Cicletanine stimulates cholesteryl ester hydrolase activities and prostacyclin production in arterial smooth muscle cells.

Cicletanine (1,3,-dihydro-6-methyl-7-hydroxy-3-(4-chlorophenyl) furo (3,4-c)pyridine) is a novel antihypertensive agent whose principal mechanisms of action may be stimulation of arterial PGI2 synthesis. Since PGI2 and related eicosanoids promote cholesteryl ester hydrolytic activities in arterial smooth muscle cells via cyclic AMP, we evaluated the effects of cicletanine on PGI2 production, the enzymes comprising the arterial cholesteryl ester cycle, and cyclic AMP generation by arterial smooth muscle cells in tissue culture. Toxicity was monitored using dye-exclusion tests. Monocyte adhesion essays were also performed to determine if cicletanine would make blood-derived monocytes less adherent to endothelium, thus less prone to initiating a pre-atherosclerotic event. Cells were exposed to a standard dose of 1.7 mM cicletanine for 2 hours. Cicletanine stimulated PGI2 production 2-3 fold over basal levels. Furthermore, cicletanine stimulated both lysosomal and cytoplasmic CE-hydrolases, with modest inhibitory effect on CE synthesis. However, cyclic AMP was not increased following cicletanine treatment. These data suggest that cicletanine may stimulate CE-hydrolase activity directly, and independently of endogenously synthesized eicosanoids. These effects were not due to toxic effects of this compound, as determined by dye exclusion assays. No effects were seen on monocyte adhesion to endothelial cells in vitro. These results suggest that in addition to being a novel, potent antihypertensive agent, cicletanine may also contribute to cholesterol mobilization in smooth muscle cells by stimulating CE hydrolysis.