Splanchnic hyposensitivity to glypressin in a hemorrhage-transfused common bile duct-ligated rat model of portal hypertension: role of nitric oxide and bradykinin.
OBJECTIVE
The portal hypotensive effect of vasopressin during hemorrhage is less effective than that during stable condition in cirrhotic patients or experimental portal hypertension (the so-called hyposensitivity phenomenon). Recent studies have demonstrated that constitutive nitric oxide activities and bradykinin in hemorrhage-transfused partially portal vein-ligated rats are responsible, at least partly, for the splanchnic hyposensitivity to glypressin (a long acting vasopressin analogue). This study investigated the relative contribution of nitric oxide synthase isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivity in rats with cirrhosis induced by common bile duct-ligation (BDL).


METHODS
Five weeks after BDL, systemic and portal hemodynamics were measured in stable or bleeding BDL rats receiving intravenous infusion of glypressin (0.2 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor), L-canavanine (a specific inducible nitric oxide synthase inhibitor) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 minutes before the infusion of glypressin. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or various inhibitors.


RESULTS
Splanchnic hyposensitivity to glypressin was demonstrated in the hemorrhage-transfused BDL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding BDL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin.


CONCLUSIONS
Constitutive nitric oxide synthase and bradykinin play major roles in the development of splanchnic hyposensitivity to glypressin observed in hemorrhage-transfused rats with biliary cirrhosis.
Chen
Chien-Ting
CT
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan.
Chu
Chi-Jen
CJ
Lee
Fa-Yauh
FY
Chang
Full-Young
FY
Wang
Sun-Sang
SS
Lin
Han-Chieh
HC
Hou
Ming-Chih
MC
Wu
Shwu-Ling
SL
Chan
Che-Chang
CC
Huang
Hui-Chun
HC
Lee
Shou-Dong
SD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D002172:Canavanine / Q000494:pharmacology; D003135:Common Bile Duct; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006975:Hypertension, Portal / Q000503:physiopathology*; D008026:Ligation; D008236:Lypressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D017082:Portal Pressure / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077585:Terlipressin
D009569:Nitric Oxide; D002172:Canavanine; D008236:Lypressin; C065679:icatibant; D000077585:Terlipressin; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester