Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction
- Lukas Moleda1,
- Jonel Trebicka2,
- Peter Dietrich1,
- Erwin Gäbele1,
- Claus Hellerbrand1,
- Rainer H Straub1,
- Tilman Sauerbruch2,
- Juergen Schoelmerich1,
- Reiner Wiest1
- 1Department of Internal Medicine, University Medical Center, Regensburg, Germany
- 2Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Correspondence to Dr Reiner Wiest, Department of Internal Medicine I, University Medical Center, D-93042 Regensburg; Germany;
- Revised 16 November 2010
- Accepted 27 November 2010
- Published Online First 12 February 2011
Background Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved.
Methods All experiments were performed in CCl4-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α1-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries.
Results NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries.
Conclusions NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.
- Portal hypertension
- splanchnic circulation
- neuropeptide Y
- gastrointestinal blood flow
- hepatic haemodynamics
- liver cirrhosis
- portal hypertension
LM and JT contributed equally to this study.
Funding This study was supported by the Regensburger Forschungsförderung in der Medizin (ReForM,to LM), the Deutsche Foschungsgemeinschaft (SFB TRR57 project 18, to JT) and BONFOR-Stiftung (to JT).
Competing interests None.
Ethics approval All experimental procedures in this study were conducted according to the German Physiological Society principles for the care and use of laboratory animals (Granted permission number 621–2531.1–23/00, government of Bavaria).
Provenance and peer review Not commissioned; externally peer reviewed.