Effect of flosequinan upon isoenzymes of phosphodiesterase from guinea-pig cardiac and vascular smooth muscle.
The effect of flosequinan and its sulphone metabolite BTS 53,554, on phosphodiesterase isoenzymes isolated from guinea-pig cardiac and vascular smooth muscle using DEAE-cellulose chromatography was investigated. Zaprinast and milrinone showed peak I and peak III selectivity, and IBMX non-selective activity respectively, against both cardiac and vascular smooth muscle isoenzymes, as expected for these reference inhibitors. Flosequinan and BTS 53,554 demonstrated non-selective inhibition with similar potency against both cardiac and vascular smooth muscle isoenzymes and, overall, were the least potent compounds tested. The high inhibitory concentrations observed (IC50 peak III 660 microM for cardiac tissue and 230 microM for vascular smooth muscle with flosequinan) relative to its clinically effective plasma concentration (10 microM) questions the relevance of phosphodiesterase inhibition to the efficacy of flosequinan in heart failure.
Frodsham
G
G
Boots Pharmaceuticals, Research Department, Nottingham, U.K.
Jones
R B
RB
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D009130:Muscle, Smooth / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015363:Quinolones; D014665:Vasodilator Agents; C047316:flosequinan; C047317:flosequinoxan; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases