Polyamines mediate uncontrolled calcium entry and cell damage in rat heart in the calcium paradox.
Brief perfusion of heart with calcium-free medium renders myocardial cells calcium-sensitive so that readmission of calcium results in uncontrolled Ca2+ entry and acute massive cell injury (calcium paradox). We investigated the hypothesis that polyamines may be involved in the mediation of abnormal Ca2+ influx and cell damage in the calcium paradox. The isolated perfused rat heart was used for these studies. Calcium-free perfusion promptly (less than 5 min) decreased the levels of polyamines and the activity of their rate-regulating synthetic enzyme, ornithine decarboxylase (ODC), and calcium reperfusion abruptly (less than 15-180 s) increased these components. alpha-Difluoromethylornithine (DFMO), a specific suicide inhibitor of ODC, suppressed the calcium reperfusion-induced increase in polyamines and the concomitant increase in myocardial cellular 45Ca influx, loss of contractility, release of cytosolic enzymes, myoglobin, and protein, and structural lesions. Putrescine, the product of ODC activity, nullified DFMO inhibition and restored the calcium reperfusion-induced increment in polyamines and the full expression of the calcium paradox. Putrescine itself enhanced the reperfusion-evoked release of myoglobin and protein in the absence of DFMO. Hypothermia blocked the changes in heart ODC and polyamines induced by calcium-free perfusion and calcium reperfusion and prevented the calcium paradox. These results indicate that rapid Ca2+-directed changes in ODC activity and polyamine levels are essential for triggering excessive transsarcolemmal transport of Ca2+ and explosive myocardial cell injury in the calcium paradox.
D000818:Animals; D002118:Calcium / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D003600:Cytosol / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007036:Hypothermia, Induced; D008854:Microscopy, Electron; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D009211:Myoglobin / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010477:Perfusion; D011073:Polyamines / Q000502:physiology*; D011700:Putrescine / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013095:Spermidine / Q000502:physiology; D013096:Spermine / Q000502:physiology
D009211:Myoglobin; D011073:Polyamines; D013096:Spermine; D009955:Ornithine Decarboxylase; D002118:Calcium; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine