8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo

OBJECTIVES The aims of the present study were to assess 1) the effect of 8- Cl-cAMP (cyclic-3'-5'-adenosine monophosphate) on vascular smooth muscle ce ll (VSMC) proliferation in vitro and 2) the efficacy of systemic administra tion of 8-Cl-cAMP on neointimal formation after balloon injury in vivo. BACKGROUND Neointimal formation after vascular injury is responsible for re stenosis after arterial stenting. Recently, 8-Cl-cAMP, a cAMP analogue that induces growth arrest, has been safely administered in phase I studies in humans. METHODS The effect of 8-Cl-cAMP on cell proliferation was first assessed on SMCs in vitro. To study the effects of cAMP in vivo, balloon injury was pe rformed in 67 rats using a 2F Fogarty balloon catheter. RESULTS The 8-Cl-cAMP markedly inhibited VSMC proliferation in vitro, reduc ed protein kinase A (PKA) RIalpha subunit expression, and induced PKA RIIbe ta subunit expression. In addition, 8-Cl-cAMP reduced, in a dose-dependent manner, neointimal area and neointima/media ratio after balloon injury. The proliferative activity, assessed by proliferating nuclear cell antigen imm unostaining, revealed a reduction of proliferative activity of VSMCs in viv o in the 8-Cl-cAMP group. Moreover, the systemic administration of 8-Cl-cAM P did not affect renal function, blood pressure and heart rate. CONCLUSIONS We conclude that 8-Cl-cAMP potently inhibits VSMC proliferation in vitro and reduces neointima formation by balloon injury in vivo after s ystemic administration. These data may have a clinical relevance in designi ng future strategies to prevent restenosis after arterial stenting and perh aps after percutaneous transluminal coronary angioplasty. (C) 2000 by the A merican College of Cardiology.