scholarly journals Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

2012 ◽  
Vol 15 (2) ◽  
pp. 318 ◽  
Author(s):  
Ridhi Parasrampuria ◽  
Imam H. Shaik ◽  
Reza Mehvar
Keyword(s):  
Biliary Excretion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rhodamine 123 ◽  
Pharmacokinetic Parameters ◽  
Sham Operation ◽  
Hepatic Ischemia ◽  
Hepatobiliary Disposition ◽  
Canalicular Transporters ◽  
Hepatic Ischemia Reperfusion

Purpose. A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twenty-four-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Preconditioning with L-alanyl-glutamine reduces hepatic ischemia-reperfusion injury in rats

2011 ◽  
Vol 26 (suppl 1) ◽  
pp. 8-13 ◽  
Author(s):  
Raimundo José Cunha Araújo Júnior ◽  
Raimundo Gerônimo da Silva Júnior ◽  
Marcelo Pinho Pessoa de Vasconcelos ◽  
Sérgio Botelho Guimarães ◽  
Paulo Roberto Leitão de Vasconcelos ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Average Weight ◽  
Sham Operation ◽  
Hepatic Ischemia ◽  
Portal Triad ◽  
Hepatic Ischemia Reperfusion ◽  
Control Sham

PURPOSE: To evaluate the effects of pre-conditioning with L-alanyl- glutamine (L-Ala-Gln) in rats subjected to total hepatic ischemia. METHODS: Thirty Wistar rats, average weight 300g, were randomly assigned to 3 groups (n=10): G-1 - Saline, G-2- L-Ala-Gln, G-3-control (Sham). G-1 and G-3 groups were treated with saline 2.0 ml or L-Ala-Gln (0.75mg/Kg) intraperitoneally (ip) respectively, 2 hours before laparotomy. Anesthetized rats were subjected to laparotomy and total hepatic ischemia (30 minutes) induced by by clamping of portal triad. Control group underwent peritoneal puncture, two hours before the sham operation (laparotomy only). At the end of ischemia (G1 and G2), the liver was reperfused for 60 minutes. Following reperfusion blood samples were collected for evaluation of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. Liver (medium lobe) was removed for immunohistochemistry study with antibody for Caspase-3. RESULTS: It was found a significant decrease (p<0.05) of ALT levels (270.6 +40.8 vs 83.3 +5.5 - p <0.05), LDH (2079.0 +262.4 vs. 206.6 +16.2 - p <0.05) and Caspase-3 expression (6.72 +1.35 vs. 2.19 +1.14, p <0.05) in rats subjected to I / R, comparing the group treated with L-Ala -Gln with G-2. Also, the ALT level was significantly lower (P<0.05) in G-1 and G-2 groups than in G-3 (control group). CONCLUSION: L-Ala-Gln preconditioning in rats submitted to hepatic I/R significantly reduces ALT, LDH and Caspase-3 expression, suggesting hepatic protection.

scholarly journals Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF-κB Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Iman O. Sherif ◽  
Nora H. Al-Shaalan
Keyword(s):  
Signaling Pathway ◽  
Normal Saline ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Sham Operation ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

The Toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway is vital in the pathogenesis of hepatic ischemia/reperfusion (HIR) injury. Dipeptidyl peptidase-4 (DPP4) inhibitors exert protective effects on IR injury of the kidney, heart, and lung; however, their effect on the liver is still unknown. Thus, the purpose of this study was to examine whether pretreatment with vildagliptin (Vilda), a DPP4 inhibitor, produces hepatic protection against IR injury and to investigate its influence on TLR4/NF-κB signaling in a rat model. Thirty male Wistar rats were divided into 3 groups: the sham group: subjected to a sham operation and received normal saline; the HIR group: subjected to HIR and received normal saline; and the Vilda + HIR group: subjected to HIR with pretreatment of 10 mg/kg/day Vilda for 10 days intraperitoneally. Hepatic ischemia lasted for 45 minutes followed by 3-hour reperfusion; then blood and liver samples were collected for biochemical and histopathological examination. The HIR group produced a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) levels and a significant reduction in the hepatic catalase level in comparison to the sham group. Moreover, a significant upregulation of gene and protein expressions of TLR4, NF-κB, and high-mobility group box-1 (HMGB1) along with caspase-3 protein expression was observed in the HIR group when compared with the sham group. Histopathological examination of the liver from the HIR group showed necrosis, sinusoidal congestion, hemorrhage, and hepatocyte degeneration. Administration of Vilda ameliorated the biochemical and histopathological changes caused by HIR. Vildagliptin showed for the first time a hepatoprotective effect in HIR injury through downregulation of TLR4/NF-κB/HMGB1 and caspase-3 hepatic expressions.

scholarly journals Effects of propofol on cardiac function and miR-494 expression in rats with hepatic ischemia/reperfusion injury

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199098
Author(s):  
Jie Lv ◽  
Xiaohua Zou ◽  
Chao Yu ◽  
Wei Ou ◽  
Chengyi Sun
Keyword(s):  
Cardiac Function ◽  
Group Treatment ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Sham Operation ◽  
Myocardial Cells ◽  
Hepatic Ischemia ◽  
Sham Operation Group ◽  
Hepatic Ischemia Reperfusion

Objective This study aimed to investigate the effects of propofol on cardiac function and miR-494 expression in rats with hepatic ischemia/reperfusion (I/R) injury. Methods Forty healthy adult male Sprague-Dawley rats were allocated to the sham operation group and three hepatic I/R injury groups. The I/R injury groups included I/R injury only (I/R group), treatment with propofol (propofol group), and treatment with propofol + overexpressed miR-494 (propofol+miR-494 group). Apoptosis of myocardial cells and changes in cardiac function indices, including left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular posterior wall thickness, as well as changes in miR-494, were monitored. Results The apoptotic rate of myocardial cells in the I/R group was higher, cardiac function was deteriorated, and miR-494 levels were elevated compared with the sham group. The apoptotic rate was lower, cardiac function was improved, and miR-494 levels were suppressed in the propofol group compared with the I/R group. The apoptotic rate was higher, cardiac function was deteriorated, and miR-494 levels were elevated in the propofol+miR-494 group compared with the propofol group. Conclusion Propofol plays a vital role in preventing myocardial cell apoptosis and improvement of cardiac function by suppressing miR-494 in a hepatic I/R injury rat model.

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