Abstract
We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinor-thromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 ± 6 min vs. 52 ± 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 ± 1 to 37 ± 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 ± 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 ± 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 ± 8vs. 68 ± 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 ± 1 ng/mg creatinine,n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.
Footnotes
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Send reprint requests to: Desmond Fitzgerald, Centre for Cardiovascular Science, Dept. of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland.
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↵1 The work was supported by grants from the Wellcome Trust and the Irish Heart Foundation.
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↵2 Present address: Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abbreviations:
- TX
- thromboxane
- t-PA
- tissue-type plasminogen activator
- GP
- glycoprotein
- aPTT
- activated partial thromboplastin time
- PT
- prothrombin time
- Received October 9, 1996.
- Accepted February 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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