Cardiovascular function in cirrhosis is deranged, with indi-
Cirrhosis is associated with abnormal cardiovascular phenomena. These include the development of hyperdynamic rect evidence of abnormal central cardiovascular regulation. We aimed to elucidate the role of brainstem cardiovascular circulation and impairment of cardiac contractility. [1][2][3][4] Hyperdynamic circulation is manifested by elevated cardiac output, nuclei in hemodynamic regulation by examining the protein product, Fos, of the immediate-early gene c-fos, in cirrhotic increased blood flow, and lowered peripheral vascular resistance and arterial blood pressure. [1][2][3] However the precise rats. Cirrhosis was induced by chronic bile duct ligation (BDL) of 25-days duration, while controls underwent a sham causes and mechanisms of this hyperdynamic circulation remain unclear. Humoral factors, such as nitric oxide, gluca-operation. To examine the effects of jaundice per se in the absence of cirrhosis, a third group of 5-day BDL rats was also gon, bile salts, and prostaglandins have been proposed, but the results to date have proved inconclusive. 5-9 studied. All rats were anesthetized with pentobarbital, and catheters were inserted to measure baseline blood pressure
Neural factors have also been implicated. Sympathetic nervous activity has been shown to be enhanced in cirrhosis, [10][11][12][13][14] and heart rate. Separate groups were then subjected to volume manipulation by a hypotensive hemorrhage or isotonic saline although the mechanism by which sympathetic activation leads to hyperdynamic circulation, and the level at which infusion, or no challenge. Ninety minutes after the volume manipulation, the animals were killed and the medulla sec-these alterations arise, remains to be elucidated. Although indirect evidence has suggested that central sympathetic tone tioned and stained for Fos by immunohistochemisty. The nucleus tractus solitarius (NTS) of the sham-operated unchal-is increased, 10-14 to date, this hypothesis has not been directly tested. lenged rats showed scant Fos immunoreactivity (27.8 { 3.3 cells), but both hemorrhage and volume infusion significantly C-fos is an immediate-early gene that is rapidly and transiently expressed within cells in the central nervous system increased Fos staining (86.0 { 3.7 and 95.2 { 8.5, respectively). In contrast, the unchallenged cirrhotic rats showed as a result of membrane depolarization and voltage-gated calcium influx. 15,16 Its protein product, Fos, can be detected markedly increased Fos in the NTS (154.6 { 27.0), but neither hemorrhage nor volume infusion significantly changed by immunohistochemistry. Basal levels of Fos immunoreactivity are known to be low, 15 and the presence of Fos immu-the amount of Fos staining. Fos staining in the ventrolateral medulla (VLM) followed a similar pattern with low staining noreactivity within neurons is therefore indicative of activation of these cells. Fos has been extensively used and in the unchallenged sham rats and increased staining in the other groups, but no differences between the unchallenged validated as a sensitive marker for identifying and characterizing neuronal activation as a response to stimulation by and the volume-manipulated cirrhotic groups. The 5-day BDL jaundiced rats showed no baseline increase in Fos staining, external factors. 17 More particularly, Fos staining has been used to identify and characterize neuronal activation and nor any significant increase after hemorrhage. These results showing baseline activation of central neuronal regions re-pathways in the brainstem in response to cardiovascular challenge. 17-21 sponsible for blood pressure homeostasis, but completely blunted responsiveness in cirrhotic rats, confirm a central
We therefore hypothesized that central regulatory mechanisms are indeed disordered, and that this would be mani-origin of disordered cardiovascular regulation. The presence of jaundice may also contribute to the central cardiovascular fested by neuronal activation in the brainstem cardiovascular control centers. Accordingly, we aimed to test this notion by hyporesponsiveness. (HEPATOLOGY 1997;26:1380-1385.) examining Fos expression in these neurons in 4-week bile duct-ligated (BDL) cirrhotic and control sham-operated rats, in the basal state and following a cardiovascular stimulation Abbreviations: BDL, bile duct-ligated; PBS, phosphate-buffered saline; NTS, nuof either volume depletion or infusion. We also studied a cleus tractus solitarius; VLM, ventrolateral medulla.
group of 5-day BDL rats with acute cholestasis but no cirrho-From the Liver Unit, Gastroenterology Research Group, University of Calgary, sis, to delineate the effect of jaundice per se.