Low doses of
sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and
liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of
portal hypertension. The aim of our study was to explore whether the combination of
propranolol and
sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and
sham-operated control rats were treated by gavage with vehicle,
propranolol (30 mg·kg(-1)·day(-1)),
sorafenib (1 mg·kg(-1)·day(-1)), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or
sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats,
propranolol and
sorafenib produced a significant (P < 0.001) and similar reduction in PP (-19 and -15%, respectively). This was achieved through different mechanisms: whereas
propranolol decreased PP by reducing portal blood flow (-35%; P = 0.03),
sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (-30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (-39%) under combined
therapy was not significantly greater than after
propranolol alone.
Sorafenib, alone or in combination with
propranolol, produced significant reduction in portal-systemic shunting (-25 and -33%, respectively), splanchnic vascularization (-37 and -41%, respectively),
liver fibrosis (38%), and hepatic neovascularization (-42 and -51%, respectively). These effects were not observed after
propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and
liver fibrosis, suggesting that this
drug combination is a potentially useful strategy in the treatment of
portal hypertension.