In a previous publication (Blood 66, 86, 1985) we suggested, on the basis of inhibitor experiments, that lipoxygenase metabolites might be involved in the release of tissue-type plasminogen activator (t-PA) from vessel walls. To test this suggestion, isolated rat hindlegs were freed of blood with Tyrode-BSA solution, and subsequently perfused with Tyrode-BSA containing various lipoxygenase metabolites. The perfusate was collected at timed intervals and assayed for t-PA activity by a spectrophoto-metric procedure. Of the compounds tested (see Table) 5-HETE did not induce PA release. However, leukotriene (LT) C4 and LTD4 dose-dependently (10-200 nM) induced the release of t-PA, which plateaued at 160 and 200 nM, respectively. Peak levels of t-PA activity were found at one minute, although the amount of t-PA released was less than that induced by PAF-acether. The PA activity released proved to be t-PA by functional and immunological criteria. Release of t-PA induced by LTC4 and LTD 4 was inhibited by the LT receptor antagonist FPL-55712 (10 μM).Prostaglandin E1 and E2, prostacyclin and ZK 36374 did not induce acute t-PA release at 0.1-2.8 μM concentrations in our model. LTC4 and LTD4 also induced an acute increase of t-PA activity in vivo in rats at a dosage of 2 μg/kg i.v.The data show that LTC4 and LTD4 can directly induce the acute release of t-PA, possibly by interacting with an endothelial LT receptor.
Formulation and evaluation of effervescent floating tablets of tizanidine hydrochloride
