title: Competitive inhibition of phosphodiesterase activity by amrinone: its implication in the cardiac effect of the drug.
abstract: The effects of amrinone on partially purified bovine heart PDE and on resting tension of isolated guinea-pig left atria were investigated. Amrinone strongly inhibited the high affinity Mg2+ dependent PDE activity present in the 105000xg supernatant fraction of heart homogenate (IC50 = 60 microM), but only weakly blocked the Ca2+-CaM-dependent PDE (IC50 = 2 mM). The inhibition of high affinity PDE was competitive in nature. In guinea-pig left atria driven at 1 Hz, amrinone induced a concentration-dependent positive inotropic effect (EC50 = 200 microM). This action was not followed by a rise of the diastolic tension, even when high amrinone concentrations (1 mM) and/or high external Ca2+ concentrations (up to 12.8 mM) were used. It is suggested that the competitive inhibition of PDE by amrinone can only partially account for its positive inotropic effect. Moreover, because of the lack of effect on diastolic tension, amrinone differs from methylxanthines and digitalis glycosides in regard to its influence on intracellular Ca2+ movements.
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000631:Aminopyridines / Q000494:pharmacology*; D000676:Amrinone; D000818:Animals; D002122:Calcium Chloride / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008274:Magnesium / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors
chemical_list: D000631:Aminopyridines; D009124:Muscle Proteins; D010726:Phosphodiesterase Inhibitors; D010042:Ouabain; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D008274:Magnesium; D000676:Amrinone; D002122:Calcium Chloride