Aminoguanidine ameliorates splanchnic hyposensitivity to glypressin in a haemorrhage-transfused rat model of portal hypertension

Abstract

1. Hyposensitivity to vasopressin is a well-documented phenomenon in animals with portal hypertension and patients with cirrhosis subjected to haemorrhage. Excessive formation of nitric oxide is at least partly responsible for the vascular hyporesponsiveness to vasoconstrictors observed in experimental portal hypertension or in rats with haemorrhagic shock. This study investigated whether addition of aminoguanidine, a preferential inducible nitric oxide synthase inhibitor, to glypressin (a long-acting vasopressin analogue) could enhance its portal hypotensive effect in portal-hypertensive rats with bleeding.2. Portal hypertension was induced by partial portal vein ligation. Fourteen days after operation, systemic and portal haemodynamics were measured in stable or bleeding portal vein-ligated rats receiving intravenous glypressin (0.07 mg/kg) or aminoguanidine (70 mg/kg) followed by glypressin infusion. In rats with a hypotensive haemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or aminoguanidine.3. Glypressin resulted in a significantly greater decrease in portal pressure in portal vein-ligated rats without bleeding than in those with bleeding (P<0.001). In contrast, glypressin induced similar changes in mean arterial pressure between the two groups (P>0.05). The addition of aminoguanidine significantly potentiated the portal-hypotensive effect of glypressin in bleeding portal vein-ligated rats (P<0.005) without an effect on the changes in mean arterial pressure induced by glypressin infusion (P>0.05).4. Splanchnic hyposensitivity to glypressin exists in a haemorrhage-transfused rat model of portal hypertension. This hyposensitivity can be ameliorated by the administration of aminoguanidine.

Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

“…However, Lee et al [155] reported administration of aminoguanidine, an iNOS inhibitor, successfully corrected the hyperdynamic circulation without affecting PHG, suggesting that iNOS and NO are important in the hyperdynamic circulation in portal hypertension, but play a limited role in PHG development. They argued that PHG should be treated by reducing portal pressure rather than reversing the hyperdynamic circulation [155,156] .…”

Inhibition of glucagon improves splanchnic hyporesponse to terlipressin in cirrhotic rats with blood retention in the gastric lumen

“…However, the magnitude of changes in mean arterial pressure and cardiac index following terlipressin administration were similar. These results suggest that the accumulation of blood in stomach, similar to that occurred in acute hemorrhage, was associated with a selective splanchnic hyporesponse to terlipressin in cirrhotic rats [11,12,42]. However, it is also possible that the portal pressure and SMA blood flow were already elevated in cirrhotic rats with portal hypertension.…”

“…However, the simultaneously infusion of glucagon antiserum or octreotide in blood gavaged-cirrhotic rats did not completely correct the splanchnic hyporesponse. It is possible that other factors (such as prostacyclin and nitric oxide) also contribute to the splanchnic hyporesponse to terlipressin in cirrhotic rats with portal hypertension [11,12]. In this study, both the infusion of glucagon antiserum and octreotide were proved to inhibit the increasing plasma glucagon concentration and the corresponding elevation of portal pressure in blood gavage-cirrhotic rats.…”

“…Terlipressin was administered by intravenous injection at a dose of 0.07 mg/kg as previously [11,12]. Octreotide was administered by intravenous injection at a dose of 8 mg/kg as previously [35,36].…”

“…However, previous studies have shown that the portal hypotensive effects of these drugs are less effective during acute variceal hemorrhage than under stable conditions [5][6][7]. The mechanisms of the splanchnic hyporesponse to vasopressin during hemorrage are poorly understood [8][9][10], but may involve increased synthesis of nitric oxide and prostacyclin [11,12].…”