lixazinone and cilostamide

In previous studies we observed that inhibition of cyclic 3',5'-nucleotide phosphodiesterase (PDE) isozymes, namely isozyme PDE3, suppresses proliferation of rat renal glomerular mesangial cells in vitro and in vivo. To determine whether activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway coupled to specific PDE isozymes modulates accelerated proliferation of renal epithelial cells, we investigated the effect of selective PDE isozyme inhibition on renal epithelial cell proliferation induced in rats by injection of folic acid (FA). In extracts from suspensions of renal cortical tubules, cAMP was metabolized predominantly by isozyme PDE4; activity of PDE3 was about three times lower. The increase in proliferative activity of renal cortical tissue from FA-injected rats, evaluated by immunostaining with Mib-1 antibody, was limited to tubular epithelial cells. Administration of the PDE3 inhibitors cilostazol or cilostamide together with the PDE4 inhibitor rolipram blocked mitogenic synthesis of DNA, as determined by (3H)-thymidine incorporation into renal cortical DNA, in FA-treated rats. FA injection caused an increase of more than 10-fold in proliferating cell nuclear antigen (PCNA) in renal cortical tissue; administration of the potent PDE3 inhibitor lixazinone or, to a lesser degree, cilostazol suppressed these high PCNA levels, whereas rolipram alone had no effect. The results indicate that FA-stimulated in vivo proliferation of renal tubular epithelial cells is down-regulated by activation of a cAMP-PKA signaling pathway linked to PDE3 isozymes. These observations are consistent with the notion that negative crosstalk between cAMP signaling and mitogen-stimulated signaling pathways regulates mitogenesis of renal cells of different terminal differentiation, including tubular epithelial cells.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cell Division; Cilostazol; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; Down-Regulation; Folic Acid; Isoenzymes; Kidney Tubules; Male; Phosphodiesterase Inhibitors; Proliferating Cell Nuclear Antigen; Pyrrolidinones; Quinazolines; Quinolones; Rats; Rats, Sprague-Dawley; Rolipram; Signal Transduction; Tetrazoles

Evaluation of a series of lactam heterocyclic analogues of cilostamide (2) as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide (3) afforded the hybrid structure RS-82856 (1), shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Blood Platelets; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Myocardium; Quinazolines; Quinolines; Quinolones; Rats; Spectrophotometry, Infrared; Structure-Activity Relationship

The solution phase interaction between ascorbic acid and the cardiotonic drug N-cyclohexyl-N-methyl-4(7-oxy 1,2,3,5-tetrahydroimidazol[2,1-b] quinazolin-2-one butyramide (RS-82856) was evaluated using a differential pulse voltammetric technique. Shifts in the peak potential of ascorbic acid to higher energy as well as decreases in peak current values were monitored as a function of RS-82856 concentration. The electrochemical data were obtained under conditions where both the drug and the ascorbic acid concentrations exhibited linear relationships with peak current values. The methodology was extended to the study of two other structurally related phosphodiesterase inhibitors cilostamide and anagrelide. The complexation of these drugs with ascorbic acid were also characterized by decreases in the diffusion currents of ascorbic acid as well as by anodic shifts in the peak potential. The significance of these observations may be related to the inhibition of cyclic nucleotide phosphodiesterase activity by both the drugs tested and the ascorbic acid.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Ascorbic Acid; Cardiotonic Agents; Drug Interactions; Electrochemistry; Platelet Aggregation Inhibitors; Quinazolines; Quinolones; Solutions