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(Circulation Research. 1998;83:1165-1177.)
© 1998 American Heart Association, Inc.

Original Contributions

Mechanisms of Stretch-Induced Changes in [Ca²⁺]_i in Rat Atrial Myocytes

Role of Increased Troponin C Affinity and Stretch-Activated Ion Channels

Pasi Tavi, Chunlei Han, , Matti Weckström

From the Departments of Physiology and Physical Sciences/Division of Biophysics and Biocenter Oulu, University of Oulu, Oulu, Finland.

Correspondence to Matti Weckström, MD, PhD, Department of Physiology, University of Oulu, Kajaanintie 52A, FIN-90220 Oulu, Finland. E-mail matti.weckstrom{at}oulu.fi

Abstract—To study the effects of stretch on the function of rat left atrium, we recorded contraction force, calcium transients, and intracellular action potentials (APs) during stretch manipulations. The stretch of the atrium was controlled by intra-atrial pressure. The Frank-Starling behavior of the atrium was manifested as a biphasic increase of the contraction force after increasing the stretch level. The development of the contraction force after step increase of the stretch (intra-atrial pressure from 1 to 3 mm Hg) was accompanied by the increase in the amplitude of the calcium transients (P<0.05, n=4) and decrease in the time constant of the Ca²⁺ transient decay. The APs of the individual myocytes were also affected by stretch; the duration of the AP was decreased at positive voltages (AP duration at 15% repolarization level, P<0.001; n=13) and increased at negative voltages (AP duration at 90% repolarization level, P<0.01; n=13). To study the mechanisms causing these changes we developed a mathematical model describing [Ca²⁺]_i and electrical behavior of single rat atrial myocytes. Stretch was simulated in the model by increasing the troponin (TnC) sensitivity and/or applying a stretch-activated (SA) calcium influx. We mimicked the Ca²⁺ influx by introducing a nonselective cationic conductance, the SA channels, into the membrane. Neither of the 2 plausible mechanosensors (TnC or SA channels) alone could produce similar changes in the Ca²⁺ transients or APs as seen in the experiments. The model simulated the effects of stretch seen in experiments best when both the TnC affinity and the SA conductance activation were applied simultaneously. The SA channel activation led to gradual augmentation of Ca²⁺ transients, which modulated the APs through increased Na⁺/Ca²⁺-exchanger inward current. The role of TnC affinity change was to modulate the Ca²⁺ transients, stabilize the diastolic [Ca²⁺]_i, and presumably to produce the immediate increase of the contraction force after stretch seen in experiments. Furthermore, we found that the same mechanism that caused the normal physiological responses to stretch could also generate arrhythmogenic afterpotentials at high stretch levels in the model.

Key Words: stretch • myocyte • Frank-Starling • Ca²⁺ • action potential

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