caa a22 4500 477120202 CHVBK 20180405111634.0 cr unu---uuuuu 170330e19960401xx s 000 0 eng 10.1007/BF00227906 doi (NATIONALLICENCE)springer-10.1007/BF00227906 Phosphodiesterase inhibition and Ca2+ sensitization [Elektronische Daten] [Ursula Ravens, Herbert Himmel, Michael Flüss, Kerry Davia, Sian Harding] 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 Ca2+-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. Kluwer Academic Publishers, 1996 thiadiazone derivatives nationallicence stereoselectivity nationallicence positive inotropic effect nationallicence action potential duration nationallicence delayed rectifier K+ current nationallicence human ventricular myocytes nationallicence Ravens Ursula Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut Himmel Herbert Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut Flüss Michael Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut Davia Kerry Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London, UK aut Harding Sian Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut Molecular and Cellular Biochemistry Kluwer Academic Publishers 157/1-2(1996-04-01), 245-249 0300-8177 157:1-2<245 1996 157 11010 https://doi.org/10.1007/BF00227906 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00227906 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ravens Ursula Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut NATIONALLICENCE 700 1- Himmel Herbert Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut NATIONALLICENCE 700 1- Flüss Michael Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut NATIONALLICENCE 700 1- Davia Kerry Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London, UK aut NATIONALLICENCE 700 1- Harding Sian Department of Pharmacology, University of Essen, Hufelandstrasse 55, Essen, Germany aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Kluwer Academic Publishers 157/1-2(1996-04-01), 245-249 0300-8177 157:1-2<245 1996 157 11010 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer