TY - JOUR
T1 - Antithrombotic properties of the thromboxane A2/prostaglandin H2 receptor antagonist S18886 on prevention of platelet-dependent cyclic flow reductions in dogs
AU - Maalej, Nabil
AU - Osman, Hashim E.
AU - Shanmuganayagam, Dhanansayan
AU - Shebuski, Ronald J.
AU - Folts, John D.
PY - 2005/5
Y1 - 2005/5
N2 - A potent thromboxane A2/PGH2 (TP)-receptor antagonist, S18886, was evaluated for its antithrombotic property in a dog model of acute periodic platelet-mediated thrombosis in stenosed coronary arteries with endothelial damage. After thrombosis had been obtained in 11 dogs, S18886 (300 μg/kg bolus) was administered IV Heart rate, systemic blood pressure, and coronary blood flow were continuously recorded. Ex vivo whole blood platelet aggregation (PA), blood pH, hematocrit, platelet count, Po2, Pco2, and bleeding times were measured before and 30 minutes after administration of S18886, S18886 completely inhibited thrombosis in all dogs in approximately 5-10 minutes. No change in heart rate, blood pressure, pH, Po 2, Pco2, platelet count, or bleeding time and a slight but significant elevation in hematocrit occurred. Infusion of epinephrine IV after complete inhibition of thrombosis by S18886 partially restored thrombosis in 3 of the 11 dogs. PA induced by collagen (4 μg/mL), collagen (0.25 μg/mL) plus epinephrine (1 μg/mL), collagen (1 μg/mL) plus epinephrine (1 μg/mL), ADP (40 μM) plus epinephrine (1 μg/mL), and phorbol 12-myristate 13-acetate (0.5 nM) were attenuated by 90 ± 8% (P < 0.005), 98 ± 2% (P < 0.05), 78 ± 6% (P < 0.005), 70 ± 10% (P < 0.005), and 28 ± 8% (P < 0.05), respectively. In conclusion, S18886 is a potent platelet inhibitor that attenuates in vivo platelet-dependent thrombosis in the experimental dog model and reduces ex vivo platelet aggregation.
AB - A potent thromboxane A2/PGH2 (TP)-receptor antagonist, S18886, was evaluated for its antithrombotic property in a dog model of acute periodic platelet-mediated thrombosis in stenosed coronary arteries with endothelial damage. After thrombosis had been obtained in 11 dogs, S18886 (300 μg/kg bolus) was administered IV Heart rate, systemic blood pressure, and coronary blood flow were continuously recorded. Ex vivo whole blood platelet aggregation (PA), blood pH, hematocrit, platelet count, Po2, Pco2, and bleeding times were measured before and 30 minutes after administration of S18886, S18886 completely inhibited thrombosis in all dogs in approximately 5-10 minutes. No change in heart rate, blood pressure, pH, Po 2, Pco2, platelet count, or bleeding time and a slight but significant elevation in hematocrit occurred. Infusion of epinephrine IV after complete inhibition of thrombosis by S18886 partially restored thrombosis in 3 of the 11 dogs. PA induced by collagen (4 μg/mL), collagen (0.25 μg/mL) plus epinephrine (1 μg/mL), collagen (1 μg/mL) plus epinephrine (1 μg/mL), ADP (40 μM) plus epinephrine (1 μg/mL), and phorbol 12-myristate 13-acetate (0.5 nM) were attenuated by 90 ± 8% (P < 0.005), 98 ± 2% (P < 0.05), 78 ± 6% (P < 0.005), 70 ± 10% (P < 0.005), and 28 ± 8% (P < 0.05), respectively. In conclusion, S18886 is a potent platelet inhibitor that attenuates in vivo platelet-dependent thrombosis in the experimental dog model and reduces ex vivo platelet aggregation.
KW - Cyclooxygenase
KW - Platelet aggregation
KW - Prostanoid endoperoxide
KW - Thrombosis
KW - Thromboxane receptor antagonist
UR - http://www.scopus.com/inward/record.url?scp=18244394040&partnerID=8YFLogxK
U2 - 10.1097/01.fjc.0000157439.49612.83
DO - 10.1097/01.fjc.0000157439.49612.83
M3 - Article
C2 - 15821433
AN - SCOPUS:18244394040
SN - 0160-2446
VL - 45
SP - 389
EP - 395
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 5
ER -