CARVEDILOL INHIBITS VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

The antiproliferative properties of carvedilol, a newly developed multiple-action antihypertensive agent, were evaluated in early passage cultured rat aortic vascular smooth muscle cells. Carvedilol (10(-7)10(-5) M) produced concentration-dependent decreases in basal and endothelin-1-stimulated mitogenesis of rat aortic vascular smooth muscle cells. The IC50 for inhibition of [H-3]thymidine incorporation by carvedilol in both basal and endothelin-1-stimulated rat aortic vascular smooth muscle cells was approximately 1 muM. Carvedilol (10 muM) inhibited basal mitogenesis by approximately 65%, and endothelin-1-stimulated mitogenesis by approximately 95%. Carvedilol (1-10 muM) also produced significant concentration-dependent inhibition of the mitogenic response mediated by thrombin (0.5 U/ml), epidermal growth factor (1 nM), platelet-derived growth factor (1 nM), and angiotensin Il (5 nM). Endothelin-1- or PDGF A/B-induced increases in cell number were also significantly inhibited by carvedilol (10 muM). The antimitogenic effect of carvedilol on cell growth was reversible. The inhibitory effect of carvedilol was not shared by other beta-adrenoceptor antagonists such as labetalol (10 muM), celiprolol (10 muM), or sotalol (10 muM), which did not significantly affect [H-3]thymidine incorporation in rat vascular smooth muscle cells. Propranolol (10 muM) was the only beta-adrenoceptor antagonist tested that inhibited [H-3]thymidine incorporation, with effects of approximately 50 and 75% on basal and endothelin-1-mediated stimulation, respectively. In contrast, celiprolol (10 muM) produced significant stimulation of DNA synthesis (125% over basal). The calcium channel antagonist nifedipine (10 muM) inhibited basal and endothelin-1-mediated mitogenesis by 58 and 72%, respectively. The present studies demonstrate that the novel multiple-action antihypertensive agent carvedilol produced antimitogenic effects in rat vascular smooth muscle, a property that may be beneficial for suppressing the progression of vascular hypertrophy associated with hypertension.