Bradykinin receptor antagonists attenuate neointimal proliferation postangioplasty

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. Brady kinin stimulated both RNA and DNA synthesis (by 175%) in smooth muscle cell s 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 [Hyp(3),Ty r(Me)(8)]bradykinin, a B-2 receptor agonist, stimulated thymidine incorpora tion by 146%, whereas B-1-selective Lys-des-Arg(9)-bradykinin had no effect . Addition of the B-2 antagonist HOE-140 reduced the stimulation by 56%, wh ereas Bi-selective des-Arg-HOE-140 had no significant effect. Similarly, HO E-140 attenuated angioplasty-induced neointimal formation in organ culture with an efficacy approaching 100% inhibition. These experiments suggest tha t bradykinin promotes smooth muscle proliferation after vascular injury, pr esumably via B-2 receptor-dependent activation of MAPK family pathways, and may explain the negative outcome of angiotensin converting enzyme inhibito r therapy on restenosis in nonrodent models.