Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043.

Abstract

MDL 17,043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one) is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated and compared with those produced by amrinone and theophylline. Dog cardiac phosphodiesterases (PDEs) were separated into three major forms and labeled PDE I, II, and III according to the order of elution during isolation by column chromatography. PDE I and II, considered to be "high-Km" enzymes for cyclic AMP, were not inhibited by MDL 17,043, amrinone, or theophylline in concentrations of 50 microM. PDE III, a "low-Km" enzyme, was strongly inhibited by MDL 17,043. Kinetic studies showed the inhibition to be characteristic of partial competitive inhibition. At 0.25 microM cyclic AMP, 1.3 microM MDL 17,043 caused 50% inhibition of PDE III (I50), while the I50 for amrinone and theophylline were estimated to be 19.5 microM and 119 microM, respectively. Dog kidney Na+, K+-ATPase was inhibited 54% by 100 microM MDL 17,043 while amrinone caused an 18% inhibition at the same concentration. Ca2+-ATPase and Ca2+ uptake by dog sarcoplasmic reticulum vesicles were unchanged by MDL 17,043 concentrations up to 300 microM and 100 microM, respectively. It is suggested that the inhibition of PDE III is related to the cardiotonic effects produced by MDL 17,043 and amrinone, although inhibition of Na+, K+-ATPase may also play a role at high concentrations of these drugs.