The combined antiischemic effects of the thromboxane receptor antagonist SQ 30,741 and tissue-type plasminogen activator.
The thromboxane-receptor antagonist, SQ 30,741, may be used as adjuvant therapy for thrombolysis and has also been shown to have antiischemic activity that is independent of its thrombolytic activity. Since tissue-type plasminogen activator (t-PA) and SQ 30,741 may be administered simultaneously, we determined whether the antiischemic effects of SQ 30,741 can be potentiated by t-PA. This was accomplished by combining doses of t-PA and SQ 30,741, which alone were not cardioprotective. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes and reperfusion for 5 hours. The dogs were treated during reperfusion with a dose of t-PA that caused approximately a 30% reduction in plasma fibrinogen alone or in combination with 1.5 mg/kg + 0.4 mg/kg/hr SQ 30,741, which started 10 minutes after initiation of ischemia. At these doses, neither t-PA nor SQ 30,741 alone significantly reduced infarct size (57% +/- 6%, 50% +/- 10%, 57% +/- 6% of the left ventricular area at risk for vehicle controls, t-PA, and SQ 30,741 respectively); however, combination treatment resulted in a significant reduction in infarct size (37% +/- 5% of the left ventricular area at risk). Higher doses of t-PA and SQ 30,741 alone significantly reduced infarct size. The protective effects of t-PA and SQ 30,741 occurred without altering peripheral hemodynamic status. No differences in collateral or reperfusion blood flow were observed between groups. Thus although SQ 30,741 may act to improve the efficacy of thrombolysis, t-PA may in turn enhance the antiischemic activity of SQ 30,741 or at least reduce the threshold dose.
Grover
G J
GJ
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, N.J. 08543-4000.
Parham
C S
CS
Schumacher
W A
WA
D000818:Animals; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C054215:SQ 30741; D013928:Thromboxane A2; D010959:Tissue Plasminogen Activator