CARVEDILOL, A CARDIOVASCULAR DRUG, PREVENTS VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION, MIGRATION, AND NEOINTIMAL FORMATION FOLLOWING VASCULAR INJURY

Carvedilol is a cardiovascular drug currently used for the treatment o f hypertension. Clinical studies have recently demonstrated efficacy i n angina and congestive heart failure. Recently, carvedilol has been s hown to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis induced by a wide varie ty of growth factors. These findings are of interest since smooth musc le proliferation and abnormal lipid metabolism are proposed to play an important role in the pathogenesis of atherosclerotic plaque formatio n and in development of stenotic lesions following vascular injury by balloon angioplasty and coronary artery bypass grafting. On the basis of these observations, the antiproliferative actions of carvedilol hav e been explored in detail. In human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 muM) produced a concentration -dependent inhibition of the mitogenesis stimulated by platelet-derive d growth factor, epidermal growth factor, thrombin, and serum, with IC 50 values ranging from 0.3 to 2.0 muM. Carvedilol also produced a conc entration-dependent inhibition of vascular smooth muscle cell migratio n induced by platelet-derived growth factor, with an IC50 value of 3 m uM. The extensive neointimal formation that occurs following balloon a ngioplasty of rat carotid arteries was markedly attenuated by carvedil ol (1 mg/kg, i.p.; twice daily starting 3 days before angioplasty and continuing until 14 days after angioplasty). Quantitative image analys is demonstrated that carvedilol reduced the neointimal growth followin g angioplasty by 84% without altering either medial or adventitial cro ss-sectional areas. These observations indicate that carvedilol may al so be effective in the treatment of pathological disorders principally associated with abnormal vascular smooth muscle growth, such as ather osclerosis and acute vascular wall injury induced by angioplasty or co ronary artery bypass grafting.