1 Scientific RepoRts | 6:31076 | DOI: 10.1038/srep31076 www.nature.com/scientificreports Decompensated liver cirrhosis and neural regulation of mesenteric vascular tone in rats: role of sympathetic, nitrergic and sensory innervations esther sastre 1,2 , Laura Caracuel 1,2 , Isabel prieto 2,3 , pablo Llévenes 1 , M. Ángeles Aller 4 , Jaime Arias 4 , Gloria Balfagón 1,2 & Javier Blanco-Rivero 1,2 We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical feld stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non-specifc nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments. Vasomotor responses to noradrenaline (NA) or CGRP were greater in LC segments, while NO analogue DEA-NO induced a similar vasodilation in both experimental groups. The release of NA was not modifed, while those of ATP, nitrite and CGRP were increased in segments from LC. Alpha 1 adrenoceptor, Rho kinase (ROCK) 1 and 2 and total myosin phosphatase (MYPT) expressions were not modifed, while alpha 2B adrenoceptor, nNOS expression and nNOS and MYPT phosphorylation were increased by LC. Together, these alterations might counteract the increased splanchnic vasodilation observed in the last phases of decompensated liver cirrhosis. Liver cirrhosis is a common disease currently ranked as one of the 10 most common causes of death in the Western world (Stewart and Day, 2003). It courses with portal hypertension (PH) related to augmented hepatic vascular resistance, caused by an increase in vasoconstrictor factors like thromboxane A 2 (TXA 2 ) 1 , and a reduc- tion in nitric oxide (NO) bioavailability 2 . Tis pathology is also associated with the development of hyperdynamic circulation 3 , in which peripheral arterial vasodilation, mainly in the splanchnic circulation, plays a major role 4 . Tis decreased splanchnic vascular resistance is associated to alterations in diferent endothelial factors in these vessels, such as increased release and sensitivity of vasodilator factors like NO 5,6 and prostaglandin I 2 (PGI 2 ) 7,8 as well as decreased response to factors like noradrenaline (NA) 9 , phenylephrine or U-46619 10,11 . Endothelial factor participation is known to change over time in the course of liver cirrhosis. Tus, although the increase in splanchnic and systemic circulation is maintained in decompensated liver cirrhosis and long-term PH models, NO involvement decreases, leading to greater participation by PGI 2 12–15 . Apart from endothelial factors, vascular tone is also determined by the participation of perivascular innerva- tion. Rat mesenteric arteries possess rich sympathetic 16 , nitrergic 17,18 and sensory 19 innervations, which respec- tively release NA and ATP, NO and calcitonin gene related peptide (CGRP), when electrically stimulated. Tese neurotransmitters participate in vasomotor tone modulation through their vasoconstrictor and vasodilator actions on smooth muscle cells. We have reported that diferent physiopathological situations, such as aging 20,21 , 1 Departamento de fisiología, facultad de Medicina, Universidad Autónoma de Madrid, españa. 2 instituto de investigación Sanitaria del Hospital Universitario La Paz (idiPAZ), Madrid, españa. 3 Departamento de cirugía General y Digestiva, Hospital la Paz, Madrid, españa. 4 cátedra de cirugía, facultad de Medicina, Universidad complutense de Madrid, españa. correspondence and requests for materials should be addressed to J.B.-R. (email: javier.blanco@ uam.es) Received: 09 February 2016 Accepted: 14 July 2016 Published: 03 August 2016 OPEN