The authors report the results of inhibition of thromboxane A2 synthetase in 49 consecutive patients with subarachnoid hemorrhage (SAH). These unselected Grade I to IV patients all had a ruptured aneurysm of the anterior circle of Willis, and were operated on within 72 hours after SAH. Twenty-seven patients were treated postoperatively by an intravenous infusion of sodium (E)-3- [4-(3-pyridylmethyl)-phenyl] -2- propenoate (OKY-1581), a selective inhibitor of thromboxane A2 synthetase, at 5 micrograms/kg/min for 10 to 14 days, and the remaining 22 patients did not receive this drug. Both groups of patients had similar age distribution and preoperative neurological conditions. A suggestive but statistically insignificant improvement was found in postoperative angiographic vasospasm, ischemic symptoms, and overall outcome in the group receiving OKY-1581. The incidence of low-density areas on the postoperative computerized tomography scans was significantly decreased in patients treated with OKY-1581 infusion.

A giant-cell glioblastoma was examined by electron microscopy and by the freeze-fracture technique. The cell membranes bordering the extensive extracellular space often showed complicated undulations and peripheral vacuoles as well as occasional microvilli or filopodia. The undulations were mainly composed of plasmalemmal vesicles as well as of large (400--800 nm in diameter) and small (30--50 nm in diameter) localized protrusions and invaginations of the cell membrane. Deep invaginations of the cell membrane apparently resulted in two separate cytoplasmic portions. Locking of protruded cytoplasmic tongues and adherens junctions were sometimes seen in closely approximated cell membranes. The average number of membrane particles per micrometer2 was 630 +/- 130 on the P face and 180 +/- 30 on the E face. The membrane particles were occasionally aggregated to form clusters about 30 to 150 micrometer in diameter. Gap junctions were occasionally found, but there were no tight junctions. Large particles about 30 nm in diameter were found in places.

SUMMARY Experimental cerebral vasospasm was induced in the canine basilar artery by an intracisternal injection of fresh autogenous arterial blood. Delayed vasospasm was defined as a reduction to less than 75% of the caliber of control basilar artery 5 days after the intracisternal blood injection. A selective inhibitor of thromboxane A 2 synthetase, sodium(E)-3-[4-(3-pyridylmethyl) phenyl]-2-methyl-2-propenoate, was infused intravenously for 1 or 2 hrs at 50 /xg/kg/min in normal animals and in animals exhibiting vasospasm. Angiographic evidence of cerebral vasospasm was not reversed. Mean regional cerebral blood flow was not significantly increased in normal and vasospastic animals, but a mean difference of regional cerebral blood flow was significantly increased only in vasospastic animals. Mean arterial blood pressure and pulse rate were not seriously changed in normal and spastic animals. Another selective thromboxane A 2 synthetaste inhibitor, (E)-3-[4-(l-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate, showed a similar effect on tbe caliber of the basilar artery, regional cerebral blood flow, blood pressure, and pulse rate, in vasospastic animals. Venous blood was taken from the internal jugular vein, and the mean platelet aggregation induced by 10 ^ig/ml of collagen was inhibited by the infusion of either selective inhibitor at 50 /ng/kg/min for 2 hrs. However, mean platelet aggregation rates in vasospastic animals before and after treatment with either selective inhibitor were not significantly different to those in normal animals. Stroke Vol 15, No 2, 1984 WHEN ARTERIAL RUPTURE occurs, prostacyclin (PGI 2 ) synthesis may be reduced at the site of rupture, and platelets, which generate thromboxane A 2 (TXA 2 ), adhere to the site of damage.1 PGI 2 formation in the canine basilar artery is significantly decreased in delayed cerebral vasospasm, 2 ' 3 and a continuous intravenous infusion of sodium(E)-3-[4-(3-pyridylmethyl) phenyl]-2-methyl-2-propenoate (OKY-1581) at the rate of 4 gm/50 ml/24 hrs until sacrifice 4 days after induction of subarachnoid hemorrhage (SAH) abolishes almost completely the occurrence of delayed cerebral vasospasm.4 PGI 2 functions as a potent relaxing action on cerebral arteries, 5 " 9 while the contractile effect of TXA 2 appears to be more pronounced on cerebral blood vessels compared to peripheral arteries. 9 Consequently, it may be postulated that delayed cerebral vasospasm could arise from a disproportionate synthesis of TXA 2 . The present study uses pyridine and imidazole derivatives of a selective inhibitor of TXA 2 synthetase; OKY-1581 and (E)-3-[4-(l-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046), 10 " 16 and examines their effects on delayed cerebral vasospasm and regional cerebral blood flow. Materials and Methods Production of Delayed Cerebral VasospasmExperimental cerebral vasospasm was produced by a transorbital administration of 8 to 12 ml of fresh autogenous arterial blood into the chiasmatic cistern of mongrel ...

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Isolated canine basilar artery contracted by prostaglandin E2, hemoglobin, or serum was relaxed in a dose-dependent manner by the addition of 10(-8)M to 10(-6)M prostacyclin (PGI2), and was scarcely relaxed by 10(-9)M PGI2. In other studies, intravenous administration of PGI2 (25 or 75 ng/kg/min), indomethacin (4 mg/kg), or indomethacin (4 mg/kg) plus PGI2 (25 ng/kg/min) failed to reverse angiographic delayed vasospasm produced in vivo in the canine basilar artery by an intracisternal injection of blood. In addition, no significant increase occurred in mean values of regional cerebral blood flow (rCBF) with any treatments, and mean rCBF difference in dogs treated by PGI2 infusion at 25 ng/kg/min was 2.5 +/- 1.2 ml/100 gm/min and only significantly increased (p less than 0.01). Mean arterial blood pressure was significantly reduced by PGI2 infusion at 25 (p less than 0.05) or 75 ng/kg/min (p less than 0.005).