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

Zygmunt Warzecha,Rafał Olszanecki,Beata Kuśnierz-Cabala,Joanna Bonior,Jakub Cieszkowski,Romana Tomaszewska,Paweł Sendur,Piotr Ceranowicz,Marcin Dembiński,Jolanta Jaworek,Kaczmarzyk Tomasz,Tadeusz Ambroży,Artur Dembiński,Ryszard Sendur

doi:10.3390/ijms18040882

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.

Highlights

Coagulation is one of the mechanisms of hemostasis
Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion led to an increase in international normalized ratio (INR) and this effect was statistically significant between the 6th hour and 9th day of pancreatic reperfusion
We found an increase in serum concentration of interleukin-1β after the development of ischemia/reperfusion-induced acute pancreatitis and this effect was followed by the spontaneous gradual normalization of the serum level of this pro-inflammatory cytokine over time

Summary

Introduction

Coagulation is one of the mechanisms of hemostasis. Its activation causes clot formation to prevent blood loss from a damaged vessel. Coagulation disorders may take the form of insufficient or excessive clotting. Insufficient clotting can result in bleeding or hemorrhage; whereas excessive activation of clotting can lead to thrombosis and/or disseminated intravascular coagulation (DIC). Thrombin and the complex of tissue factor plus active factor VII can stimulate protease activated receptors (PARs) [1,2]. This in turn can induce the expression of adhesion molecules leading to leukocyte-mediated injury [3,4]. The CD40 ligand stimulates the synthesis of the tissue factor and increases the level of pro-inflammatory interleukin-6 and interleukin-8 [3,6]

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Methods

Conclusion