Failing myocardium expresses reduced levels of the SR Ca2+- ATPase (SERCA) and increased levels of B-type natriuretic peptide (BNP). In isolated rabbit myocardium, BNP antagonizes the upregulation of SERCA expression caused by elevation of preload (Kögler, Circulation 2006). We analyzed SERCA, BNP, and GAPDH mRNA expression in human end-stage heart failure (HF) (dilated cardiomyopathy (DCM; n=5)) and control tissue (non-failing donor hearts; n=4) at baseline and in electrically stimulated HF muscle strips incubated under different mechanical loading conditions over 6h (37UC, [Ca2+]o 1,25 mM). Failing myocardium expressed enhanced BNP levels (BNP/GAPDH mRNA ratio: control 0,22±0,07, DCM 2,73±0,78; +1140%, p<0,05) while SERCA/GAPDH mRNA ratio was reduced by 41%. Preload did not upregulate SERCA in human HF preparations (SERCA/GAPDH: unloaded 0,16±0,02, elevated preload 0,13±0,03). BNP/GAPDH mRNA ratio likewise remained unaffected by load in human HF muscle strips (unloaded 2,52±0,65, elvated preload 2,67±0,62). Normal rabbit myocardium compensates elevated preload by upregulating SERCA and thereby optimizing Ca2+ homeostasis. This adaptation is not effective in human failing myocardium, potentially due to highly stimulated endogenous BNP expression. This mechanism may contribute to the clinical progression of HF.