Increased levels of
endothelin (ET) have been demonstrated in the ischemic brain, and ET receptor antagonism has been shown to improve outcome in
cerebral ischemia. However, no previous work has been carried out evaluating the role of ET and its antagonism in
brain trauma as compared to experimental
stroke. In this study, we evaluated changes in brain ET levels following
closed head injury (CHI) and the effects of
SB 234551, an
endothelin-A- (ET(A)) selective antagonist, and
SB 209670, a mixed
endothelin-A- and -B- (ET(A)/ET(B)) antagonist, on outcome in CHI and focal
stroke. Male Sabra rats were subjected to CHI (weight drop model). Male Sprague Dawley rats were subjected to focal
stroke (intraluminal
suture model). Motor function(s) were assessed and immunoreactive ET (irET) and the degree of
cerebral edema were measured for 24 h after CHI.
Brain swelling (
edema), neurological deficits and forebrain
infarct volumes were measured 24 h after focal
stroke. Antagonists (total doses of 7.5, 15, 30 or 60 mg/kg) were administered intravenously for 6-24 h (beginning 15 min after injury). Control rats were infused with vehicle. CHI resulted in increased ET levels in the directly contused hemisphere at 12 and 24 h. In addition,
SB 234551 significantly reduced neurological deficits (decreased 30%) and
brain edema (decreased 40%) following CHI (p < 0.05 at 60 mg/kg dose).
SB 209670 had no effects on CHI outcome. Focal
stroke studies yielded similar results.
SB 234551 reduced focal
stroke-induced neurological deficits by 50%,
brain swelling by 54% and the degree of
infarction by 36% (p < 0.05 at 30 mg/kg).
SB 209670 did not provide any neuroprotection in focal
stroke. These data indicate that ET plays a significant role in the pathophysiology of CHI, and that selectively targeting ET(A)-receptors similarly in both CHI and
stroke might be a therapeutic opportunity.