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

Portal hypertension is associated with hyperdynamic circulation, but the pathogenesis remains unclear. To clarify the role of central cardiovascular regulatory mechanisms, several protocols were conducted in rats with portal hypertension due to portal vein stenosis (PVS). 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. This was correlated with development of cardiovascular changes measured at the same time points. Finally, Fos expression in the nucleus tractus solitarius (NTS) was blocked by local microinjection of c-fos antisense oligonucleotides twice daily for 5 days following PVS. The results showed that Fos-positive neurons were significantly increased in the paraventricular nucleus of hypothalamus, supraoptic nucleus, ventrolateral medulla, and 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. Administration of c-fos antisense oligonucleotides eliminated the hyperdynamic circulation in PVS rats, but had no effect on sham-operated controls. We 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.