Inhibition of fibrinolysis by cellular glutathione depletion in the rabbit

Abstract The effect of cellular glutathione depletion on fibrinolytic activity in the arterial wall and on the levels of components of the plasma fibrinolytic system was studied in rabbits. Intraperitoneal administration of buthionine sulphoximine (4.5 mmol/kg body wt), an inhibitor of gamma-glutamyl cysteine synthetase, induced a significant reduction in liver glutathione concentrations with a peak decrease of 51% at 7 hours and a progressive return to normal values. The glutathione concentration in aortic tissue was also significantly reduced 7 h after administration of the depleting agent. Fibrinolytic activity in the arterial wall was inhibited following buthionine sulphoximine administration and only reappeared at 24 hours postinjection. Diethyl maleate administration (3.2 mmol/kg body wt i.p.) also depleted liver and aortic glutathione and inhibited fibrinolysis in the arterial wall. Treatment with both glutathione-depleting agents induced a significant reduction in the functional activity of tissue plasminogen activator (t-PA) (-61% and -27% respectively for buthionine sulphoximine or diethyl maleate) and a significant increase in that of plasminogen activator-inhibitor (PAI) (+61% and +27% respectively), while alpha-2-antiplasmin activity was not modified. Our data suggest a modulatory role of glutahione in the release and/or clearance of the components of the fibrinolytic system in the rabbit.