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EMD 53998 acts as Ca(2+)-sensitizer and phosphodiesterase III-inhibitor in human myocardium.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 1995 Sep-Oct; Vol. 90 (5), pp. 365-71. - Publication Year :
- 1995
-
Abstract
- Unlabelled: The effect of EMD 53998 (EMD) (0.1-100 mumol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca(2+)-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0.1-300 mumol/l), isoprenaline (Iso) (0.001-3 mumol/l) as well as CaCl2 (1.8-15 mmol/l Ca2+) were investigated. The positive inotropic responses were examined in electrically driven (1 Hz, 37 degrees C) human left ventricular papillary muscle strips from terminally failing hearts (NYHAIV, n = 24) and nonfailing donor hearts (NF, n = 9). The effect of EMD on the Ca(2+)-sensitivity of skinned fiber preparations from the very same human failing hearts were studied as well. EMD and pimobendan increased force of contraction (FOC) in a concentration-dependent manner. As judged from the EC50-values, EMD increased FOC more potently than pimobendan. EMD was significantly more effective than pimobendan to increase FOC in papillary muscle strips from NYHA IV (EMD: +2.5 +/- 0.1 mN; pimobendan: +0.8 +/- 0.2 mN) as well as from nonfailing hearts (EMD: +3.1 +/- 0.5 mN; pimobendan: +1.2 +/- 0.2 mN). Only in terminally failing myocardium, EMD increased FOC as effectively as Iso. After inotropic stimulation with EMD, pimobendan, or Iso, carbachol (1000 mumol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP-dependent mode of action. In skinned fiber experiments, EMD increased Ca(2+)-sensitivity significantly more (p < 0.01) than pimobendan.<br />In Conclusion: EMD increases FOC in human myocardium via sensitizing of the contractile proteins towards Ca2+ and by inhibition of phosphodiesterase III-isoenzymes. EMD is a potent calcium sensitizing agent in human myocardium. Thiadiazinone derivatives could be one step in the evolution to more potent and selective calcium-sensitizers.
- Subjects :
- Adolescent
Adrenergic beta-Agonists pharmacology
Adult
Aged
Cyclic Nucleotide Phosphodiesterases, Type 3
Female
Heart Failure physiopathology
Humans
Isoproterenol pharmacology
Male
Middle Aged
Papillary Muscles metabolism
Papillary Muscles physiopathology
Pyridazines pharmacology
3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors
Calcium metabolism
Cardiotonic Agents pharmacology
Heart Failure drug therapy
Myocardial Contraction drug effects
Papillary Muscles drug effects
Phosphodiesterase Inhibitors pharmacology
Quinolines pharmacology
Thiadiazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0300-8428
- Volume :
- 90
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 8585857
- Full Text :
- https://doi.org/10.1007/BF00788497