Maximal Ca²⁺-activated force elicited by tetanization of ferret papillary muscle and whole heart: Mechanism and characteristics of steady contractile activation in intact myocardium

Rapid (8-12 Hz) stimulation of intact heart muscle treated with ryanodine results in steady contractile activation known as tetanus, the amplitude of which can be graded by changing extracellular Ca²⁺ concentration ([Ca²⁺](o)). The mechanism of the sustained force generation was explored in ferret papillary muscles by measuring membrane potential and by determining the responsiveness of force and intracellular free Ca²⁺ concentration ([Ca²⁺](i), estimated with aequorin) to dihydropyridine Ca channel ligands. Membrane potential during tetani ranged from -25 to -60 mV, suggesting that fast or slow Ca channels, or Na-Ca exchange, might be mediating Ca²⁺ entry. Dihydropyridine effects indicated that slow Ca channels play a predominant role: The agonist Bay K 8644 (0.3-1 μM) increased force and aequorin luminescence, whereas the antagonist nitrendipine (1-30 μM) abolished the tetanus. Under conditions analogous to those in the papillary muscle experiments, tetani were produced in whole Langendorff-perfused ferret hearts following exposure to ryanodine. Contraction saturated as a function of [Ca²⁺](o) in both papillary muscles and whole hearts; i.e., as [Ca²⁺](o) was increased above 10 mM, no further increase in force or pressure generation occurred. In contrast, aequorin luminescence measured in the papillary muscles showed no such saturation. Thus, maximal Ca²⁺-activated force (or pressure) was achieved during tetani at [Ca²⁺](o) ≥ 10 mM. Calculations of wall stress during tetani in whole heart (15 mM [Ca²⁺](o)) agree well with direct measurements of maximal tension in papillary muscles (5.84 g/mm² vs. 6.41 g/mm², respectively). We conclude that maximal Ca²⁺-activated force (or pressure) can be produced during tetani at high [Ca²⁺](o) in either whole hearts or isolated papillary muscles following exposure to ryanodine.