Medial Smooth Muscle Cell Proliferation in the Balloon Injured Rabbit Aorta: Effect of a Thiazole Compound with Platelet Inhibitory Activity

Summary

Twenty-seven adult male New Zealand rabbits (3–4 kgs) were used in this study. Six rabbits received vehicle, 3 groups of 6 each received doses of 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)- thiazole, (U-53,059), at 0.3 mg/kg, 3.0 mg/kg and 30.0 mg/kg/day respectively. Drug and vehicle doses were given orally each day starting 3 days before balloon injury and continuing for the entire 2 week time period. Three rabbits were used as nontreated sham controls. In the vehicle and U-53,059 treated groups aortae were denuded of endothelial cells by balloon catheter injury. Two weeks after injury platelet aggregation to collagen was measured and the aortae removed for analysis of surface characteristics by scanning electron microscopy and lesion size by morphometry. All doses of U-53,059 inhibited platelet aggregation. The 3.0 and 30.0 mg/kg groups had the greatest inhibitory effect. All balloon injured aortae had the same morphologic characteristics. All vessels had similar extent and intensity of Evan’s blue staining, similar areas of leukocyte/platelet adhesion, and a myointimal cell cover of transformed smooth muscle cells. The myointimal proliferative response was not inhibited at any of the drug doses studied.

Key Words

Anti-atherogenic - Proliferation - Platelet - Adhesion - Inhibition and leukocyte

• References

• 1 Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell. Proliferation of smooth muscle as a key event in the genesis of the lesions of atherosclerosis Science 1973; 180: 1332-1339
• 2 Ross R, Glomset J, Karuja B, Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscles in vitro. Proc Natl Acad Sci, USA 1974; 71: 1207-1210
• 3 Rutherford RB, Ross R. Platelet factors stimulate fibroblasts and smooth muscle cells quiescent in plasma serum to proliferate. J Cell Biol 1976; 69: 196-203
• 4 Gajdusek C, De CosletsP, Ross R, Schwartz S. An endothelial cell-derived growth factor. J Cell Biol 1980; 85: 467-472
• 5 Martin BM, Gimbrone jr MA, Unanue ER, Cotran RS. Stimulation of non-lymphoid mesenchymal cell proliferation by a macrophage derived growth factor. J Immunol 1981; 126: 1510-1515
• 6 Glenn KC, Ross R. Human monocyte-derived growth factor(s) for mesenchymal cells. Activation of secretion by endotoxin and con- canavalin A (Con A) Cell 1981; 25: 603-615
• 7 Nishizawa EE, Mendoza AR, Honohan T, Annis KA. A thiazole compound with potential antithrombotic activity. Thromb Haemostas 1982; 47: 173-176
• 8 Schaub RG, Nishizawa EE. Platelet accumulation onto the balloon injured rabbit aorta: A comparison of two cycloocygenase inhibitors. Thromb Haemostas 1983; 50: 393 (Abstr)
• 9 Wu KK, Yao-Chang C, Fordham E, Chung-Hsin T, Rayudu G, Matayoshi D. Differential effects of two doses of aspirin on platelet vessel wall interaction in vivo. J Clin Invest 1981; 68: 382-387
• 10 Stehbens WE. Endothelial permeability in experimental aneurysms and arteriovenous fistulas in rabbit as demonstrated by the uptake of Evan’s blue. Atherosclerosis 1978; 30: 343-349
• 11 Schaub RG, Lynch PR, Stewart GJ. The response of canine veins to three types of abdominal surgery: A scanning electron microstopic study. Surgery 1978; 83: 411-426
• 12 Minick CR, Murphy GE, Campbell WG. Experimental induction of atheroarteriosclerosis by the synergy of allergic injury to arteries and lipid-rich diet I. Effect of repeated injections of horse serum in rabbits fed a dietary cholesterol supplement. J Exp Med 1966; 124: 635-652
• 13 Harker L, Slichter S, Scott CR, Ross R. Homocystinemia: Vascular injury and arterial thrombosis. N Engl J Med 1974; 291: 537-543
• 14 Hendriksen T, Mahoney EM, Steinburg D. Interactions of plasma lipoproteins with endothelial cells. Ann N Y Acad Sci 1983; 401: 102-116
• 15 Minick CR. Immunologic arterial injury and atherogenesis. In: Atherosclerosis II. Springer-Verlag; New York, Heidelberg, Berlin: 1980. pp 330-333
• 16 Schaub RG, Rawlings CA, Keith Jr JC. Platelet adhesion and myointimal proliferation in canine pulmonary arteries. Am J Pathol 1981; 103: 13-22
• 17 Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis: The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58: 731-741
• 18 Spaet TH, Stemerman MB, Keith FJ, Lejunieks I. Intimal injury and regrowth in the rabbit aorta: Medial smooth muscle cells as a source of neointima. Circ Res 1975; 36: 58-70
• 19 Clowes AW, Collazza RE, Kamovsky MO. A morphologic and permeability study of luminal smooth muscle cells after arterial injury in the rat. Lab Invest 1978; 39: 141-150
• 20 Kincaid-Smith P. Modification of the vascular lesions of rejection in advanced renal allografts by dipyridamole and anticoagulants. Lancet 1969; 2: 920-922
• 21 Metke MP, Lee JT, Fuster V, Josa M, Kaye MP. Reduction of intimal thickening in canine coronary bypass vein grafts with dipyridamole and aspirin. Am J Cardiol 1979; 43: 1144-1148
• 22 Chesebro JH, Clements IP, Fuster V, Elveback LR, Smith HC, Bardsley WT, Frye RL, Holmes DR, Vlietstna RE, Pluth JR, Wallace RB, Puga FJ, Orszulak TA, Piehler JM, Schaff HV, Danielson GK. A platelet inhibitor drug trial in coronary artery bypass operations. Benefit of preoperative dipyridamole and aspirin therapy on early postoperative vein graft patency New Eng J Med 1982; 307: 73-78
• 23 Boncheck LI, Boerboom LE, Olinger GN, Pepper JR, Munns J, Hutchinson L, Kissebah AH. Prevention of lipid accumulation in experimental vein bypass grafts by antiplatelet therapy. Circulation 1982; 66: 338-341
• 24 Schaub RG, Keith Jr JC, Rawlings CA. The effect of acetylsalicylic acid on vascular damage and myointimal proliferation in canine arteries subjected to chronic injury by Dirofilaria immitis infection. Am J Vet Res 1983; 44: 449-454
• 25 Fuster V, Bowie EW, Lewis JC, Fass DN, Owen CA, Brown AL. Resistance to arteriosclerosis in pigs with von Willebrands’ disease. Spontaneous and high cholesterol diet-induced arteriosclerosis J Clin Invest 1978; 61: 722-730
• 26 Friedman RJ, Burns ER. Role of platelets in the proliferative response of the injured artery. Progress in Hemostasis and Thrombosis. Spaet TH. (ed) Grune & Stratton; New York. 1978. 4 249-278
• 27 Griggs TR, Reddick RL, Sultzer D, Brinkhous KM. Susceptibility to atherosclerosis in aortas and coronary arteries of swine with von Willebrands’ disease. Am J Pathol 1981; 102: 137-145
• 28 Clowes AW, Kamovsky MJ. Failure of certain antiplatelet drugs to affect myointimal thickening following arterial endothelial injury in the rat. Lab Invest 1977; 36: 452-464
• 29 Friedman RJ, Wenz B, Moore S, Gauldie J, Gant M, Tiell M, Spaet TH. The effect of thrombocytopenia on experimental atherosclerosis lesion formation in rabbits. J Clin Invest 1977; 60: 1191-1201
• 30 Clopath P. The effect of acetylsalicylic acid on the development of atherosclerotic lesions in miniature swine. Br J Exp Pathol 1980; 61: 440-443
• 31 Schaub RG, Rawlings CA, Keith Jr JC. Effect of long term aspirin treatment on platelet adhesion to chronically damaged pulmonary arteries. Thromb Haemostas 1983; 46: 680-683