Combination of Fosinopril and Pravastatin Decreases Platelet Response to Thrombin Receptor Agonist in Monkeys

Abstract

Abstract-Both angiotensin-converting enzyme (ACE) inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been shown to decrease cardiovascular morbidity and mortality. Results from clinical trials have suggested that HMG-CoA reductase inhibition might exert a beneficial effect independent of its lipid-lowering effect, and ACE inhibition may exert a benefit independent of blood-pressure lowering. To test the hypothesis that such an effect might be mediated by alteration in platelet reactivity, we studied 55 monkeys receiving both, 1, or neither of the ACE inhibitor fosinopril and the HMG-CoA reductase inhibitor pravastatin. Platelet responsiveness to collagen and to the thrombin receptor agonist (TRA) SFLRRN-NH 2 was determined by aggregometry. For each agonist, the maximum rate and extent of aggregation were measured for each dose, and the concentration required for half-maximal response (C 50 ) was determined. Each drug, when given alone, slightly decreased the dose of agonist required to produce 50% response in the rate and extent of platelet aggregation relative to control. The combination of the 2 drugs, however, produced a significant increase in the dose of TRA required to produce 50% response in the rate and extent of aggregation relative to either drug alone or the control group. This was not true for collagen. The magnitude of the change relative to the control group, 47% for rate and 30% for extent of aggregation, could confer considerable protection by changing the threshold for thrombin-induced platelet aggregation and, thus, decrease thrombosis. (Arterioscler Thromb Vasc Biol. 1998;18:1643-1646.)Key Words: angiotensin-converting enzyme inhibitors Ⅲ platelet aggregation Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors C ardiovascular disease is the leading cause of death in the United States. 1 Most of the morbidity and mortality of this disease results from the rupture of atherosclerotic plaques in the vessel wall. This event leads to exposure of the thrombogenic inner components of the plaque to circulating blood, resulting in platelet activation and aggregation and activation of the coagulation system. Subsequently, a thrombus forms.2 The use of angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering drugs has decreased cardiovascular morbidity and mortality below that expected from the resulting mild reduction in blood pressure and minor reduction in severity of coronary stenosis.2-4 Therefore, in addition to their well-known actions, these drugs probably have other protective effects on the processes that lead to cardiovascular disease and thrombosis. It is possible that these drugs may affect platelet function.In this randomized trial, we studied platelet responsiveness to collagen and a thrombin receptor agonist (TRA) in monkeys that were treated with an ACE inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, both drugs, or neither drug. Methods MaterialsThe highly purified peptide TRA SFLRRN-NH 2 (PMIS387) wa...

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