MECHANISMS OF STRETCH-INDUCED CHANGES IN [CA2- ROLE OF INCREASED TROPONIN-C AFFINITY AND STRETCH-ACTIVATED ION CHANNELS(](I) IN RAT ATRIAL MYOCYTES )

To study the effects of stretch on the function of rat left atrium, we recorded contraction force, calcium transients, and intracellular act ion potentials (APs) during stretch manipulations. The stretch of the atrium was controlled by intra-atrial pressure. The Frank-Starling beh avior of the atrium was manifested as a biphasic increase of the contr action force after increasing the stretch level. The development of th e contraction force after step increase of the stretch (intra-atrial p ressure from 1 to 3 mm Hg) was accompanied by the increase in the ampl itude 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 myocy tes were also affected by stretch; the duration of the AP was decrease d at positive voltages (AP duration at 15% repolarization level, P<0.0 01; n = 13) and increased at negative voltages (AP duration at 90% rep olarization level, P<0.01; n=13). To study the mechanisms causing thes e changes we developed a mathematical model describing [Ca2+](i) and e lectrical behavior of single rat atrial myocytes. Stretch was simulate d in the model by increasing the troponin (TnC) sensitivity and/or app lying a stretch-activated (SA) calcium influx. We mimicked the Ca2+ in flux by introducing a nonselective cationic conductance, the SA channe ls, into the membrane. Neither of the 2 plausible mechanosensors (TnC or SA channels) alone could produce similar changes in the Ca2+ transi ents or APs as seen in the experiments. The model simulated the effect s of stretch seen in experiments best when both the TnC affinity and t he SA conductance activation were applied simultaneously. The SA chann el activation led to gradual augmentation of Ca2+ transients, which mo dulated the APs through increased Na+/Ca2+-exchanger inward current. T he role of TnC affinity change was to modulate the Ca2+ transients, st abilize the diastolic [Ca2+](i) and presumably to produce the immediat e 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.