Journal of Gastroenterology and Hepatology (2001) 16, 70–78 ity of septic shock are increased both in humans and in animal models. 1–4 Vasodilation associated with septic shock is caused in part by an overproduction of nitric oxide (NO), which in this case is synthesized by the INTRODUCTION Endotoxic shock results in high mortality. In cirrhosis, the frequency of sepsis and the morbidity and mortal- ENDOTOXIN, LIVER AND PANCREAS Aortic hyporeactivity to norepinephrine induced by lipopolysaccharide in cirrhotic rats: Beneficial effects of a non-steroidal anti-inflammatory drug coupled with a nitric oxide donor PASCALE LEFILLIATRE,* PHILIPPE SOGNI,* ,† VIVIANE BERTRAND, † PIERO DEL SOLDATO, ‡ DOMINIQUE PATERON,* RICHARD MOREAU* AND DIDIER LEBREC* *Laboratoire d’Hémodynamique Splanchnique et de Biologie Vasculaire, Institut National de la Santé et de la Recherche Médicale U-481, Hôpital Beaujon, Clichy, † UPRES-A Laboratoire de Recherche Chrirugicale et de Biologie Hépatiques, Université Paris V and Service d’Hépato-Gastroentérologie, Hôpital Cochin, Paris, and ‡ NicOx, Paris, France Abstract Background and Aims: Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodila- tion that is related to nitric oxide (NO) synthase 3 overactivity. Septic shock is frequently associated with cirrhosis and with a vascular induction of NO synthase 2. The aims of this study were to compare the effects of lipopolysaccharide (LPS) in normal and cirrhotic rats, and to test the effects of a-non- steroidal anti-inflammatory drug (NSAID) coupled with a (NO) donor. Methods: Cirrhotic rats received NO-flurbiprofen, flurbiprofen or vehicle followed by LPS or placebo 15 min later. The heart rate and mean arterial pressure of rats were monitered for 5 h. Thoracic aortic rings were removed and contracted with the use of norepinephrine. Nitric oxide synthase activity was measured in the aorta and stomach of cirrhotic rats. Results: Arterial pressure decreased in cirrhotic rats in the vehicle/LPS and flurbiprofen/LPS groups. After LPS administration, the heart rate of rats increased in all groups. In the aortic rings, LPS induced hyporeactivity to norepinephrine in all groups except the NO-flurbiprofen group. This hyporeactivity was abolished after preincubation with N w -nitro-L-arginine (L-NNA). N w -nitro-L-arginine had no effect on norepinephrine-induced vasoconstriction in the NO-flurbiprofen/LPS group. Nitric oxide synthase 2 activity in the stomach and aorta of cirrhotic rats was increased in each group except in the NO- flurbiprofen group after LPS administration. Pretreatment with NO–NSAID prevented aortic hypore- activity to norepinephrine in cirrhotic rats treated with LPS as it probably inhibited the NO synthase 2 induction. Conclusions: These findings suggest that NO-flurbiprofen has a beneficial hemodynamic effect in cir- rhotic rats and may help to prevent LPS aortic hyporeactivity. © 2001 Blackwell Science Asia Pty Ltd Key words: cirrhosis, endotoxin, nitric oxide synthase, nitric oxide, portal hypertension, non-steroidal anti-inflammatory drug. Correspondence: Dr D Lebrec, INSERM, Hôpital Beaujon, 92118 Clichy, France. Email: ebrec@bichat.inserm.fr Accepted for publication 27 July 2000.