Verapamil and flunarizine protect the isolated perfused rat liver against warm ischemia and reperfusion injury.
Using the model of the isolated perfused rat liver, we investigated the influence of the two pharmacologically different calcium channel blockers, verapamil and flunarizine, on changes of ion homeostasis, liver weights, pH deviations and enzyme activities during warm ischemia (37 degrees C) and reperfusion. The LDH and GLDH activities were determined and the calcium, potassium, and sodium concentrations were measured in the effluent. Warm ischemia (180 min) caused an increased enzyme release, a high influx of calcium and sodium into the liver and a massive potassium efflux current. Normoxic reperfusion led to a further increase in hepatic enzyme release and although the loss of potassium ceased, the calcium influx into the liver continued. By the end of reperfusion the liver weight had increased significantly (P < 0.01) in the control group. The two calcium entry blockers were added to the perfusate in various concentrations. Both substances protected the liver against warm ischemia and normoxic reperfusion damage, but they did not inhibit calcium inflow. However, the potassium efflux was significantly reduced by all concentration tasted (P < 0.001). After reperfusion the liver weights were significantly lower in the treated groups (P < 0.001) than in control animals. Thus, the calcium entry blockers verapamil and flunarizine protect liver cells against damage caused by warm ischemia and reperfusion. Furthermore, they prevent the disruption of intracellular potassium homeostasis, which seems to be related to improved volume regulation of liver cells.
Konrad
T
T
Center of Internal Medicine, University of Frankfurt, Germany.
Bloechle
C
C
Haller
G
G
Broelsch
C E
CE
Usadel
K H
KH
Kusterer
K
K
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D005444:Flunarizine / Q000494:pharmacology / Q000627:therapeutic use*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D006706:Homeostasis; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use*
D014700:Verapamil; D007770:L-Lactate Dehydrogenase; D005969:Glutamate Dehydrogenase; D005444:Flunarizine; D011188:Potassium; D002118:Calcium