The Ca'+ uptake by the sarcoplasmic reticulum (SR) can be affected by direct modulation of the Ca2+ pump or by removing the inhibitory effect of dephosphorylated phospholamban. The effect of these mechanisms was assessed using ellagic acid and 1-(3,4-dimethoxypheny1)-3-dodecanone. Both compounds (30 pmolll) enhanced SR-Ca" uptake in rabbit cardiomyocytes by 65.3 t 13 % and 44.3 5 6.7 % for 1-(3,4-dimethoxyphenyl)-3-dodecanone and ellagic acid, respectively (at pCa 6.2). A similar effect was observed in cardiac SR microsomes (59.5 t 7.4% and 45.1 t 6.7) with 30 pmol/l 1-(3,4-dimethodoxyphenyl)-3-dodecanone and ellagic acid, respectively. 1-(3,4-DimethoxyphenyI)-3-dodecanone increased Ca" storage by cardiac SR microsomes mainly at high [Ca'+] with a 57% increase of V,,,,,, whereas ellagic acid increased V,,, to a smaller extent (22%) and stimulated Ca2+ uptake at lower [CaZ+] with a leftward-shift of the pCdATPase relationship by pCa 0.24. Ellagic acid also differed from 1-(3,4-dimethoxylphenyl)-3-dodecanone in that it produced a Ca" sensitizing effect only in cardiac SR microsomes (by pCa 0.3) whereas 1-(3,4-dimethoxyphenyl)-3-dodecanone stimulated the ATPase, at saturating Ca2+, in both cardiac and skeletal muscle SR vesicles. It is suggested that 1-(3.4-dimethoxypheny1)-3-dodecanone stimulates directly the Ca2+-ATPase activity, in contrast to ellagic acid which enhances the cardiac SR-CaZ+ uptake by interacting with phospholamban, as confirmed by the lack of additive effect between ellagic acid and monoclonal antibodies raised against phospholamban. 1-(3,4-dimethoxyphenyl)-3-dodecanone and ellagic acid constitute attractive pharmacological tools to investigate the functional consequences of enhancing SR Ca'+, uptake by affecting different mechanisms.
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