Inhibition of platelet-vessel wall interactions by thromboxane receptor antagonism in a human in vitro system: potentiation of antiplatelet effects of aspirin.

BACKGROUND: Pharmacological inhibition of arachidonic acid metabolism has proven therapeutically useful in the prevention of cardiovascular events. METHODS: We have investigated the ability of Bay u 3405, a synthetic thromboxane antagonist, to interfere with platelet aggregation and arachidonic acid metabolism. The antiplatelet action was also analysed in a perfusion system in which vascular subendothelium was exposed to circulating human blood (10 min; shear rate = 800 s-1). Platelet interactions were morphometrically analysed and results compared with those obtained in studies with blood from donors taking aspirin (acetylsalicylic acid, ASA) (500 mg day-1). The additional effect of Bay u 3405 on the antiplatelet action of ASA was also evaluated. RESULTS: Bay u 3405 caused a dose-dependent inhibition of platelet aggregation induced by U46619 with a maximal effect at concentrations > or = 0.01 microgram mL-1. Higher concentrations (> or = 0.05 micrograms mL-1) also inhibited aggregations induced by ADP or collagen. Bay u 3405 did not interfere with platelet arachidonic acid metabolism. In perfusion studies, Bay u 3405 (0.01 microgram mL-1) significantly decreased the total surface of the vessel covered by platelets (%CS = 18.7 +/- 1.09 vs. 24.4 +/- 1.94; P < 0.05) and the formation of large aggregates %T = 7.5 +/- 0.87 vs. 19.3 +/- 1.61; P < 0.01). ASA treatment reduced platelet aggregate formation (%T = 13.7 +/- 2.06; P < 0.05) but did not affect the total surface covered by platelets. The in vitro addition of Bay u 3405 to blood from ASA-treated donors further reduced the formation of large aggregates (%T = 2.7 +/- 0.79; P < 0.01 vs. ASA). CONCLUSIONS: In vitro effect of Bay u 3405 on platelet function were superior to those observed with ASA. The thromboxane antagonism antagonism provided by Bay u 3405 further enhanced the inhibition of platelet aggregate formation found after ASA treatment.

[Acoustic distortion product recording in patients with sensorineural hearing loss]. / Registro de productos de distorsión acústica en pacientes con hipoacusia neurosensorial.

Distortion products are a subtype of otoacoustic emission. The normality of distortion products reflects correct outer hair cell function. Test results obtained from patients with neurosensorial, cochlear and retrocochlear hearing loss were analyzed, focusing on four points: correlation with audiometric results, reliability for the follow-up of dynamic cochlear disorders, frequency specificity, and topographic diagnosis.

Measurement of ionized cytoplasmic calcium mobilization with the photoprotein aequorin in human polymorphonuclear leukocytes activated by platelet activating factor (PAF).

The use of the sensitive photoprotein aequorin as a Ca2+ indicator in human polymorphonuclear leukocytes (PMN) not pretreated with cytochalasin B and stimulated with platelet activating factor (PAF) may help cast more light on the relative importance of intracellular and extracellular Ca2+ in PMN function. PAF elicits Ca2+ mobilization in PMN (resuspended in the presence of 1 mM extracellular Ca2+), in a concentration-dependent manner. The Ca2+ chelator ethyleneglycoltetraacetic acid (EGTA) abolishes Ca2+ mobilization, suggesting that almost all Ca2+ mobilized by PAF derives from the external medium. Aggregation and enzymatic release parallel the Ca2+ mobilization triggered by PAF. In contrast PAF appears to be only a weak stimulus of superoxide anion production (compared to the phorbol ester phorbol 12-myristate 13-acetate (PMA] and leukotriene B4 (LTB4) synthesis (compared to the Ca2+ ionophore A23187). The fact that PAF elicits Ca2+ mobilization, aggregation, secretion and LTB4 generation in human PMN supports the role of this phospholipid as a powerful mediator of physiopathological events involving PMN activation.

Effects and interaction studies of triflusal and other salicylic derivatives on cyclooxygenase in rats.

Triflusal (TR) is a new salicylic acid derivative used clinically as an antiplatelet drug. Both aspirin (ASA) and TR inhibit platelet cyclooxygenase but the effects of these drugs are different. TR (0.5-2 mM) strongly inhibited platelet aggregation and malondialdehyde formation induced by arachidonic acid. The IC50 was 0.8 mM for TR and less than 0.1 mM for ASA. Deacetylated compounds, salicylic acid (SA) and HTB (the main metabolite of TR) were apparently competitive and reversible inhibitors of cyclooxygenase and HTB was 15 times more potent than SA. They did, however, partially prevent the inhibitory effects of ASA and TR in vitro. A similar effect was observed ex vivo in rats treated with HTB (100 mg/k i.p.) before TR or ASA (20 and 5 mg/kg i.v., respectively). Moreover, TR at 10 and 20 mg/kg i.v., inhibited thromboxane production by more than 50% while its effect on vascular cyclooxygenase was negligible. These findings indicated that TR is a weaker inhibitor of cyclooxygenase than ASA, and that HTB interferes with the effect of TR and ASA, despite the fact that HTB is a more potent reversible inhibitor than SA with probably a higher affinity for this enzyme.