Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin

Hyposensitivity to vasopressin is a well documented phenomenon in animals w ith portal hypertension and patients with cirrhosis subject to haemorrhage. Haemorrhage is associated with the endogenous release of bradykinin, which may subsequently stimulate the formation of nitric oxide (NO). The present study investigated the relative contribution of NO synthase (NOS) isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivi ty to a long-acting vasopressin analogue, glypressin, in rats with portal h ypertension induced by partial portal vein ligation (PVL). At 14 days after the operation, systemic and portal haemodynamics were measured in stable o r bleeding PVL rats receiving an intravenous infusion of glypressin (0.07 m g/kg). In the treatment groups, N-G-nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor), L-canavanine (a specific inhibitor of induc ible NOS) or HOE 140 (a bradykinin B-2 receptor antagonist) was administere d 45 min before the infusion of glypressin. In rats with a hypotensive haem orrhage, 4.5 mi of blood was withdrawn and 50% of the withdrawn blood was r e-infused before the administration of glypressin or various inhibitors. Sp lanchnic hyposensitivity to glypressin was demonstrated in the haemorrhage/ transfused PVL rats. The infusion of L-NAME elevated the mean arterial pres sure in the bleeding PVL rats without the modulation of portal pressure. Th e addition of L-NAME or HOE 140, but not L-canavanine, significantly and si milarly potentiated the portal-hypotensive effects of glypressin. It is con cluded that constitutive NOS and bradykinin are responsible, at least partl y, for the splanchnic hyposensitivity to glypressin observed in the early s tages of the haemorrhage/transfused rat model of portal hypertension.