Background-This review article deals with the role of calcium in ische
mic cell death. A calcium-related mechanism was proposed more than two
decades ago to explain cell necrosis incurred in cardiac ischemia and
muscular dystrophy. In fact, an excitotoxic hypothesis was advanced t
o explain the acetylcholine-related death of muscle end plates. A simi
lar hypothesis was proposed to explain selective neuronal damage in th
e brain in ischemia, hypoglycemic coma, and status epilepticus. Summar
y of Review-The original concepts encompass the hypothesis that cell d
amage in ischemia-reperfusion is due to enhanced activity of phospholi
pases and proteases, leading to release of free fatty acids and their
breakdown products and to degradation of cytoskeletal proteins. It is
equally clear that a coupling exists between influx of calcium into ce
lls and their production of reactive oxygen species, such as .O-2(-),
H2O2, and .OH. Recent results have underscored the role of calcium in
ischemic cell death. A coupling has been demonstrated among glutamate
release, calcium influx, and enhanced production of reactive metabolit
es such as .O-2(-), .OH, and nitric oxide. It has become equally clear
that the combination of .O-2(-) and nitric oxide can yield peroxynitr
ate, a metabolite with potentially devastating effects. The mitochondr
ia have again come into the focus of interest. This is because certain
conditions, notably mitochondrial calcium accumulation and oxidative
stress, can trigger the assembly (opening) of a high-conductance pore
in the inner mitochondrial membrane. The mitochondrial permeability tr
ansition (MPT) pore leads to a collapse of the electrochemical potenti
al for H+, thereby arresting ATP production and triggering production
of reactive oxygen species. The occurrence of an MPT in vivo is sugges
ted by the dramatic anti-ischemic effect of cyclosporin A, a virtually
specific blocker of the MPT in vitro in transient forebrain ischemia.
However, cyclosporin A has limited effect on the cell damage incurred
as a result of 2 hours of focal cerebral ischemia, suggesting that fa
ctors other than MPT play a role. It is discussed whether this could r
eflect the operation of phospholipase A(2) activity and degradation of
the lipid skeleton of the inner mitochondrial membrane. Conclusions-C
alcium is one of the triggers involved in ischemic cell death, whateve
r the mechanism.