Parathyroid hormone-related peptide (PTHrP) was found to improve contractile function of stunned myocardium in pigs. The peptide is released from coronary endothelial cells during ischemia and significantly improves post-ischemic recovery. The present study was aimed to decide whether such an induction of contractile responsiveness of the heart requires co-activation of adjacent cells or is a genuine phenomenon of cardiomyocytes. A second aim of this study was to decide whether such an improvement is linked to depressed cell function in general or oxidative inhibition. Isolated adult ventricular cardiomyocytes from rats were constantly paced at 0.5 Hz for 10 min. Cells were exposed to a brief oxidative inhibition by addition of 0.5 mmol/l potassium cyanide (KCN) in the presence of glucose. Under these conditions, cells stopped beating after 280 s on average. 30 s before they stopped to beat, cells had already developed a reduction in cell shortening, maximal relaxation and contraction velocity. In the co-presence of PTHrP (1-34) (100 nmol/l) cells continued to beat regular and did not develop reduced cell shortening, irrespectively of oxidative inhibition. In a second attempt, cells were exposed to the NO donor SNAP (100 micromol/l) or 8-bromocGMP (1 mmol/l). As expected both agents reduced cell shortening significantly. This reduction in cell shortening was attenuated in co-presence of PTHrP, too. Finally, we investigated the effect of PTHrP on cell shortening at different extracellular concentrations of calcium. Although, PTHrP increased intracellular calcium at 2 and 5 mmol/l extracellular calcium, respectively, it improved cell shortening only at 5 mmol/l extracellular calcium. Thus, the beneficial effect of PTHrP on cell shortening was independent from intracellular calcium but dependent on the steepness of the calcium gradient between intra- and extracellular calcium. In conclusion, our study shows that PTHrP is able to improve cell shortening rapidly and directly irrespectively of the reason for the reduced cell function. Improved electromechanical coupling rather than intracellular calcium handling seems to be the most important mechanism.