Inhibitory effects of mesoionic 3‐aryl substituted oxatriazole‐5‐imine derivatives on vascular smooth muscle cell mitogenesis and proliferation in vitro

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Abstract
The effects of oxatriazole‐type (GEA 3162 and GEA 5624) nitric oxide (NO) donors on mitogenesis and proliferation were studied in vascular smooth muscle cell (VSMC) culture. The effects of the GEA‐compounds were compared with well‐known NO‐donors 3‐morpholinosydnonimine (SIN‐1) and S‐nitroso‐N‐acetylpenicillamine (SNAP). All NO‐donors released NO and increased the production of cyclic GMP concentration‐dependently. The production of cyclic GMP was inhibited by the guanylate cyclase inhibitor, ODQ (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one). The NO‐donors inhibited basal and serum‐induced DNA synthesis concentration‐dependently. The GEA‐compounds were needed in concentrations 10 times lower than SIN‐1 and SNAP. GEA 3162, SIN‐1 and SNAP were also able to inhibit serum‐induced cell proliferation. GEA 5624 was ineffective. The antimitogenic effect of NO‐donors was not reduced by inhibiting the guanylate cyclase. These results suggest that NO inhibits serum‐induced DNA synthesis and proliferation of VSMC by a cyclic GMP‐independent mechanism. The oxatriazole‐type NO‐donor GEA 3162 was found to be a more potent inhibitor of mitogenesis and cell proliferation than SIN‐1 and SNAP. British Journal of Pharmacology (1998) 125, 402–408; doi:10.1038/sj.bjp.0702076