TPEN attenuates hepatic apoptotic ischemia/ reperfusion injury and remote early cardiac dysfunction.
The release of cardioactive substances during hepatic ischemia/reperfusion injury generates toxic free radicals that inflict hepatic and remote cardiac damage. The aim of the study was to determine whether TPEN, a potent iron chelator, ameliorates the apoptotic hepatic and cardiac function injuries. Three groups of isolated rat livers were studied: (1) continuously perfused with Krebs-Henseleit solution; (2) subjected to 120 min of ischemia and 15 min of reperfusion; (3) as in group 2, with TPEN administered prior to ischemia. Isolated hearts were perfused for 65 min with the effluent of the reperfused livers. Results showed that TPEN administration reduced the release of norepinephrine, epinephrine, dopamine, prostaglandin E2 and angiotensin II, decreased intrahepatic caspase-3 activity, and decreased the mean hepatocyte apoptotic index (TUNEL assay) (p = 0.001). Perfusion with post-ischemic hepatic effluent caused a transient 15-min increase in left ventricular contraction and coronary flow (p < 0.05), followed by a decrease in cardiac function at one hour. TPEN reduced the transient elevation in left ventricular contraction p < 0.05), but did not prevent the subsequent decrease in cardiac function. In conclusion, TPEN attenuates post-ischemic apoptotic hepatic injury by modulating caspase-3-like activity and reduces the cardioactive substances released from the liver.
Hochhauser
E
E
The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Tel Aviv, Israel.
Ben-Ari
Z
Z
Pappo
O
O
Chepurko
Y
Y
Vidne
B A
BA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology*; D007511:Ischemia / Q000628:therapy*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors
D002614:Chelating Agents; D005029:Ethylenediamines; D020169:Caspases; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine