Synergistic inhibition of vascular smooth muscle cell migration by phosphodiesterase 3 and phosphodiesterase 4 inhibitors.
Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP or cGMP and terminate their signaling. Two important families of PDEs that regulate cAMP signaling in cardiovascular tissues are the cGMP-inhibited PDEs (PDE3) and the cAMP-specific PDEs (PDE4). In this study, we have used a combination of an in vitro motility assay and a sensitive method for the measurement of cAMP in order to determine the relative roles of PDE3 and of PDE4 in the regulation of cAMP-mediated inhibition of VSMC migration. Our data demonstrate that forskolin, an activator of adenylyl cyclases, causes concentration-dependent inhibition of platelet-derived growth factor-induced VSMC migration. Incubation of cultured VSMCs with a PDE4-selective inhibitor, Ro 20-1724, markedly potentiated both the antimigratory effect and the increase in cAMP caused by forskolin. Cilostamide, a PDE3-selective compound, did not affect either the antimigratory activity of forskolin or its ability to increase cAMP. Cilostamide and Ro 20-1724 interacted synergistically to potentiate the inhibition of VSMC migration by forskolin and caused a supra-additive increase in cAMP. These data are consistent with an important role for both PDE3 and PDE4 in the regulation of cAMP-mediated inhibition of VSMC migration.
Palmer
D
D
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Tsoi
K
K
Maurice
D H
DH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D015363:Quinolones; D011994:Recombinant Proteins; D000077214:Becaplermin; D005576:Colforsin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C021294:cilostamide; C010192:9-(2-hydroxy-3-nonyl)adenine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine; D015056:1-Methyl-3-isobutylxanthine