Naunyn-Schmiedeberg's Arch Pharmacol (1995) 352:424 428 © Springer-Verlag 1995 Ralf Kinscherf • Jfirgen Metz • Petra Wiilfroth Etofibrate suppresses neointima formation of the ballooned common carotid artery of rats Received: 17 January 1995/Accepted: 12 May 1995 Abstract The inhibition of neointima formation by drugs is a major goal to prevent restenosis following angioplasty. In the present study, the effect of etofibrate on blood lipids and vessel wall was investigated using a balloon injury rat model. Two weeks after ballooning the common carotid artery neointima formation was quantified by morphometric measurement of the neoin- timal area and cellularity in vessel cross sections, and by fluorometric evaluation of the DNA content. Etofi- brate (160 mg/kg/day) had no effect on plasma trig- lyceride levels, but reduced serum cholesterol by about 25%. The injury-induced increase of both the neointimal area and the DNA-content was significantly inhibited by 47% (P <0.005) and 34% (P <0.05), re- spectively, in the drug-treated animals in comparison to the untreated control rats. The ratio of neointima and media was significantly (P < 0.001) reduced from 152.9 _+11.6% (controls) to 82.84 _+12.59% in the etofi- brate-treated group. The cellularity (numerical profile and volume density of nuclei) in the neointima was similar in both groups. In conclusion, injury-induced neointima formation is reduced in etofibrate-treated animals, which could be due to an inhibition of smooth muscle cell proliferation. Key words Balloon injury • Carotid artery " Fibrates • Neointima • Rat Introduction Neointimal thickening and smooth muscle cell prolifer- ation after arterial injury are influenced by a variety of R. Kinscherf (~)" J. Metz Department of Anatomy and Cell Biology III, University of Heidelberg, INF 307, D-69120 Heidelberg, Germany P. Wiilfroth Merz + Co., Department of Pharmacology, Frankfurt, Germany different factors, which can originate from blood con- stituents or are released by cells which eventually inter- act with the vessel wall, such as thrombocytes or mac- rophages. As restenosis is the major limitation of the long-term success after angioplasty, numerous pharma- cological interventions, including antiplatelet agents (Thornton et al. 1984) and Ca2tantagonists (Whit- worth et al. 1986) have been tried in clinical studies, while inhibitors of Na +-H +-exchange (Kranzh/Sfer et al. 1993) have been investigated in experimental animals. The balloon injury rat model has been established to investigate the multiple interactions between blood ele- ments and the vessel wall and the effect of drugs, which interfere with different risk factors and/or promotors of the restenosing process. Etofibrate, a lipid lowering drug used in the treat- ment of several forms of hyperlipoproteinemia has al- ready been shown to interfere with different risk factors of arteriosclerosis. In addition to its effects on lipids and lipoproteins (Lp) (Series et al. 1988), including Lp(a) (K16r et al. 1994), etofibrate renders low-density lipoprotein (LDL) particles less susceptible to lipid peroxidation (Wiilfroth et al. 1992). Etofibrate de- creases thromboxane formation, platelet aggregation (Kriiger and Thiemann 1987), plasma viscosity and fibrinogen (Sp6ttl and Froschauer 1976). PAI-1 expres- sion is decreased (Fujii and Wiilfroth; submitted) while fibrinolytic activity is increased (Leschke and Strauer 1992). Because of these different antiarteriosclerotic and antithrombotic properties the effect of etofibrate has been investigated in a rat model of angioplasty. Materials and methods Animal model. The study was designed as a randomized, blind trial. 25 age-matched, male Lewis rats (300 350 g) were randomized by number and subjected to a blinded protocol of drug treatment and deendothelialization. Fourteen rats were treated with etofibrate twice daily (80 mg/kg body weight) starting one week before surgery and continuing until the animals were sacrificed. Drug was dissolved