CA2- DIFFERENTIAL IN-VITRO EFFECTS OF TRAHYDRO-3,6-METHANO-1,5-BENZODIAZOCINE-2,4-DIONE, A NOVEL PURELY CA2+-SENSITIZING AGENT, AND YL)-6-METHYL-3,6-DIHYDRO-2H-1,3,4-THIADIAZIN-2-ONE ON SKINNED FIBERS AND ISOLATED VENTRICULAR STRIPS( SENSITIZATION IN IDIOPATHIC DILATED HUMAN MYOCARDIUM )

etrahydro-3,6-methano-1,5-benzodiazocine-2,4-dione (CAS 165755-40-8, s ensitizing agent devoid of any other positive inotropic mechanism, par ticular 48506) is a novel Ca2+ sensitizing agent devoid of any other p ositive inotropic mechanism, particularly phosphodiesterase (PDE) III inhibition. -tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H- 1,3,4-t hiadiazin-2-one (GAS 120223-04-3, EMD 53998) is a PDE III inhibitor wi th a Ca2+ sensitizing activity residing in its (+)-enantiomer, EMD 570 33 (GAS 147527-31-9). In skinned fibres and electrically stimulated le ft ventricular strips from idiopathic dilated human hearts, New York H eart Association (NYHA) class IV, the Ca2+ sensitizing and inotropic e ffects of the benzodiazocine CGP 48506 and the thiadiazinones EMD 5399 8 or EMD 57033 were compared. Both CGP 48506 and EMD 53998 induce a le ft shift of the Ca2+ activation curve of force towards lower Ca2+ conc entrations in skinned fibres, which indicates Ca2+ sensitization. Only EMD 53998, but not CGP 48506, increases skinned fibre force al both m inimum (resting) and maximally activating Ca2+ concentrations. This is taken as an argument for a principal difference in the mechanisms of the Ca2+ sensitizing actions of the two compounds. CGP 48506 is shown not to influence the amplitude of the Ca2+ transient in rat cardiomyoc ytes.