Effect of combination of a tissue-type plasminogen activator and an endothelin receptor antagonist, FR139317, in the rat cerebral infarction model.

We were interested to investigate if a combination of a modified tissue-type plasminogen activator, SUN9216, which is constructed by modifying a single amino acid (Asn117-Gln117) to yield a tissue-type plasminogen activator lacking finger and growth factor domains with a long half-life in blood, and an endothelin receptor antagonist, FR139317, (R)2-[(R)-2-[(S)-2[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4- methyl-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3- (2-pyridyl)propionic acid, has greater thrombolytic efficacy than a thrombolytic agent alone in reducing the size of cerebral infarction. The thrombotic occlusion of the rat middle cerebral artery was induced by a photochemical reaction between rose bengal and green light, which causes endothelial injury followed by platelet adhesion and formation of a platelet-rich thrombus. SUN9216 (1 mg/kg) was injected intravenously 30 min after the middle cerebral artery occlusion and the time for reopening of the middle cerebral artery by SUN9216 was monitored for a 60-min period under an operating microscope. In the rats in which thrombolysis was achieved with SUN9216, the size of the cerebral infarction was significantly (P < 0.05) reduced as compared with that in the rats treated with saline and was comparable to the reduction produced by the combination doses. It is concluded that, under the present experimental conditions, endothelin may not be involved in the impaired local cerebral blood flow after thrombolysis.