Acceleration of Ca2+ waves in monocrotaline-induced right ventricular hypertrophy in the rat.

BACKGROUND: Triggered arrhythmias arise from delayed afterdepolarizations (DADs), with Ca(2+) waves playing an important role in their formation. In ventricular hypertrophy, however, it remains unclear how Ca(2+) waves change their propagation features and affect arrhythmogenesis. We addressed this important issue in a rat model of hypertrophy. METHODS AND RESULTS: Rats were given a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). After 4 weeks, MCT-rats showed high right ventricular (RV) pressure and RV hypertrophy. Trabeculae were dissected from 36 right ventricles. The force was measured using a silicon strain gauge and regional intracellular Ca(2+) ([Ca(2+)](i)) was determined using microinjected fura-2. Reproducible Ca(2+) waves were induced by stimulus trains (2 Hz, 7.5s). MCT-rats showed a higher diastolic [Ca(2+)](i) and faster and larger Ca(2+) waves (P<0.01). The velocity and amplitude of Ca(2+) waves were correlated with the diastolic [Ca(2+)](i) both in the Ctr- and MCT-rats. The velocity of Ca(2+) waves in the MCT-rats was larger at the given amplitude of Ca(2+) waves than that in the Ctr-rats (P < 0.01). The amplitude of DADs was correlated with the velocity and amplitude of Ca(2+) waves in the Ctr- and MCT-rats. CONCLUSIONS: The results suggest that an increase in diastolic [Ca(2+)](i) and an increase in Ca(2+) sensitivity of the sarcoplasmic reticulum Ca(2+) release channel accelerate Ca(2+) waves in ventricular hypertrophy, thereby causing arrhythmogenesis.

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 ([Ca2+]o = 2.3 +/- 0.2 mmol/L), 11 Ca2+ waves in the presence of 10 micromol/L KB-R7943 ([Ca2+]o = 2.5 +/- 0.5 mmol/L), and 8 Ca2+ waves in the presence of 1 micromol/L cilnidipine ([Ca]o = 4.1 +/- 0.3 mmol/L) were measured at a sarcomere length of 2.1 microm (23.9 +/- 0.8 degrees 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 approximately 40% of the initial value by 10 micromol/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.

Spatial non-uniformity of excitation-contraction coupling can enhance arrhythmogenic-delayed afterdepolarizations in rat cardiac muscle.

AIMS: We examined whether non-uniform muscle contraction affects delayed afterdepolarizations (DADs) by dissociating Ca(2+) from myofilaments within the border zone (BZ) between contracting and stretched regions. METHODS AND RESULTS: Force, sarcomere length (SL), membrane potential, and [Ca(2+)](i) dynamics were measured in 31 ventricular trabeculae from rat hearts. Non-uniform muscle contraction was produced by exposing a restricted region of muscle to a jet of solution containing 20 mmol/L 2,3-butanedione monoxime (BDM). DADs were induced by 7.5 s-2 Hz stimulus trains at an SL of 2.0 microm (24 degrees C, [Ca(2+)](o) 2.0 mmol/L). The BDM jet enhanced DADs (n = 6, P < 0.05) and aftercontractions (n = 6, P < 0.05) with or without 100 micromol/L streptomycin and occasionally elicited an action potential. A stretch pulse from an SL of 2.0 microm to 2.1 or 2.2 microm during the last stimulated twitch of the trains accelerated Ca(2+) waves in proportion to the increment of force by the stretch (P < 0.01) with or without streptomycin. In the presence of 1 mmol/L caffeine, rapid shortening of the muscle after the stretch pulse increased [Ca(2+)](i) within the BZ, whose amplitude correlated with the increment of force by the stretch (n = 15, P < 0.01). CONCLUSION: These results suggest that non-uniform muscle contraction can enhance DADs by dissociating Ca(2+) from myofilaments within the BZ and thereby cause triggered arrhythmias.