title: Amlodipine improves hepatic hemodynamic and metabolic function in the isolated perfused rat liver after sequential cold and warm ischemia.
abstract: Amlodipine, a long acting calcium antagonist, was used to reduce the adverse effects of ischemic/reperfusion injury studied in isolated perfused rat livers. Amlodipine (10 mumol/L) was added to University of Wisconsin (UW) solution in which the liver was stored for 24 hr at 4 degrees C and incorporated in the saline flush used to displace the UW solution before 20 min of warm ischemia (at 37 degrees C) and reperfusion. Initial median blood flow at 15 min was significantly higher after amlodipine treatment (2.78 vs. 1.41 ml/min/g of liver without amlodipine treatment, P = 0.013) as was the area under the curve of blood flow for the entire 3-hr perfusion (472 vs. 316 ml/g of liver, P = 0.003). Amlodipine treatment induced corresponding increases in oxygen delivery (1302 vs. 896 mumol of O2/g of liver over 3 hr of perfusion, P = 0.003) and oxygen consumption (279 vs. 242 mumol of O2/g of liver over 3 hr, P = 0.06). Initial bile flow at 15 min was increased 4-fold by amlodipine treatment (17.27 vs. 4.59 mg/hr/g of liver for sequential cold and warm ischemia, P = 0.013), and the median area under the curve of bile flow for the entire perfusion increased to 92.2 vs. 53.9 mg/g of liver (P = 0.0006). Amlodipine treatment also reduced glucose release into the perfusate (116 vs. 149 mmol/L/g of liver min over 3 hr, P = 0.03) and prevented hepatocyte injury by reducing alanine aminotransferase release both initially (0.43 vs. 0.96 IU/L/g of liver, P = 0.055) and overall (343 vs. 797 IU/L/g of liver min, P = 0.048). When amlodipine was added only to the UW solution, blood flow increased by 66% initially (P = 0.02) and 32% overall (P = 0.013), but there was no corresponding improvement in hepatic function. Amlodipine may reduce hepatic ischemic/reperfusion injury by cytoprotective effects on parenchymal and non-parenchymal hepatocytes during both preservation and reperfusion leading to an improvement in liver microcirculation and an inhibition of the release of toxic mediators.
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, United Kingdom.
authors.forename: T
authors.initials: T
authors.lastname: Piratvisuth
authors.forename: J B
authors.initials: JB
authors.lastname: Dunne
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.forename: J M
authors.initials: JM
authors.lastname: Tredger
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D003080:Cold Temperature; D006439:Hemodynamics / Q000187:drug effects; D007511:Ischemia / Q000503:physiopathology*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D009926:Organ Preservation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013696:Temperature
chemical_list: D017311:Amlodipine