Ca2+ sensitization in idiopathic dilated human myocardium. Differential in vitro effects of (+)-(5-methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazoci ne-2,4-dione, a novel purely Ca2+sensitizing agent, and (+)-5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-meth yl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one on skinned fibres and isolated ventricular strips.
(+)-(5-Methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione (CAS 165755-40-8, CGP 48506) is a novel Ca2+ sensitizing agent devoid of any other positive inotropic mechanism, particularly phosphodiesterase (PDE) III inhibition. 5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-met hyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one (CAS 120223-04-3, EMD 53998) is a PDE III inhibitor with a Ca2+ sensitizing activity residing in its (+)-enantiomer, EMD 57033 (CAS 147527-31-9). In skinned fibres and electrically stimulated left ventricular strips from idiopathic dilated human hearts, New York Heart Association (NYHA) class IV, the Ca2+ sensitizing and inotropic effects of the benzodiazocine CGP 48506 and the thiadiazinones EMD 53998 or EMD 57033 were compared. Both CGP 48506 and EMD 53998 induce a left shift of the Ca2+ activation curve of force towards lower Ca2+ concentrations in skinned fibres, which indicates Ca2+ sensitization. Only EMD 53998, but not CGP 48506, increases skinned fibre force at both minimum (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 cardiomyocytes. On the other hand, both CGP 48506 and EMD 57033 show comparable, though quantitatively different, positive inotropic effects in electrically stimulated left ventricular strip preparations. It is unclear whether the PDE III inhibitory component of the profile of actions of EMD 57033 may play a role in preventing the increase in diastolic tension as expected from the skinned fibre experiments. It is noteworthy that both Ca2+ sensitizing agents act as positive inotropic compounds in the end-stage failing human heart where other inotropic agents like beta 1-adrenergic agonists or PDE inhibitors have been described to fail.
Herzig
J W
JW
Department of Research and Development, Ciba-Geigy Limited, Basel, Switzerland.
Chiesi
M
M
Depersin
H
H
Grüninger
S
S
Hasenfuss
G
G
Kubalek
R
R
Leutert
T
T
Pieske
B
B
Pioch
K
K
Wenk
P
P
Holubarsch
C
C
D000814:Aniline Compounds; D001392:Azocines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013829:Thiadiazines / Q000494:pharmacology*; D014966:Xanthenes
D000814:Aniline Compounds; D001392:Azocines; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D013829:Thiadiazines; D014966:Xanthenes; C070609:EMD 53998; C095056:BA 41899; C059715:Fluo-3; D002118:Calcium