The calcium channel blocker nisoldipine minimizes the release of tumor necrosis factor and interleukin-6 following rat liver transplantation.
Kupffer cells, when activated, release toxic cytokines such as tumor necrosis factor (TNF), which can cause tissue injury. Takei et al. have reported that nisoldipine, a calcium channel blocker which decreases phagocytotic activity by Kupffer cells, also diminishes liver and lung injury and dramatically improves survival following liver transplantation. Therefore, we studied the effect of nisoldipine on the time course of TNF and interleukin-6 (IL-6) release following cold storage and liver transplantation in the rat. Livers were stored under survival and non-survival conditions in cold Euro-Collins solution in the presence or absence of nisoldipine (1.4 microM). After storage, the effluent was collected for determination of cytokines. The liver was then transplanted orthotopically and serum was collected at various time intervals for up to 5 h. In the effluent, TNF levels were very low in both the control and nisoldipine-treated groups and IL-6 was not measurable. Furthermore, when livers were stored under survival conditions and transplanted (liver stored in the cold for 4 h), serum TNF (2 U/ml) and IL-6 (350 U/ml) values were minimal in both the control and nisoldipine-treated groups. In contrast, when livers were stored under non-survival conditions and transplanted (liver stored in the cold for 10 h), TNF levels increased to 15 +/- 2 U/ml, 150 min after graft reperfusion, an increase which was prevented by nisoldipine (6.5 U/ml). Serum IL-6 levels were also elevated 300 min after transplantation in livers stored for 10 h. Nisoldipine also reduced the release of this cytokine. Serum transaminases (SGOT) were elevated to values around 2000 U/l 5 h following transplantation. In the nisoldipine-treated group, values were lower between 60 and 300 min. In the lung, interstitial and alveolar edema and cellular infiltration were detectable 5 h postoperatively and were diminished by nisoldipine. These data confirmed that TNF and IL-6 release were minimal following cold storage and transplantation of livers stored under survival conditions, but were elevated transiently after transplantation under non-survival conditions. Nisoldipine prevented cytokine release, most likely by blocking the activation of Kupffer cells, which may explain how it decreases liver and lung injury very early following liver transplantation.
Savier
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E
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill 27599-7365, USA.
Shedlofsky
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SI
Swim
A T
AT
Lemasters
J J
JJ
Thurman
R G
RG
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism*; D007700:Kinetics; D016031:Liver Transplantation / Q000502:physiology*; D015737:Nisoldipine / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D015424:Reperfusion; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D002121:Calcium Channel Blockers; D015850:Interleukin-6; D015737:Nisoldipine; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors