Effects of 6-[p-(4-Phenylacetylpiperazin-l-yl)-phenyl]-4,5-Dihydro-3(2H)-Pyridazinone (CCI 17810) and Aspirin on Experimental Arterial Thrombosis in Rats

Summary

An experimental model for arterial thrombosis has been investigated in rats. A loop of polythene tubing inserted in the left carotid artery induced thrombus formation on the arterial wall at the points of contact with the tips of the cannula. Sprague Dawley (CFY) rats were more susceptible to the thrombotic stimulus than were Wistar (WAG) rats. Whole blood platelet adhesiveness measured by a glass bead column method was higher in CFY rats than in WAG rats.

6 - [p - (4-Phenylacetylpiperazin-1 - yl) - phenyl] - 4,5 - dihydro-3(2H)-pyridazinone (CCI 17810) inhibited thrombus formation in CFY rats. Both the incidence of occlusion of the cannulated artery and the mean thrombus weight were reduced by CCI 17810 in doses of 25, 50 or 100 mg/kg administered orally twice daily; the effects were dose-related.

The effects of aspirin depended on the dose administered. A high dose (200 mg/kg) did not inhibit thrombus formation whereas a low dose (20 mg/kg) reduced the incidence of occlusion and the mean thrombus weight. These results are in accord with the differential effects of aspirin on platelet and blood vessel wall cyclooxygenase.

Key words

Pyridazinone derivative

• References

• 1 Blakely JA. Platelet suppressing drugs in arterial disease. Thromb Haemostas 1978; 39: 294-303
• 2 Claggett GP, Collins GJ. Platelets, thromboembolism and the clinical utility of antiplatelet drugs. Surg Gynecol Obstet 1978; 147: 257-272
• 3 Roden SM, Kendall MJ. Antiplatelet drugs in thrombotic disease. J Clin Pharmacol 1978; 2: 185-197
• 4 Tsu EC. Antiplatelet drugs in arterial thrombosis: a review. Am J Hosp Pharm 1978; 35: 1507-1515
• 5 Lecker D, Griffett EM, Kinnon SM, Smith GM, Kumar AK, Tomich EG. Effects of 6-[p-(4-phenylacetylpiperazin-l-yl)-phenyl]-4,5-dihydro 3(2H)-pyridazinone (CCI 17810) on platelet aggregation and adhesiveness. Submitted for publication
• 6 Hirsh J. Relevance of platelet function tests in assessing the antithrombotic effects of drugs. In: Hirsh J, Cade JF, Callus AS, Schönbaum E. (Ed) Platelets, Drugs and Thrombosis . Proceedings of a Symposium held at McMaster University, Hamilton, Ontario, 16-18 October 1972, Karger 1975. p. 212-218
• 7 Chan KE. Experimental production of acute arterial thrombosis in the carotid artery of the rat. Thromb Diathes Haemorrh 1967; 18: 565-569
• 8 Hornstra G, Vendelmans-Starrenburg A. Induction of experimental arterial occlusive thrombi in rats. Atherosclerosis 1973; 17: 369-382
• 9 Williamson JR. A practical integrated method for the electronic counting of platelets, leucocytes and erythrocytes. In: Baker FJ. ed. Progress in Medical Laboratory Technique: 1967. 4: (Butterworth) 118-131
• 10 Lecker D, Smith GM. Potentiation of the platelet inhibitory effects of prostacyclin by 6-[p-(4-Phenylacetylpiperazin-l-yl)-phenyl]-4,5-dihydro-3(2H)-pyridazinone (CCI 17810). Submitted for publication
• 11 Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nature (New Biology) 1971; 231: 235-237
• 12 Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U.S.A. 1975; 72: 3037-3076
• 13 Hamberg M, Svensson J, Samuelsson B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U.S.A. 1975; 72: 2994-2998
• 14 Moncada S, Gryglewski RJ, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976; 263: 663-665
• 15 Baenziger NL, Dillender MJ, Majerus PW. Cultured human skin fibroblasts and arterial cells produce a labile platelet-inhibitory prostaglandin. Biochem Biophys Res Commun 1977; 78: 294-301
• 16 Livio M, Villa S, De Gaetano G. Aspirin, thromboxane and prostacyclin in rats: a dilemma resolved. Lancet 1978; I: 1307
• 17 Meng K, Seuter F. Effect of acetylsalicylic acid on experimentally induced arterial thrombosis in rats. Naunyn-Schmiedeberg's Arch Pharmacol 1977; 301: 115-119