EFFECT OF CI-930 (2H)-PYRIDAZINONE-4,5-DIHYDRO-6-[4-(1H-IMIDAZOLYL) PHENYL]-5-METHYL-MONOHYDROCHLORIDE] AND ROLIPRAM ON HUMAN CORONARY-ARTERY SMOOTH-MUSCLE CELL-PROLIFERATION

Experiments were conducted to determine bow selective inhibitors of ce rtain cyclic nucleotide phosphodiesterase (PDE) families, namely CI-93 0 (PDE3 inhibitor; 3-(2H)-pyridazinone-4,5-dihydro-6-[4-( 1H-imidazoly l) phenyl]-5-methyl monohydro chloride) and rolipram (PDE4 inhibitor), may affect human coronary artery smooth muscle cell (HCASMC) prolifer ation. CI-930- and rolipram-inhibitable PDEs accounted for most of the cyclic AMP hydrolyzing activity in HCASMC. Twenty micromolar CI-930 a nd 20 mu M rolipram used individually attenuated proliferation of HCAS MC from some, but not all donors, as measured by flow cytometry. The s imultaneous addition of 10 mu M CI-930 plus 10 mu M rolipram caused gr eater attenuation. This attenuation represented a reduction of the num ber of cells entering the S phase of the cell cycle and not merely a d elay in cell cycle traverse. No statistically significant elevation of cyclic AMP was detected following the addition of either PDE inhibito r individually, but the combination produced significant elevations. I t is concluded that CI-930- and rolipram-inhibitable PDE isozymes are expressed in HCASMC and that selective inhibitors of these isozymes ca n attenuate HCASMC proliferation. The data suggest that selective PDE inhibitors may prevent restenosis in patients following percutaneous t ransluminal coronary angioplasty because of their effect on HCASMC pro liferation, and they may also be useful in retarding the progression o f atherosclerosis in individuals at risk. PDE3 and PDE4 inhibitors in combination are more effective than the inhibitors used individually. (C) 1998 Elsevier Science Inc.