligation (BDL), a commonly used animal model of obstructive cirrhosis, is associated with elevated circulating vasopressin, cytokines, and activation of the renin-angiotensin system (33, 37–40). In this model, TRPV4 protein content is increased in the SON as is its expression in lipid rafts within the hypothalamus (41).…”

Hyperdynamic mesenteric circulation in cirrhosis: humoral or neural mechanism?

“…In the CNS, neurons that have been activated show nuclear Fos (the protein product of the immediate‐early gene c‐fos ) staining by immunohistochemistry. Lee's lab has demonstrated that neurons in the CV‐regulatory nuclei listed above show persistent activation in portal hypertensive and cirrhotic rats .…”