Selective antagonism of endothelin-A-receptors improves outcome in both head trauma and focal stroke in rat.
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.
Barone
F C
FC
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmacology, King of Prussia, Pennsylvannia 19406, USA. Frank_C_Barone@SBPHD.com
Ohlstein
E H
EH
Hunter
A J
AJ
Campbell
C A
CA
Hadingham
S H
SH
Parsons
A A
AA
Yang
Y
Y
Shohami
E
E
D000818:Animals; D006259:Craniocerebral Trauma / Q000188:drug therapy*; D004149:Dioxoles / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D020521:Stroke / Q000188:drug therapy*
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; D018696:Neuroprotective Agents; D011720:Pyrazoles; D044022:Receptor, Endothelin A; C113973:SB 234551; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-