Phosphodiesterase inhibitory profile of some related xanthine derivatives pharmacologically active on the peripheral microcirculation.
The cyclic nucleotide phosphodiesterase (PDE) inhibitory profile of four related xanthine derivatives: pentoxifylline (BL 191), propentofylline (HWA 285), torbafylline (HWA 448) and albifylline (HWA 138), pharmacologically active on the peripheral and/or cerebral microcirculation was established using the four main PDE isoforms present in rat heart cytosol. HPLC on a Mono Q ion-exchange column resolved four separate cyclic nucleotide PDE activities: a calmodulin-activated fraction (PDE I), a cGMP-stimulated fraction (PDE II), a cAMP-specific rolipram-sensitive fraction (PDE IV) and a cGMP-inhibited fraction (PDE III). Among the four compounds studies, only torbafylline and pentoxifylline inhibited more efficiently the calcium plus calmodulin-stimulated than the basal activity of PDE I. The four xanthine derivatives inhibited more potently the cGMP-stimulated than the basal activity of the cGMP-stimulatable PDE II, propentofylline being the most inhibitory (IC50: 20 microM). Except for propentofylline, which exhibited a marked selectivity toward the rolipram-sensitive PDE versus the cGMP-inhibited PDE III, the other xanthines modestly (IC50 in the 10(-4) M range) inhibited both cAMP-specific isoforms with similar potency. Propentofylline proved to be the best inhibitor whatever the considered isoform whereas torbafylline exhibited the weakest inhibitory potency with, however, some selectivity for PDE I.
Meskini
N
N
INSERM unité 352, Institut National des Sciences Appliquées de Lyon, Villeurbanne, France.
Némoz
G
G
Okyayuz-Baklouti
I
I
Lagarde
M
M
Prigent
A F
AF
D000818:Animals; D006352:Heart Ventricles / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000494:pharmacology*
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D014970:Xanthines; C062028:1-(5-hydroxy-5-methylhexyl)-3-methylxanthine; C032114:propentofylline; C061298:torbafylline; D010727:Phosphoric Diester Hydrolases; D010431:Pentoxifylline