To elucidate whether myocardial CD38/cyclic ADP-ribose (cADPR) signaling plays a physiological role, we investigated the heart of CD38 knockout mice (CD38KO). In CD38KO, the myocardial cADPR content was reduced-by 85% compared with wildtype mice (WT). Cardiac hypertrophy developed only in mates. At 36degreesC, none of the parameters for Ca2+ transients and forces of the papillary muscles differed between WT and CD38KO. In contrast, at 27degreesC, at which cADPR does not work, the peak [Ca2+](i) was increased and the decline in [Ca2+](i) was accelerated in CD38KO compared with WT. In CD38KO, the protein expression of SR Ca2+ ATPase type2 (SERCA2) and the SERCA2-to-phospholamban ratio were increased compared with WT. The ryanodine receptor protein was increased only in female CD38KO compared with WT. These data suggest that the CD38/cADPR signaling plays an important role in intracellular Ca2+ homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender. (C) 2003 Elsevier Inc. All rights reserved.