The present study was designed to elucidate whether or not the positive inotropic effects of isoprenaline, milrinone, and DPI 201-106 in myocardial tissue from various sources reveal reliable results for the failing human heart. Therefore, in vitro positive inotropic responses were studied in human papillary muscle strips from patients with moderate heart failure (NNYHA II-III), human atrial trabeculae (HAT), isolated papillary muscles from Wistar-Kyoto rats (WK), and from spontaneously hypertensive rats (SHR). Results were compared with the effects of the compounds in papillary muscle strips from patients with severe heart failure (NYHA IV). In NYHA IV, positive inotropic responses were smaller for isoprenaline and milrinone than in NYHA II-III. The response to DPI 201-106 was more pronounced. In HAT, the effects of isoprenaline and milrinone were greater than in NYHA IV. The positive inotropic effect of DPI 201-106 was similar. In SHR, only the positive inotropic effect of isoprenaline was smaller than in WK. The effects of DPI 201-106 and milrinone did not differ. These data show that inotropic responses in NYHA II-III, HAT, WK, and SHR differ from the severely failing myocardium. It is concluded that new positive inotropic agents should be screened in human myocardial tissue from patients with heart failure, as experimental results from other sources may be irrelevant in this respect.