Immediate early gene expression in the central nervous system in portal hypertension: Functional and immunohistochemical studies

Portal hypertension is associated with hyperdynamic circulation, but the pathogenesis remains unclear. To clarify the role of central cardiovascular regulatory mechanisms, I used portal vein stenosis (PVS) induced portal hypertension in rats in the present study. Neuronal activation was quantified by immunohistochemical staining for Fos, the protein product of the c-fos gene. Fos expression in several brain nuclei with cardiovascular-regulatory roles was examined at 1,3,5 and 10 days following PVS surgery. The results showed that Fos-positive neurons were significantly increased in the paraventricular nucleus of hypothalamus, supraoptic nucleus, ventrolateral medulla (VLM) and nucleus tractus solitarius (NTS), detectable at day 1 and persistently increased at every day examined in the PVS rats. However, the hyperdynamic circulation developed between days 3 to 5. Capsaicin treatment not only significantly reduced the number of Fos-positive neurons in portal hypertensive and cirrhotic rats, but also attenuated hemorrhage-induced Fos and double-positive cells (TH and Fos) in both the NTS and VLM. These results suggest that disordered function in Capsaicin-sensitive nerves and central dysregulation contribute to blunted cardiovascular responsiveness in cirrhosis and prehepatic portal hypertension. Finally, Fos expression in the NTS was blocked by local microinjection of c-fos antisense oligonucleotides twice daily for 5 days following PVS. c-fos antisense oligonucleotides eliminated the hyperdynamic circulation in PVS rats, but had no effect on sham-operated controls. I conclude that the activation of central cardiovascular-regulatory nuclei, through a c-fos-dependent pathway, is necessary for development of hyperdynamic circulation in portal-hypertensive rats.