Abstract
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 (∼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 (∼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 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-HT1B/D oralpha-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/Creceptors play a major role only in high-shear rate thrombus formation.
Footnotes
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Send reprint requests to: Gareth W. John, Ph.D., Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, 17 avenue Jean Moulin, 81106 Castres cédex, France.
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↵1 Part of this work was presented at the 68th Scientific Sessions of the American Heart Association, Anaheim, CA, November 13–16, 1995, and was published in abstract form in Circulation92: suppl. I, A2979, 1995.
- Abbreviations:
- CFR
- cyclic flow reduction
- COX
- cyclooxygenase
- GP
- glycoprotein
- HR
- heart rate
- 5-HT
- 5-hydroxytryptamine
- I.D.
- internal diameter
- MAP
- mean arterial pressure
- NS
- not significant
- SQ 29
- 548, [1S-[1α,2α(5Z),3α,4α]]-7-[3-[[2-(phenylaminocarbonyl)hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
- TP receptor
- thromboxane A2/prostanoid receptor
- TxA2
- thromboxane A2
- U-46619
- 9,11-dideoxy-9α,11α-methanoepoxy-prostaglandin F2α
- vWf
- von Willebrand factor
- Received July 23, 1996.
- Accepted October 11, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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