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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: UNLABELLED. Meshes: 3',5'-Cyclic-AMP Phosphodiesterases, Adolescent, Adrenergic beta-Agonists, Adult, Aged, Calcium, Cardiotonic Agents, Cyclic Nucleotide Phosphodiesterases, Type 3, Female, Heart Failure, Humans, Isoproterenol, Male, Middle Aged, Myocardial Contraction, Papillary Muscles, Phosphodiesterase Inhibitors, Pyridazines, Quinolines, Thiadiazines.
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Does eMD 53998 act as Ca ( 2+ ) -sensitizer and phosphodiesterase III-inhibitor in human myocardium? Context: 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.
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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. Final Decision: yes