Evidence of nitric oxide, a flow-dependent factor, being a trigger of liver regeneration in rats

The hypothesis tested was that the hemodynamic consequence of partial hepat ectomy (PHX) triggers the cascade of events that leads to liver regeneratio n. After PHX, all the portal flaw must go through the remaining vascular be d, thus producing increased shear stress and release of nitric oxide (NO), which then initiates the next stages of the regeneration process. As an ind ex of triggering of the regeneration cascade, we used an in vitro bioassay detecting the appearance of proliferating factors (PFs; various growth fact ors, cytokines, and hormones) in plasma 4 h after two-thirds PHX in rats. P F levels, assessed using proliferation of cultured hepatocytes, were elevat ed in two-thirds PHX rats, fully blocked by the NO synthase inhibitor N-G-n itro-L-arginine methyl eater (L-NAME), and restored by L-arginine. L-NAME i nhibited liver weight restoration at 48 h but resulted in high mortality. L -NAME lacked toxic effects in non-PHX rats. NO was directly antiproliferati ve on cultured cells, suggesting that the proliferative effect of NO in viv o was secondary to the activation of other proliferative stimuli. The data support the hypothesis that vascular sheer stress induced release of NO fol lowing PHX serves as a primary trigger to initiate the regeneration process .