PHOSPHODIESTERASE INHIBITION AND CA2+ SENSITIZATION

Inhibitors of phosphodiesterase type III (PDE III) enhance cardiac con tractile force by elevating the intracellular calcium concentration [C a2+](i) by impairing cAMP degradation thus increasing cAMP levels. The drugs are more effective in healthy than in failing hearts since basa l cAMP production is diminished in the latter. However, long term trea tment with PDE-III inhibitors does not appear to be beneficial due to increased risk of potentially lethal arrhythmias caused by augmentatio n of [Ca2+](i) [1). This risk should be absent in Ca2+ sensitizers. Re cently, thiadiazinone derivatives have been synthetized in which the p otency for Ca2+ sensitization is many-fold larger than the potency for PDE-III inhibition. The Ca2+-sensitizing action resides in the [+]-en antiomers, while the [-]-enantiomers show weak PDE-III inhibition. In the enantiomer pair [+]-EMD 60263 and [-]-EMD 60264, only the former c oncentration-dependently increased force of contraction in isolated ca rdiac preparations and myocytes. In the Langendorff-perfused guinea-pi g heart, force was reversibly increased, whereas [-]-EMD 60264 even pr oduced a negative inotropic response despite of its PDE inhibitory act ivity. Heart rate, however, was reduced by both enantiomers. Perfusion pressure remained unaffected. The effects were fully reversible upon wash-out of the enantiomers. [+]-EMD 60263 also enhanced cell shorteni ng of human myocytes from both normal and failing hearts. In contrast to the opposite effects on contractility, both enantiomers prolong the action potential duration by blocking the rapidly activating componen t of the delayed rectifier K+ current. Thus they also possess class II I antiarrhythmic activity. The therapeutic potential of these agents h as yet to be assessed in clinical studies.