title: Interplay between platelet-derived 5-hydroxytryptamine and arachidonic acid metabolites limits the thrombolytic efficacy of streptokinase against canine platelet-rich coronary thrombosis.
abstract: The comparative contributions of arachidonic acid (AA) metabolites and 5-hydroxytryptamine (5-HT) to the delay of reperfusion and rate of reocclusion after coronary thrombolysis with streptokinase were assessed in dogs using (a) single TXA2 synthase inhibition; (b) single 5-HT2-receptor blockade; (c) dual TXA2 synthase inhibition/PGH2 receptor antagonism; (d) 5-HT2-receptor blockade combined with TXA2 synthase inhibition; and (e) 5-HT2-receptor blockade combined with dual TXA2 synthase/PGH2-receptor antagonism. In open-chest anesthetized dogs, occluding coronary thrombi were induced by severe intimal injury in combination with critical artery stenosis. Fifty minutes after occlusive thrombus formation, the animals received intravenously (i) saline (S); (ii) ketanserin, 0.3 mg/kg (K), a 5-HT2-receptor antagonist; (iii) ridogrel, either at a low dose 0.3 mg/kg (R 0.3), exerting single TXA2 synthase inhibition; or (iv) at 5 mg/kg (R 5), exerting additional TXA2/PGH2-receptor antagonism; or (v) the combination of either dose of ridogrel with ketanserin. Ten minutes later, all dogs received streptokinase (SK; 1,000 IU/kg i.v. + 100 IU/kg/min i.v. infusion for 90 min). High-grade thrombolysis (> or = 50% coronary reperfusion vs. prethrombosis value as assessed by flow measurements) with SK occurred in 3/11 dogs treated with S, in 5/7 with R 0.3 and K, and in 7 of 7 dogs in the other medication groups; this occurred within > or = 55 min with S, R 0.3, and K, within 37 +/- 12 min with R 5 (p < 0.05 vs. solvent and R 0.3), and within 38 +/- 5 and 23 +/- 5 min with R 0.3 + K and R 5 + K, respectively (p < 0.05 vs. S, R 0.3, and K). The occurrence of reocclusion within 120 min after the cessation of SK administration was significantly reduced in all treatment groups, except K. That of cyclic flow reduction was reduced by R 5, R 0.3 + K, and R 5 + K. The peak extent of coronary reperfusion was highest in the K + R groups (S = 33% of preocclusion value; K = 60%; R 0.3 = 68%; R 5 = 76%; K + R 0.3 = 80%, p < 0.05 vs. S; and K + R 5 = 89%, p < 0.05 vs. solvent, R 0.3, and K). This study shows that the interplay between AA metabolites and 5-HT is involved in the platelet-dependent reduction in the thrombolytic efficacy of streptokinase in lysing coronary thrombi.
authors.affiliation: Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Vandeplassche
authors.forename: C
authors.initials: C
authors.lastname: Hermans
authors.forename: L
authors.initials: L
authors.lastname: Van Dael
authors.forename: L
authors.initials: L
authors.lastname: Wouters
authors.forename: F
authors.initials: F
authors.lastname: De Clerck
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004285:Dogs; D005260:Female; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D015425:Myocardial Reperfusion; D010421:Pentanoic Acids / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013300:Streptokinase / Q000627:therapeutic use*; D015912:Thrombolytic Therapy; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D010421:Pentanoic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012702:Serotonin Antagonists; D016718:Arachidonic Acid; D012701:Serotonin; D007650:Ketanserin; D013300:Streptokinase; D013930:Thromboxane-A Synthase; C060219:ridogrel