Objective: Although the myocardial force-interval and relaxation- interval relations are considered to be mechanical expressions of myocardial Ca2+ handling, correlation of these phenomena with altered Ca2+ kinetics in the intact state is limited. Thus, I sought to determine the impact of selective impairment of physiologic sarcoplasmic reticulum Ca2+ release, achieved by the use of the drug ryanodine, on these relations in the intact animal. Methods: Twelve dogs instrumented with left ventricular manometers and piezoelectric dimension crystals were studied before and after ryanodine (4 μg/kg intravenously). End-systolic elastance was measured at paced heart rates of 120-180 bpm to determine the force-frequency response. Mechanical restitution and relaxation restitution were determined by measuring contractile (single beat elastance) and relaxation (peak negative dP/dt) responses for beats delivered at graded extrasystolic intervals, with normalized responses expressed as a function of extrasystolic interval. Results: Ryanodine accelerated mechanical restitution (time constant 60.3±3.9 versus 81.7±10.1 ms, p<0.05) and reduced maximal contractile response (107.5±2.1 versus 122.1±5.7%, p<0.05), slowed early relaxation restitution (time constant 65.5±13.8 versus 36.8±3.8 ms, p<0.05) without changing late relaxation restitution kinetics, and amplified the force- frequency response (end-systolic elastance, 180 bpm, 19.4±4.3 versus 11.4±1.2 mm Hg/ml, p<0.05). Conclusions: These findings suggest that in the intact animal, Ca2+ handling by the sarcoplasmic reticulum is a primary determinant of mechanical restitution and early relaxation restitution, but not late relaxation restitution. Conversely, ryanodine induced augmentation of the force-frequency response indicates a central role for sarcolemmal Ca2+ influx in producing frequency potentiation.