A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle.
Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.
Centre de Recherche Pierre Fabre, Castres, France.
Christophe
C
Pignier
Markus
M
Keller
Bruno
B
Vié
Bernard
B
Vacher
Maurice
M
Santelli
Ernst
E
Niggli
Marcel
M
Egger
Bruno
B
Le Grand
D000818:Animals; D000889:Anti-Arrhythmia Agents; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; C510982:F90927; D004970:Estrone; D002110:Caffeine; D002118:Calcium; D004121:Dimethyl Sulfoxide