Contribution of Na⁺/Ca²⁺ exchange current to the formation of delayed afterdepolarizations in intact rat ventricular muscle

Aim: To evaluate the role of the Na⁺-Ca²⁺ exchange current in the induction of arrhythmias during Ca²⁺ waves, we investigated the relationship between Ca²⁺ waves and delayed afterdepolarizations (DADs) and further investigated the effect of KB-R7943, an Na⁺-Ca²⁺ exchange inhibitor, on such relationship in multicellular muscle. Methods: Force, sarcomere length, membrane potential, and [Ca²⁺]_i dynamics were measured in 32 ventricular trabeculae from rat hearts. After the induction of Ca²⁺ waves by trains of electrical stimuli (400, 500, or 600 ms intervals) for 7.5 seconds, 23 Ca²⁺ waves in the absence of KB-R7943 and cilnidipine ([Ca ²⁺]_o = 2.3 ± 0.2 mmol/L), 11 Ca²⁺ waves in the presence of 10 μmol/L KB-R7943 ([Ca²⁺]_o = 2.5 ± 0.5 mmol/L), and 8 Ca²⁺ waves in the presence of 1 μmol/L cilnidipine ([Ca²⁺]_o = 4.1 ± 0.3 mmol/L) were measured at a sarcomere length of 2.1 μm (23.9 ± 0.8°C). Results: The amplitude of DADs correlated with the velocity (r = 0.90) and the amplitude (r = 0.90) of Ca²⁺ waves. The amplitude of DADs was significantly decreased to ∼40% of the initial value by 10 μmol/L KB-R7943. Conclusions: These results suggest that the velocity and the amplitude of Ca²⁺ waves determine the formation of DADs principally through the activation of the Na⁺-Ca²⁺ exchange current, thereby inducing triggered arrhythmias in multicellular ventricular muscle.