title: Phosphodiesterase inhibition and Ca2+ sensitization.
abstract: Inhibitors of phosphodiesterase type III (PDE III) enhance cardiac contractile force by elevating the intracellular calcium concentration [Ca2+]i by impairing cAMP degradation thus increasing cAMP levels. The drugs are more effective in healthy than in failing hearts since basal cAMP production is diminished in the latter. However, long term treatment with PDE-III inhibitors does not appear to be beneficial due to increased risk of potentially lethal arrhythmias caused by augmentation of [Ca2+]i[1). This risk should be absent in Ca2+ sensitizers. Recently, thiadiazinone derivatives have been synthetized in which the potency for Ca2+ sensitization is many-fold larger than the potency for PDE-III inhibition. The Ca(2+)-sensitizing action resides in the [+]-enantiomers, while the [-]-enantiomers show weak PDE-III inhibition. In the enantiomer pair [+]-EMD 60263 and [-]-EMD 60264, only the former concentration-dependently increased force of contraction in isolated cardiac preparations and myocytes. In the Langendorff-perfused guinea-pig heart, force was reversibly increased, whereas [-]-EMD 60264 even produced a negative inotropic response despite of its PDE inhibitory activity. 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 shortening 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 component of the delayed rectifier K+ current. Thus they also possess class III antiarrhythmic activity. The therapeutic potential of these agents has yet to be assessed in clinical studies.
authors: Department of Pharmacology, University of Essen, Germany.
authors: U
authors: U
authors: Ravens
authors: H M
authors: HM
authors: Himmel
authors: M
authors: M
authors: Flüss
authors: K
authors: K
authors: Davia
authors: S E
authors: SE
authors: Harding
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism*; D002986:Clinical Trials as Topic; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012016:Reference Values; D013237:Stereoisomerism; D015996:Survival Rate; D013829:Thiadiazines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010726:Phosphodiesterase Inhibitors; D013829:Thiadiazines; C088204:EMD 60263; D000242:Cyclic AMP; D002118:Calcium