Effect of CI-930 [3-(2 H)-pyridazinone-4,5-dihydro-6-[4-(1 H-imidazolyl) phenyl]-5-methyl-monohydrochloride] and rolipram on human coronary artery smooth muscle cell proliferation

Abstract

Experiments were conducted to determine how selective inhibitors of certain cyclic nucleotide phosphodiesterase (PDE) families, namely CI-930 (PDE3 inhibitor; 3-(2 H)-pyridazinone-4,5-dihydro-6-[4-(1 H-imidazolyl) phenyl]-5-methyl monohydro chloride) and rolipram (PDE4 inhibitor), may affect human coronary artery smooth muscle cell (HCASMC) proliferation. CI-930- and rolipram-inhibitable PDEs accounted for most of the cyclic AMP hydrolyzing activity in HCASMC. Twenty micromolar CI-930 and 20 μM rolipram used individually attenuated proliferation of HCASMC from some, but not all donors, as measured by flow cytometry. The simultaneous addition of 10 μM CI-930 plus 10 μM rolipram caused greater attenuation. This attenuation represented a reduction of the number of cells entering the S phase of the cell cycle and not merely a delay in cell cycle traverse. No statistically significant elevation of cyclic AMP was detected following the addition of either PDE inhibitor individually, but the combination produced significant elevations. It is concluded that CI-930- and rolipram-inhibitable PDE isozymes are expressed in HCASMC and that selective inhibitors of these isozymes can attenuate HCASMC proliferation. The data suggest that selective PDE inhibitors may prevent restenosis in patients following percutaneous transluminal coronary angioplasty because of their effect on HCASMC proliferation, and they may also be useful in retarding the progression of atherosclerosis in individuals at risk. PDE3 and PDE4 inhibitors in combination are more effective than the inhibitors used individually.