Calcium-mediated damage during post-ischaemic reperfusion.
Ca2+ gain during reperfusion after an ischaemic episode may be of primary importance in the development of cell death and tissue necrosis. These studies were undertaken to examine the possibility of modifying Ca2+ gain by introducing interventions only upon reperfusion. Electron microscopy did not reveal the presence of holes in the sarcolemma prior to reperfusion, indicating that Ca2+ entry at the moment of reperfusion is not through rents in the sarcolemma. Reperfusion with acidotic buffer (pH 6.4 or 6.6) after 60 min ischaemia attenuated Ca2+ gain. However, this attenuation persisted only as long as the acidotic conditions were maintained. Conversely, reperfusion under alkalotic conditions (pH 7.9) exacerbated Ca2+ gain. Reperfusion with hypoxic buffer after 60 min ischaemia did not alter Ca2+ gain, but readmission of oxygen after a period of hypoxic post-ischaemic reperfusion triggered a further gain in Ca2+. Addition of 5 microM nifedipine to the reperfusion medium slowed Ca2+ gain, while 1 microM Bay K 8644, a calcium agonist, enhanced the gain at early times of reperfusion. Addition of 20 microM W-7, a calmodulin antagonist, to the reperfusion medium had no effect on post-ischaemic Ca2+ gain. Therefore, we have shown that it is possible to alter post-ischaemic Ca2+ gain by introducing interventions only upon reperfusion. However, Ca2+ gain could only be delayed, rather than prevented and ultimately no long-term protection was achieved. These results indicate that post-ischaemic Ca2+ gain is highly pH-sensitive and that entry of Ca2+ through voltage-activated slow channels may contribute to the early gain.
Nayler
W G
WG
University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia.
Panagiotopoulos
S
S
Elz
J S
JS
Daly
M J
MJ
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D003327:Coronary Disease / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D009206:Myocardium / Q000648:ultrastructure; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000494:pharmacology
D002147:Calmodulin; D013449:Sulfonamides; C017967:W 7; D010100:Oxygen; D002118:Calcium