SYNERGISTIC INTERACTIONS BETWEEN SELECTIVE PHARMACOLOGICAL INHIBITORSOF PHOSPHODIESTERASE ISOZYME FAMILIES PDE-III AND PDE-IV TO ATTENUATEPROLIFERATION OF RAT VASCULAR SMOOTH-MUSCLE CELLS

Citation
Xl. Pan et al., SYNERGISTIC INTERACTIONS BETWEEN SELECTIVE PHARMACOLOGICAL INHIBITORSOF PHOSPHODIESTERASE ISOZYME FAMILIES PDE-III AND PDE-IV TO ATTENUATEPROLIFERATION OF RAT VASCULAR SMOOTH-MUSCLE CELLS, Biochemical pharmacology, 48(4), 1994, pp. 827-835
Citations number
43
Categorie Soggetti
Pharmacology & Pharmacy",Biology
Journal title
ISSN journal
00062952
Volume
48
Issue
4
Year of publication
1994
Pages
827 - 835
Database
ISI
SICI code
0006-2952(1994)48:4<827:SIBSPI>2.0.ZU;2-Z
Abstract
The interaction between selective inhibitors of 3',5'-cyclic-nucleotid e phosphodiesterase (PDE) III (cyclic GMP inhibited phosphodiesterase) and selective inhibitors of PDE IV (Ro 20-1724 inhibited phosphodiest erase) to attenuate fetal bovine serum-stimulated incorporation of [H- 3]thymidine into DNA and cell proliferation was studied in a line (A10 ) of vascular smooth muscle cells (VSMC). The nonselective PDE inhibit ors 3-isobutyl-1-methylxanthine (IBMX) and papaverine attenuated DNA s ynthesis with EC(50) values (16 and 18 mu M, respectively) in the same range as their published IC50 values (2-50 and 2-25 mu M, respectivel y) as PDE inhibitors. The selective PDE III inhibitors CI-930 and cilo stamide used alone attenuated DNA synthesis with EC(50) values (>300 a nd 5.3 mu M, respectively) that were much higher than published IC50 v alues (0.15-0.46 and 0.005-0.064 mu M, respectively) for inhibition of PDE III. In the presence of the PDE IV inhibitor rolipram (10 mu M), their EC(50) values were shifted (0.66 and 0.16 mu M, respectively) mu ch closer to their respective IC50 values. When the selective PDE IV i nhibitors rolipram and Ro 20-1724 were used alone, they attenuated DNA synthesis with EC(50) values (111 and >100 mu M, respectively) much h igher than their IC50 values (0.6-2.6 and 2-13 mu M, respectively) as inhibitors of PDE IV, but 10 mu M CI-930 (PDE III inhibitor) shifted t heir EC(50) values (0.56 and 1.5 mu M, respectively) much closer to th eir IC50 values. In experiments that assessed VSMC proliferation using the MTT (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] m ethod, IBMX and papaverine attenuated proliferation with EC(50) values (27 and 58 mu M, respectively) close to their IC50 values. CI-930 and cilostamide used alone did not cause 50% attenuation of proliferation at the highest concentrations tested (100 and 10 mu M, respectively). In the presence of 5 mu M rolipram, however, their effects were enhan ced greatly with EC(50) values (0.86 and 0.23 mu M, respectively) that were close to their IC50 values as PDE III inhibitors. Similarly, rol ipram and Ro 20-1724 attenuated VSMC proliferation with EC(50) values close to their IC50 values in the presence (2.1 and 4.6 mu M, respecti vely) but not in the absence (>100 and >10 mu M, respectively) of 2 mu M CI-930. The interactions between PDE III inhibitors and PDE IV inhi bitors to attenuate DNA synthesis and VSMC proliferation were synergis tic as determined by the combination index. The data demonstrate that the synergistic interactions that attenuate incorporation of [H-3]thym idine into DNA are accompanied by synergistic attenuations of VSMC div ision. The closeness of the EC(50) values of PDE III inhibitors when P DE IV is blocked, and of the PDE IV inhibitors when PDE III is blocked , to their respective IC50 values as selective PDE inhibitors supports the view that the effects on DNA synthesis and cell division are caus ed by inhibition of the respective PDE isozymes. A hypothesis is propo sed to explain the synergistic interactions.