Vol. 280, Issue 2, 761-769, 1997

Differential Involvement of Serotonin 2A/C and Thromboxane A₂/Prostanoid Receptors in High- vs. Low-Shear Rate Arterial Thrombosis in Rabbits¹

Jean-Pierre Valentin, Sylvie Vieu, Frédéric Bertolino, Philippe Fauré and Gareth W. John

Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases (J.-P.V., S.V., F.B., G.W.J.), and Laboratoire d'Anatomie et Cytologie Pathologiques (P.F.), Castres, France

Experiments performed in 226 pentobarbitone-anesthetized rabbits were designed to investigate the involvement of thromboxane/prostanoid and 5-hydroxytryptamine (5-HT)_2A/C receptors during arterial thrombus formation in distinct low- and high-shear rate thrombosis models. Antithrombotic activities of the thromboxane/prostanoid receptor antagonist SQ 29,548 and two chemically distinct 5-HT_2A/C receptor antagonists, ritanserin and ketanserin, were assessed first in low-shear rate (~600 sec¹) arterial thrombosis, produced by insertion of a silk thread as thrombogenic substrate into the central section of an extracorporeal arteriovenous shunt established between the left carotid artery and the right jugular vein (n = 77), and second in high-shear rate (~40,000 sec¹) arterial thrombosis, produced by critical stenosis and local endothelial injury of a carotid artery, characterized by cyclic flow reductions (CFRs) due to recurrent platelet aggregation and subsequent dislodgement of the thrombus (n = 149). Under low shear rate, SQ 29,548 (10-2500 µg/kg plus 10-2500 µg/kg/hr i.v.), but not ritanserin or ketanserin (both at 2500 µg/kg i.v.), dose-dependently inhibited thrombus formation. In contrast, under high shear rate, SQ 29,548 (10-160 µg/kg plus 10-160 µg/kg/hr i.v.) and both ritanserin and ketanserin (both at 10-2500 µg/kg i.v.) dose-dependently reduced CFR frequency, with ID₅₀ values of 35 µg/kg (95% confidence limits, 24-58 µg/kg), 77 µg/kg (95% confidence limits, 40-132 µg/kg) and 89 µg/kg (95% confidence limits, 36-285 µg/kg) i.v., respectively. Furthermore, local infusion of the stable thromboxane A₂ analog U-46619 (0.63 µg/kg/min) or 5-HT (20.8 µg/kg/min) proximal to the site of injury and stenosis in rabbits pretreated with either SQ 29,548 (40 µg/kg plus 40 µg/kg/hr i.v.) or ritanserin (160 µg/kg i.v.), respectively, restored CFR frequency to vehicle group levels in animals whose CFR frequency was previously reduced. The inhibitory activity of ketanserin and ritanserin on CFRs could not be attributed to 5-HT_1B/D or alpha-1 adrenoceptor antagonist properties or to any hypotensive activity. These results provide firm evidence that thromboxane/prostanoid receptors are involved in arterial thrombosis in rabbits independently of the shear rate, whereas 5-HT_2A/C receptors play a major role only in high-shear rate thrombus formation.