Dose-related cardioprotection by ifetroban in relation to inhibition of thrombosis and ex vivo platelet function.
The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.
Gomoll
A W
AW
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J. 08543, USA.
Schumacher
W A
WA
Ogletree
M L
ML
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006439:Hemodynamics / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D018375:Neutrophil Activation / Q000187:drug effects; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000187:drug effects; D013927:Thrombosis / Q000517:prevention & control
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D017482:Receptors, Thromboxane; C078904:ifetroban