Barone F C, White R F, Elliott J D, Feuerstein G Z, Ohlstein E H
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S404-7.
Previously, we demonstrated that cerebral focal ischemic tissue exhibits a significant increase in immunoreactive endothelin (ET). Because increased ET might exacerbate the consequences of cerebral ischemia, we evaluated the effects of the orally active ETA/B receptor antagonist SB 217242 on middle cerebral artery occlusion (MCAO) in the spontaneously hypertensive rat (SHR). SHRs were treated b.i.d. with vehicle or with 3 or 15 mg/kg SB 217242 p.o. for 7 days. Permanent MCAO was performed on day 7 and animals were sacrificed on day 8. Forebrains were stained and the extent of cerebral (i.e., cortical) infarction was determined using image analysis. Hemispheric swelling (%), hemispheric infarct (%), and infarct volume (mm3) were quantitated for each animal. SB 217242 treatment produced a significant decrease in ischemic brain injury. Hemispheric infarction and infarct volume were reduced after the 15 mg/kg treatment (12.0 +/- 1.1% and 69 +/- 6 mm3) compared to vehicle (17.3 +/- 1.5% and 99 +/- 8 mm3) (p < 0.05). No significant effects on hemispheric swelling were observed. This is the first demonstration of an ET receptor antagonist exhibiting efficacy in cerebral focal ischemia. The fact that a 30% reduction in ischemic brain injury can be demonstrated after oral administration of SB 217242 suggests that ET antagonists may be of therapeutic utility in focal stroke.
此前，我们证明脑局灶性缺血组织中免疫反应性内皮素（ET）显著增加。由于ET增加可能会加重脑缺血的后果，我们评估了口服活性ETA/B受体拮抗剂SB 217242对自发性高血压大鼠（SHR）大脑中动脉闭塞（MCAO）的影响。将SHR每日两次用赋形剂或3或15mg/kg SB 217242口服治疗7天。在第7天进行永久性MCAO，并在第8天处死动物。对前脑进行染色，并使用图像分析确定脑（即皮质）梗死的范围。对每只动物的半球肿胀（%）、半球梗死（%）和梗死体积（mm³）进行定量。SB 217242治疗使缺血性脑损伤显著减轻。与赋形剂组（17.3±1.5%和99±8mm³）相比，15mg/kg治疗后半球梗死和梗死体积减小（12.0±1.1%和69±6mm³）（p<0.05）。未观察到对半球肿胀有显著影响。这是首次证明ET受体拮抗剂在脑局灶性缺血中具有疗效。口服SB 217242后可证明缺血性脑损伤减少30%，这一事实表明ET拮抗剂可能对局灶性中风具有治疗作用。
