B. Vollrath et al., LAZAROIDS AND DEFEROXAMINE ATTENUATE THE INTRACELLULAR EFFECTS OF OXYHEMOGLOBIN IN VASCULAR SMOOTH-MUSCLE, Cardiovascular Research, 30(4), 1995, pp. 619-626
Objectives: While it is probable that the cerebrovascular spasm which
occurs after subarachnoid haemorrhage results from the action of haemo
globin, the mechanism of that process remains unclear. These studies w
ere thus designed to test the hypothesis that the action of oxyhaemogl
obin results from the iron-catalyzed formation of free radicals and su
bsequent lipid peroxidation resulting in intracellular changes in the
second messengers for contraction. Methods: Levels of intracellular ca
lcium and of inositol (1,4,5)-trisphosphate were measured in cultured
vascular smooth muscle cells derived from primate cerebral arteries. C
ontractility of rings of canine cerebral vessels were examined in vitr
o using standard pharmacological techniques. Vessels in spasm were obt
ained from the ''two haemorrhage'' canine model and the presence of va
sospasm was confirmed angiographically. In each case, the effects of o
xyhaemoglobin and sometimes of free radicals generated from iron salts
were examined in the presence and in the absence of free-radical scav
enging agents or the iron chelating agent, deferoxamine. Results: Oxyh
aemoglobin produces a slowly-developing sustained contraction of arter
ial rings which is accompanied by a sustained elevation of intracellul
ar calcium. It also produces a transient but significant elevation of
inositol (1,4,5)-trisphosphate, but this is not correlated with the de
velopment of sustained constriction. Deferoxamine and the lazaroid com
pounds U-74389G and U-83836E were effective in preventing the effects
of oxyhaemoglobin and free radicals in the models tested, although in
vessels in spasm, all effects were smaller. Conclusions: The present s
tudy provides results which are consistent with the hypothesis that th
e actions of haemoglobin on vascular smooth muscle are mediated by the
formation of free radicals which subsequently affect intracellular ca
lcium concentrations. This also implies that agents which impair free
radical production or other processes leading to iron-catalyzed lipid
peroxidation, are of potential value in cerebrovascular spasm.