Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

Abstract

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

“…We have also found that pretreatment with low doses of acenocoumarol resulted in a significant reduction of serum IL-1β concentration and limitation of AP severity. These important findings are consistent with an earlier report on the acenocoumarol-related reduction in IL-1β release in ischemia/reperfusion-induced AP and indicate that acenocoumarol is a universal protective agent in AP [34]. …”

“…Induction of AP by cerulein administration led to reduction of pancreatic DNA synthesis by around 45% and this effect was reversed by pretreatment with low doses of acenocoumarol. This our result is similar to that observed in rats pretreated with acenocoumarol before induction of AP evoked by pancreatic ischemia followed by reperfusion [34] showing that pancreatoprotective effect of acenocoumarol is independent of primary cause of AP.…”

“…This concept is supported by our present observation that pretreatment with acenocoumarol given at the dose of 150 μg/kg/day causes a five-fold increase in INR. Lack of protective effect of pretreatment with acenocoumarol given at the dose of 150 μg/kg/day is also in harmony with previous observation that this dose of acenocoumarol does not prevent the development of ischemia/reperfusion-induced AP [34]. …”

“…for 7 days with saline. Acenocoumarol was given at the dose of 50, 100 or 150 μg/kg/dose because previous studies [34] showed that these doses caused an increase of international normalized ratio (INR) to a range between 2.5 and 3.5. This value of INR is recommended in the most clinical conditions related to coagulation disorders [61].…”

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

“…In a recent experimental study, pretreatment with low doses of acenocoumarol, a vitamin K antagonist, attenuated ischemia/reperfusion-induced AP and was associated with reduced leukocyte inflammatory infiltration of the pancreas as well as diminished pancreatitis-induced increase in serum IL-1β concentrations [198]. The results were confirmed in another model of experimental AP, i.e., cerulein-induced AP in rats [199].…”