ISSN:
1435-1803
Keywords:
EMD 53998
;
calciumsensitizer
;
human myocardium
;
heart failure
;
positive inotropic agents
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The effect of EMD 53998 (EMD) (0.1–100 μmol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca2+-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0,1–300 μmol/l), isoprenaline (Iso) (0.001–3 μmol/l) as well as CaCl2 (1.8–1.5 mmol/l Ca2+) were investigated. The positive inotropic response were examined in electrically driven (1 Hz, 37°C) human left ventricular papillary muscle strips from terminally failing hearts (NYHA IV, n=24) and nonfailing donor hearts (NF, n=9). The effect of EMD on the Ca2+-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 μmol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP dependent mode of action. In skinned fiber experiments, EMD increased Ca2+-sensitivity significantly more (p〈0.01) than pimobendan. 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00788497
