ObjectiveThe liver is innervated by the vagus nerve. Its efferent neurotransmitters acetylcholine (ACh) and vasoactive intestinal peptide (VIP) are both well-known vasodilators. A study was undertaken to determine whether electrical vagus nerve stimulation (STIM) influences portal vein pressure.MethodsThe left vagus nerve upstream of the hepatic branch was stimulated at 5 Hz (ACh release) and 10 Hz (VIP release) in normal and cirrhotic rats.ResultsSTIM at both frequencies decreased portal pressure in normal rats while, in cirrhotic rats, only 10 Hz STIM resulted in long-lasting reduction of portal pressure. Hepatic branch vagotomy prevented the STIM-induced decrease in pressure, proving that the effect is a direct hepatic effect. Deafferentation of the left vagus nerve by pretreatment with capsaicin did not change the effect of STIM, showing that the vagus efferents and not the afferents are responsible for the decrease in portal pressure. Injecting microspheres before and after STIM showed that STIM did not lead to redistribution of systemic blood flow but decreased portal pressure by lowering intrahepatic resistance. Using in situ liver perfusion to evaluate the intrahepatic effect of ACh and VIP, both neurotransmitters significantly decreased the perfusion pressure in normal rats. VIP also decreased portal pressure in cirrhotic rats, confirming the results of STIM. This VIP-induced decrease in pressure could be prevented by a VIP receptor 2 antagonist. L-NAME did not inhibit the VIP effect in cirrhotic rats, indicating that VIP does not act via nitric oxide.ConclusionHigh-frequency electrical vagus stimulation improves portal hypertension in cirrhotic rats, most likely through release of VIP, binding to VIP receptor 2. As the technology is already in use for other applications, vagus nerve stimulation might be an important new strategy in the treatment of portal hypertension.