Bradykinin has been linked to the development of restenosis in response to vascular injury. We therefore examined the effect of bradykinin on vascular smooth muscle cell growth and neointimal formation in organ culture. Bradykinin stimulated both RNA and DNA synthesis (by 175%) in smooth muscle cells from either porcine or human coronary arteries and increased cell number in a concentration-dependent manner. Both p42/44 mitogen-activated protein kinase (MAPK) and p38 kinase were also activated. Treatment with [Hyp³,Tyr(Me)⁸]bradykinin, a B₂ receptor agonist, stimulated thymidine incorporation by 146%, whereas B₁-selective Lys-des-Arg⁹-bradykinin had no effect. Addition of the B₂ antagonist HOE-140 reduced the stimulation by 56%, whereas B₁-selective des-Arg-HOE-140 had no significant effect. Similarly, HOE-140 attenuated angioplasty-induced neointimal formation in organ culture with an efficacy approaching 100% inhibition. These experiments suggest that bradykinin promotes smooth muscle proliferation after vascular injury, presumably via B₂ receptor-dependent activation of MAPK family pathways, and may explain the negative outcome of angiotensin converting enzyme inhibitor therapy on restenosis in nonrodent models.