Cardiac effects of r-79595 and its isomers (r-80122 and r-80123) in an acute heart-failure model - a new class of cardiotonic agents with highly selective phosphodiesterase-iii inhibitory propertiesSCHNEIDER, J., BECK, E., HEERS, C., CONRAD, C., DECOURCELLES, DD., WILFFERT, B. & Peters, T., Nov-1992, In : Naunyn-Schmiedebergs Archives of Pharmacology. 346, 5, p. 563-572 10 p.
Research output: Contribution to journal › Article › Academic › peer-review
R 79595 (N-cyclohexyl-N-methyl-2-[[[phenyl (1,2,3,5-tetrahydro-2 oxoimidazo [2,1-b]-quinazolin-7-yl) methylene] amin] oxy] acetamide) and its isomers represent a novel class of compounds with phosphodiesterase (PDE) inhibitory and cardiotonic (positive inotropic) actions. The cardiac effects of this class of compounds were investigated in the hexobarbital-depressed heart-lung preparation of the guinea-pig.
After induction of heart failure (reduction of cardiac output to 25% of the initial value) cumulative addition of R 79595 or its isomers R 80122 (E-isomer) and R 80123 (Z-isomer) concentration-dependently reversed the cardiac depressant effects of hexobarbitone-Na. With regard to reconstitution of contractility and cardiac function R 80122 (E-isomer) was 10 fold more potent than R 79595 (1:1 mixture of the isomers) and nearly 100 fold more potent than R 80123 (Z-isomer).
Furthermore, the cardiotonic action of the most potent isomer (R 80122) was compared to the effects of several positive inotropic reference compounds. The order of cardiotonic potency was as follows: (-)-adrenaline > R 80122 = adibendan > digitoxin > milrinone = enoximone > theophylline. Adibendan (EC50 value: 6.7 +/- 1.8 x 10.(-8) mol/l), which showed cardiotonic effects in the same concentration range as R 80122 (EC50 Value: 6.1 +/- 1.3 x 10(-8) mol/1), was significantly (p
The cardiotonic effects of R 80122 could be observed in the low concentration range of 3 x 10(-8) to 1 x 10(-6) mol/l, whereas enoximone (EC50 value: 1.2 +/- 0.1 x 10(-5) mol/1) and milrinone (EC50 value: 8.9 +/- 3.5 x 10(-6) Mol/1) elicited positive inotropic effects at 100 fold higher concentrations.
Digitoxin was 10 fold less and theophylline was 300 fold less potent than R 80122 with regard to reconstitution of heart function. The cardiotonic effects of R 80122 were not accompanied by an increase in heart rate as found with milrinone, theophylline or (-)-adrenaline in this model.
Furthermore, the PDE inhibitory effect of R 79595 and its E-isomer R 80122 were investigated in partially purified isoenzymes from guinea-pig ventricles. The IC50 values of R 79595 and R 80122 on PDE I - IV were compared to the IC50 values of adibendan, milrinone, enoximone and theophylline. The selectivity of an inhibitor for PDE III was evaluated by division of its IC50 values on PDE I, II and IV by the IC50 value on PDE III. R 80122 was the most potent and selective PDE III inhibitor. The IC50 value was 0.017 +/- 0.001 mumol/l. IC50 ratios ranged from 2353 (ODE II/PDE III) to 7000 (PDE I/PDE III). The PDE IV/PDE III ratio for R 80122 (5118) was more than 10 times higher than the PDE IV/PDE III ratio calculated for adibendan (333) which displayed the highest PDE III selectivy and potency (IC50 0.36 +/- 0.04 mumol/l) among the reference compounds. Milrinone and enoximone also preferentially inhibited PDE III, whereas theophylline inhibited all four isoenzymes in an unselective manner with low potency.
Since the EC50 values of R 80122 for cardiotonic effects and the IC50 value for PDE III inhibition were of the same order of magnitude, it can be assumed that potent and selective PDE III inhibition may be in part responsible for the cardiotonic effects of R 80122 observed in the acute heart failure model.
The potent cardiotonic properties and the absence of positive chronotropy revealed by this study suggest that R 80122 might exert a beneficial effect in the treatment of acute heart failure.
|Number of pages||10|
|Journal||Naunyn-Schmiedebergs Archives of Pharmacology|
|Publication status||Published - Nov-1992|
- PHOSPHODIESTERASE-III INHIBITION, ACUTE HEART FAILURE, CARDIOTONIC EFFECTS, GUINEA-PIG HEART, CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE, VENTRICULAR MUSCLE, MILRINONE, AMP, CONTRACTILITY, ISOENZYMES, SUBCLASSES, ENOXIMONE, SURGERY