Differential involvement of serotonin 2A/C and thromboxane A2/prostanoid receptors in high- vs. low-shear rate arterial thrombosis in rabbits.
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-HT2A/C receptor antagonists, ritanserin and ketanserin, were assessed first in low-shear rate (approximately 600 sec(-1)) 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 (approximately 40,000 sec(-1)) 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 microg/kg plus 10-2500 microg/kg/hr i.v.), but not ritanserin or ketanserin (both at 2500 microg/kg i.v.), dose-dependently inhibited thrombus formation. In contrast, under high shear rate, SQ 29,548 (10-160 microg/kg plus 10-160 microg/kg/hr i.v.) and both ritanserin and ketanserin (both at 10-2500 microg/kg i.v.) dose-dependently reduced CFR frequency, with ID50 values of 35 microg/kg (95% confidence limits, 24-58 microg/kg), 77 microg/kg (95% confidence limits, 40-132 microg/kg) and 89 microg/kg (95% confidence limits, 36-285 microg/kg) i.v., respectively. Furthermore, local infusion of the stable thromboxane A2 analog U-46619 (0.63 microg/kg/min) or 5-HT (20.8 microg/kg/min) proximal to the site of injury and stenosis in rabbits pretreated with either SQ 29,548 (40 microg/kg plus 40 microg/kg/hr i.v.) or ritanserin (160 microg/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-HT1B/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-HT2A/C receptors play a major role only in high-shear rate thrombus formation.
Valentin
J P
JP
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Vieu
S
S
Bertolino
F
F
Fauré
P
P
John
G W
GW
D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016893:Carotid Stenosis / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005231:Fatty Acids, Unsaturated; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006834:Hydrazines / Q000494:pharmacology*; D007601:Jugular Veins / Q000601:surgery; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010974:Platelet Aggregation; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011982:Receptors, Prostaglandin / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D017482:Receptors, Thromboxane / Q000502:physiology*; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013314:Stress, Mechanical
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010069:Oxadiazoles; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011982:Receptors, Prostaglandin; D011985:Receptors, Serotonin; D017482:Receptors, Thromboxane; D012702:Serotonin Antagonists; D016713:Ritanserin; C090701:GR 127935; C045749:SQ 29548; D007650:Ketanserin; D001241:Aspirin; D011224:Prazosin