Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds

D de Cheffoy de Courcelles, K de Loore, E Freyne and PA Janssen

Janssen Research Foundation, Beerse, Belgium.

Four cyclic AMP (cAMP)-phosphodiesterases (PDE) belonging to families I, II, III and IV were identified in homogenates from human failing hearts. On fractionation of cardiac membranes, the cyclic GMP (cGMP)- inhibitable cAMP-PDE III copurified with the sarcoplasmic reticulum. cAMP-PDE activities were separated from the soluble fraction by DEAE- ion exchange chromatography and identified as belonging to the four different families of cAMP-PDEs. Various cAMP-PDE inhibitors, mostly cardiotonic compounds, were tested for their inhibitory potency on the different cAMP-PDEs and their selectivity for the type III isoenzyme was determined. Isobutylmethylxanthine, papaverine, theophylline and dipyridamole inhibited PDE activity in a weak and nonselective manner. Milrinone, enoximone, adibendan, pimobendan, bemoridan and the newly synthesized 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline derivatives, R 81267 and R 80122 were selective PDE III inhibitors. However, the IC50 values on this enzyme varied from 10 microM for enoximone to 0.036 microM for R 80122. The selectivity of the drugs for PDE III was calculated by division of the IC50 value for PDE I, II or IV by the IC50 value for PDE III. PDE I/PDE III ratio ranged from 95 for enoximone to near 28,000 for R 80122; the PDE II/PDE III ratios ranged from 95 for enoximone to 3,500 for R 80122. Although there was strong variation between the drugs, most of them showed a high selectivity for PDE III in comparison to PDE I and to PDE II. In contrast, PDE IV appeared to be more sensitive to these substances.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 263, Issue 1, pp. 6-14, 10/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

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