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001-es BibID:	BIBFORM015114
Első szerző:	Kaheinen, Petri
Cím:	Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+- sensitizing effect but not to stereoselective phosphodiesterase inhibition. / Kaheinen P., Pollesello P., Hertelendi Z., Borbely A., Szilagyi S., Edes I., Nissinen E., Haikala H., Papp Z.
Dátum:	2006
ISSN:	1742-7835
Megjegyzések:	In order to clarify the mechanisms of the positive inotropic actions of levosimendan and its optical isomer, dextrosimendan, we compared their concentration-dependent effects in intact papillary muscles, permeabilized cardiomyocytes and in purified phosphodiesterase enzyme preparations of guinea-pig hearts. In papillary muscles twitch tension increased with EC50 values of 60 nM and 2.8 microM for levosimendan and dextrosimendan, respectively. Hence, the two enantiomers exhibited a 47 times potency difference in their positive inotropic effects in a preparation where theoretically Ca2+-sensitization and phosphodiesterase inhibition could both contribute to the positive inotropic effects. In guinea-pig cardiomyocytes, levosimendan and dextrosimendan increased isometric force production (at pCa 6.2) due to Ca2+-sensitization with EC50 values of 8.4 nM and 0.64 microM, respectively, with a similar relative potency difference of 76. A major difference appeared in their relative pharmacological potencies, however, when the inhibitory effects of the two enantiomers were assayed on phosphodiesterase III, purified from guinea pig left ventricle (i.e. the phosphodiesterase isoenzyme which is dominant in that tissue). Levosimendan was a 427 times more potent phosphodiesterase inhibitor than dextrosimendan, with IC50 values of 7.5 nM, and 3.2 microM, respectively. Taken together, our data support the hypothesis that levosimendan and dextrosimendan exert their positive inotropic effects via a stereoselective Ca2+-sensitizing mechanism and not via stereoselective inhibition of phosphodiesterase III in the myocardium.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Basic & Clinical Pharmacology & Toxicology. - 98 : 1 (2006), p. 74-78. -
További szerzők:	Pollesello, Piero Hertelendi Zita (1978-) (orvos) Borbély Attila (1978-) (kardiológus) Szilágyi Szabolcs (1976-) (kardiológus) Édes István (1952-) (kardiológus) Nissinen, E. Haikala, Heimo Papp Zoltán (1965-) (kardiológus, élettanász)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat DOI
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001-es BibID:	BIBFORM015109
Első szerző:	Szilágyi Szabolcs (kardiológus)
Cím:	Two inotropes with different mechanisms of action : contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone / Szilagyi S., Pollesello P., Levijoki J., Haikala H., Bak I., Tosaki A., Borbely A., Edes I., Papp Z.
Dátum:	2005
Megjegyzések:	We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P<0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P<0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8+/-8% (mean+/-SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 microM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban egyetemen (Magyarországon) készült közlemény
Megjelenés:	Journal of Cardiovascular Pharmacology. - 46 : 3 (2005), p. 369-376. -
További szerzők:	Pollesello, Piero Levijoki, Jouko Haikala, Heimo Bak István (1975-) (vegyész, analitikus, farmakológus) Tósaki Árpád (1958-) (kísérletes farmakológus, gyógyszerész) Borbély Attila (1978-) (kardiológus) Édes István (1952-) (kardiológus) Papp Zoltán (1965-) (kardiológus, élettanász)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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