Broad-spectrum and selective serine protease inhibitors prevent expressionof platelet-derived growth factor-BB and cerebral vasospasm after subarachnoid hemorrhage - Vasospasm caused by cisternal injection of recombinant platelet-derived growth factor-BB

Background and Purpose - Plasma serine protease cascade, including the comp lement system and thrombin, is activated in the subarachnoid space during t he acute phase after subarachnoid hemorrhage (SAH). To examine the effect o f protease cascade-based inflammation and subsequent vascular repair in the development of cerebral vasospasm, we examined the effect of 2 synthetic s erine protease inhibitors - FUT-175, an inhibitor of thrombin and the compl ement system, and argatroban, a selective inhibitor of thrombin - on the de velopment of cerebral vasospasm in a rabbit SAH model. Methods - One hundred Japanese White male rabbits were used in the study. T he SAH was simulated by a single injection of autologous arterial blood int o the cisterna magna. To evaluate the development of cerebral vasospasm, th e caliber of the basilar artery was measured on x-ray film before and at 2 days after SAH. Nine groups of rabbits (n=6 each) were treated with continu ous intravenous injection of FUT-175 (2.5, 5, 10, or 20 mg/d), argatroban ( 1.25, 2.5, or 5 mg/d), or the same amount of saline (vehicle) for 48 hours, starting 40 minutes after SAH. Two days after SAH, the expression of homod imer of platelet-derived growth factor-BE (PDGF-BB) in the basilar artery w as examined with immunohistochemical techniques. In 20 normal rabbits, 5 mu g of recombinant PDGF-BB or vehicle was injected into the cisterna magna, a nd the basilar arteries were examined on angiograms for 48 hours. Results-Significant differences were observed in the caliber of the basilar arteries between the vehicle group and the groups with the 3 larger doses of FUT-175 (vehicle, 52 +/-5.0%; 5 mg, 79 +/-5.7%; 10 mg, 80 +/-2.5%; 20 mg , 80 +/-3.7%) and between the vehicle group and the groups with the 2 large r doses of argatroban (vehicle, 52 +/-6.4%; 2.5 mn, 81 +/-9.0%; 5 mg, 85 +/ -4.1%) (P <0.05). In the histological examination, administration of effect ive doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the endothelial and medial smooth muscle cell layers. Exogenous PDGF-BB cau sed delayed and prolonged vasoconstriction on normal basilar arteries. Conclusions - Activation of the serine protease cascade and/or thrombin aft er SAH was demonstrated to play an essential role in the development of cer ebral vasospasm. The expression of PDGF-BB-like protein in the arterial wal ls correlated with the development of cerebral vasospasm. Elevated PDGF-BB level in the subarachnoid space was found to induce delayed and chronic vas oconstriction.