TCV-116, A NOVEL ANGIOTENSIN-II RECEPTOR ANTAGONIST, PREVENTS INTIMALTHICKENING AND IMPAIRMENT OF VASCULAR FUNCTION AFTER CAROTID INJURY IN RATS

Inhibitory effects of TCV-116 {(+/-)-l-(cyclohexyloxycarbony-loxy)ethy l enyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate}, a novel angiotens in II AT1 subtype receptor antagonist, on the proliferation of vascula r smooth muscle cells and the impairment of endothelium-dependent vasc ular relaxation were examined in the rat carotid balloon injury model. DNA content in the carotid artery was increased 3 days after carotid balloon injury and reached a plateau 14 days after the injury. Benefic ial effects of TCV-1 16 in this model were examined 14 days after the injury. Oral administration of TCV-116 at 1 and 10 mg/kg/day significa ntly inhibited the increase in DNA content by 69 and 85%, respectively . Histological examination demonstrated that TCV-116 at 1 and 10 mg/kg significantly inhibited intimal thickening by 43 and 58%, respectivel y. Cilazapril (1 0 mg/kg/day p.o.) also inhibited intimal thickening b y 48%. Contracting or relaxing vascular responses to phenylephrine or sodium nitroprusside did not differ between uninjured and injured arte ries. However, acetylcholine-induced endothelium-dependent relaxation was greatly reduced in injured arteries; maximal relaxation was 6 +/- 2% (n = 17). TCV-116 at 1 and 10 mg/kg significantly ameliorated the i mpairment of vascular relaxation; maximal relaxation was 25 +/- 8 (n = 7) and 51 +/- 12% (n = 5), respectively. In uninjured arteries, L-N(G )-monomethyl arginine (300 muM), an inhibitor of endothelium-derived r elaxing factor synthesis, inhibited acetylcholine (10 muM)-induced rel axation by 58 +/- 4% (n = 5). Scanning electron micrographs demonstrat ed that TCV-116 (10 mg/kg/day) enhanced restoration of endothelial cel ls in the carotid artery 14 days after injury. These results show that TCV-116, an AT1 antagonist, inhibits smooth muscle proliferation and ameliorates the decrease in endothelium-dependent relaxation via the r estoration of endothelial cells after carotid balloon injury. TCV-116 may be a useful drug for the treatment of restenosis after percutaneou s transluminal coronary angioplasty.