An indazole derivative, YC-1, was identified in this study to be capable of reversibly and effectively inhibiting proliferation of rat AIO vascular smooth-muscle cells (VSMCs) in vitro. YC-1 (1-100 1uM) dose-dependently inhibited [3H]thymidine incorporation into DNA in rat AlO VSMCs that were synchronized by serum depletion and then restimulated by addition of 10 % foetal calf serum (FCS), whereas FCS-induced [3H]thymidine incorporation into rat synchronized endothelial cells was unaffected by this agent. The dose of YC-1 required to cause inhibition of FCS-induced proliferation was similar to that necessary for the formation of cellular cyclic GMP (cGMP). Guanylate cyclase activity in soluble fractions of VSMCs was activated by (1-100 ,uM), whereas cGMP-specific phosphodiesterase activity was unaffected by this compound. The anti-proliferative effect of YC-1 was mimicked by 8-bromo-cGMP, a membrane-permeable cGMP analogue, and was antagonized by KT 5823 (0.2,M), a selective inhibitor of protein kinase G. The anti-proliferative

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