Haeme oxygenase mediates hyporeactivity to phenylephrine in the mesenteric vessels of cirrhotic rats with ascites.
OBJECTIVE
Haeme oxygenase could play a role in the pathogenesis of arterial vasodilation in cirrhosis. The aim of this study was to verify the role of haeme oxygenase in the hyporesponsiveness to phenylephrine of small mesenteric arteries in rats with CCl(4) induced cirrhosis, with and without ascites.


METHODS
Pressurised small resistance mesenteric arteries were challenged with increasing doses of phenylephrine. Dose-response curves were evaluated under basal conditions, after inhibition of haeme oxygenase with chromium-mesoporphyrin, after inhibition of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine-methyl-ester (L-NAME), and then after inhibition of both NOS and haeme oxygenase. Haeme oxygenase protein expression was also analysed.


RESULTS
Twenty six control rats and 35 rats with cirrhosis (17 with and 18 without ascites) were studied. Response to phenylephrine was lower in non-ascitic and ascitic cirrhosis than in controls. Chromium-mesoporphyrin increased the response to phenylephrine only in ascitic cirrhosis (p<0.001). L-NAME increased the response to phenylephrine in controls (p<0.001) and in ascitic and non-ascitic cirrhosis (p = 0.002, p<0.001, respectively) but the final response in non-ascitic cirrhosis was similar to that of control rats while it remained impaired in ascitic cirrhosis. Addition of chromium-mesoporphyrin to L-NAME improved the response to phenylephrine in ascitic cirrhosis (p<0.01), with final values not different from those of the other two groups. Protein expression of the inducible isoform of haeme oxygenase was increased in the mesenteric vessels of cirrhotic rats.


CONCLUSIONS
Haeme oxygenase mediates hyporeactivity to phenylephrine in the mesenteric vessels of experimental cirrhosis with ascites. NOS plays a major role only in the first stage of the disease.
Bolognesi
M
M
Clinica Medica 5, Dipartimento di Medicina Clinica e Sperimentale, Policlinico Universitario, Via Giustiniani 2, 35128 Padova, Italy. massimo.bolognesi@unipd.it
Sacerdoti
D
D
Di Pascoli
M
M
Angeli
P
P
Quarta
S
S
Sticca
A
A
Pontisso
P
P
Merkel
C
C
Gatta
A
A
D000818:Animals; D001201:Ascites / Q000503:physiopathology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D008652:Mesoporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008652:Mesoporphyrins; D014662:Vasoconstrictor Agents; C427471:chromium mesoporphyrin; D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D019331:NG-Nitroarginine Methyl Ester