Effect of thromboxane receptor antagonists on renal artery thrombosis in the cynomolgus monkey

WA Schumacher, HJ Goldenberg, DN Harris and ML Ogletree

Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey.

The effect of the thromboxane (Tx) A2-receptor antagonists SQ 28,668 and SQ 30,741 on platelet function and renal artery thrombosis was studied in the dialurethane-anesthetized cynomolgus monkey. Both antagonists competitively inhibited the aggregation of platelet rich plasma in vitro to arachidonic acid and U-46,619, a Tx-mimetic. SQ 30,741 was 4 to 7 times more potent than SQ 28,668 against either of these agonists. Thrombotic cyclical blood flow reductions (CFRs) were elicited by placing a critical stenosis at a crush injury site on the left renal artery. After allowing 10 consecutive CFRs, of which 95% required shaking of the vessel to restore flow, a single i.v. injection of either SQ 28,668 (1 mg/kg, n = 6), SQ 30,741 (1 mg/kg, n = 8) or vehicle (2 ml of 0.2% Na2CO3 + 10% ethanol, n = 4) was administered. Antithrombotic activity was defined as the spontaneous restoration of flow and was accompanied by a reduction in the rate of flow decline during the CFRs. Spontaneous flow restoration was observed in animals treated with SQ 28,668 (five of six) and SQ 30,741 (six of eight) but not vehicle (zero of four). The rate of flow decline was reduced only with SQ 28,668 (56 +/- 8%) and SQ 30,741 (53 +/- 10%) treatments. The antithrombotic activities of SQ 28,668 and SQ 30,741 lasted 68 +/- 6 and 224 +/- 21 min, respectively. The threshold antithrombotic dose was found to be lower for SQ 30,741 (0.20 +/- 0.03 mg/kg) than SQ 28,668 (0.61 +/- 0.09 mg/kg) in additional experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 243, Issue 2, pp. 460-466, 11/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics

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