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.
OBJECTIVE
Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodilation 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 nonsteroidal 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 Nw-nitro-L-arginine (L-NNA). Nw-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 hyporeactivity 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 cirrhotic rats and may help to prevent LPS aortic hyporeactivity.
Lefilliatre
P
P
Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, Institut National de la Santé et de la Recherche Médicale U-481, H pital Beaujon, Clichy, France.
Sogni
P
P
Bertrand
V
V
Del Soldato
P
P
Pateron
D
D
Moreau
R
R
Lebrec
D
D
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D014662:Vasoconstrictor Agents; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D019001:Nitric Oxide Synthase; D009638:Norepinephrine