Positive force- and [Ca2+]i-frequency relationships in rat ventricular trabeculae at physiological frequencies

The isometric force-frequency relationship of isolated rat ventricular trabeculae (diameter <250 mu m) was examined at 24, 30, and 37 degrees C at stimulation frequencies (0.1-12 Hz) encompassing the physiological range. Some muscles were microinjected with fura PE3 to monitor the diastolic and systolic intracellular concentration of Ca2+ ([Ca2+](i)). At a near-physiological external Ca2+ concentration ([Ca2+](o)) of 1 mM, a positive force-frequency relationship was demonstrated at all temperatures. The force-frequency relationship became negative at high frequencies (e.g., >6 Hz at 30 degrees C) at 1 mM [Ca2+](o) or at low frequencies at 8 mM [Ca2+](o). The twitch and Ca2+ transient became shorter as stimulation frequency increased; these changes were related to changes in systolic, rather than diastolic, [Ca2+](i) and were not blocked by inhibitors of Ca2+/calmodulin-dependent protein kinase II. The positive force-frequency relationship of rat trabeculae was caused by a frequency-dependent loading of the sarcoplasmic reticulum (SR) with Ca2+. We suggest that at high frequencies, or under conditions of Ca2+ overload, this loading saturates. Processes that tend to decrease SR Ca2+ release will then predominate, resulting in a negative force-frequency relationship.