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Antiplatelet and antihypertensive actions of ridogrel



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Thromboxane plays a principal role in platelet aggregation, and is a potent vasoconstrictor. It is now understoood, that the receptor for thromboxane (TP) responds to multiple endogenous ligands. Inhibiting the synthesis of thromboxane does not prevent functional responses mediated by TP receptors. Ridogrel is an investigational drug with dual activities as an antagonist of TP receptors, and an inhibitor of thromboxane synthase. Single doses of ridogrel ranging 1.5 to 125 milligrams per kilogram reduced serum (platelet-derived) thromboxane B2 synthesis, they did not affect urinary thromboxane B2 excretion or blood pressure,in twelve-week-old Spontaneously Hypertensive Stroke-Prone Rats (SHR-SP). In contrast, repeated doses of ridogrel 12.5 milligrams per kilogram every twelve hours for seven days, reduced renal thromboxane B2 synthesis without affecting renal prostacyclin synthesis. Blood pressure was reduced despite an increase in plasma renin activity. The pressor response to the TP receptor agonist U46,619 was shifted to the right following ridogrel pre-treatment, confirming competitive TP receptor antagonism. More importantly, the pressor responses to angiotensin II and noradrenaline were also blunted by ridogrel pre-treatment. The reduction in vasopressor responses to those agents, following repeated administration of ridogrel, suggests modulation of vascular responses by a more generalized mechanism, or that a TP receptor-mediated component contributes to the contractile responses caused by a number of vasopressor agents. The dual actions of a thromboxane synthase inhibitor/TP receptor antagonist (TSI-TPA) drug such as ridogrel, have the potential to improve endothelial dysfunction, and attenuate TP receptor-mediated contraction. Furthermore, the redirection of arachidonic acid metabolism toward the synthesis of prostacyclin, and the enhancement of intracellular cAMP generation, would favour vasorelaxation, reduce shear stress and increase erythrocyte deformability in the micro-circulation. It remains to be proven whether any or all of these effects explain the antihypertensive response to extended treatment with ridogrel. Untreated twelve-week old SHR-SP excrete less urinary thromboxane B2 than normotensive Wistar-Kyoto or Sprague-Dawley rats, suggesting that reduced renal thromboxane A2 synthesis is a compensatory response to hypertension; a compensatory response which ridogrel augments. An especially attractive prospect is that TSI-TPA drugs may provide anti-platelet activity while lowering blood pressure. A subset of patients may derive additional benefit from the potential antiasthmatic, uricosuric and gastric-protective effects of ridogrel.





Doctor of Philosophy (Ph.D.)







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