EFFECTS OF ANTIPLATELET AGENTS ON PLATELETS EXPOSED TO SHEAR STRESS

[摘要] Shear stress levels of the order of those associated with artifical heart valves and extracorporeal circulatory devices are sufficient to stimulate platelets to aggregate, to release chemicals that potentiate aggregation and blood coagulation, to cause impairment of platelet function, and to induce platelet lysis. There is evidence that certain drugs, called antiplatelet agents, alter platelet behavior in a way that reduces adhesion, aggregation, and secretion while causing no significant adverse effects on hemostasis. The objective of this study was to investigate the effects of antiplatelet agents on the response of platelets subjected to a well-defined shear stress field produced by a rotational viscometer. Antiplatelet agents studied include aspirin (acetysalicylic acid, or ASA), prostaglandin E(,1) (PGE(,1)) in combination with theophylline, and prostaglandin I(,2) (PGI(,2), or prostacyclin) in combination with theophylline.ASA inhibits the formation of thromboxane A(,2), a potent endogenous platelet aggregating agent, by irreversibly acetylating the platelet enzyme cyclo-oxygenase at its active site. PGE(,1) and PGI(,2) stimulate the platelet enzyme adenyl cyclase to convert platelet ATP to cyclic-AMP, which is a potent inhibitor of platelet aggregation. Theophylline inhibits the platelet enzyme phosphodiesterase, which breaks down cyclic-AMP to AMP. Theophylline, in combination with PGE(,1) or PGI(,2), maintains a high level of cyclic-AMP in the platelets and so potentiates the effects of PGE(,1) and PGI(,2).Samples of platelet-rich plasma were exposed to shear stress in a specially-designed rotational viscometer for 5 minutes at 23(DEGREES)C. Platelet response was characterized by the following measurements made before and after exposure to shear stress:(1)the particle count, which is used to indicate shear-induced platelet aggregation and lysis, (2)the level of ('14)C-radiolabelled serotonin in the plasma, which is used to indicate that the platelet release reaction and/or lysis has been induced, (3)the level of the enzyme lactic dehydrogenase in the plasma, which is used to indicate shear-induced platelet lysis, (4)the ability to aggregate in response to ADP, which indicates platelet functional capacity, and (5)the ability to aggregate in response to collagen, which provides additional information on platelet functional capacity.Results of the ASA study indicate that pretreatment of the platelets with 50 (mu)M ASA before exposure to shear stress caused little or no effect on shear-induced platelet aggregation and lysis. These results also indicate that formation of thromboxane A(,2) is not important in shear-induced platelet aggregation.The ASA pretreatment caused a small reduction of shear-induced serotonin release at stress levels equal to or greater than 200 dynes/cm('2), but not at lower stress levels. It was concluded that ASA does not cause a significant suppression of the response of platelets to the effects of shear stress.The results of the PGE(,1)-theophylline study, using final concentrations of 1 (mu)M and 100 (mu)M, respectively, were very similar to those of the PGI(,2)-theophylline study, using final concentrations of 0.01 (mu)M and 500 (mu)M, respectively. Both of these drug combinations caused a large reduction in the platelet aggregation response to a mechanical stimulus (shear stress) and to chemical stimuli (ADP and collagen). Thus, over a wide range of conditions, PGE(,1) (or PGI(,2)) and theophylline were much more effective than ASA in inhibiting platelet aggregation.It was also observed that PGE(,1) (or PGI(,2))-theophylline pretreatment caused an increase in shear induced platelet lysis and serotonin release at stress levels equal to or greater than 150 dynes/cm('2). This indicates that the PGE(,1) (or PGI(,2))-theophylline pretreatment caused increased platelet fragility.

[发布机构] Rice University

[效力级别] engineering