Mechanisms of Stretch-Induced Changes in [Ca ²⁺ ] _i in Rat Atrial Myocytes

Abstract

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 (PϽ0.05, nϭ4) and decrease in the time constant of the Ca 2ϩ 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, PϽ0.001; nϭ13) and increased at negative voltages (AP duration at 90% repolarization level, PϽ0.01; nϭ13). To study the mechanisms causing these changes we developed a mathematical model describing [Ca 2ϩ ] 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 Ca 2ϩ 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 Ca 2ϩ 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 Ca 2ϩ transients, which modulated the APs through increased Na ϩ /Ca 2ϩ -exchanger inward current. The role of TnC affinity change was to modulate the Ca 2ϩ transients, stabilize the diastolic [Ca 2ϩ ] 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.

Mitogen-activated Protein Kinases p38 and ERK 1/2 Mediate the Wall Stress-induced Activation of GATA-4 Binding in Adult Heart

“…Isolated Rat Atria Preparation-In another set of experiments, the isolated rat atrial appendix, prepared as described previously, was used (23). Briefly, the rats were decapitated and their hearts were rapidly removed and placed in oxygenated cool (25°C) buffer solution consisting of (in mM) NaCl 137, KCl 5.6, CaCl 2 2.2, HEPES 5.0, MgCl 2 1.2, and glucose 2.5 (pH 7.4), which was also used for superfusion of the atrial preparation.…”

Floppy Mitral Valve (FMV)/Mitral Valve Prolapse (MVP) and the FMV/MVP Syndrome: Pathophysiologic Mechanisms and Pathogenesis of Symptoms

“…Papillary muscle traction may result in left ventricular contraction and relaxation abnormalities and activation of stretch receptors. Stretch receptor activation may result in membrane depolarization and cardiac arrhythmias [77,78,79]. …”

Ca 2+ channel remodeling in perfused heart: effects of mechanical work and interventions affecting Ca 2+ cycling on sarcolemmal and sarcoplasmic reticulum Ca 2+ channels

“…These conditions were chosen on the basis of the results of preliminary experiments, in which increasing amounts of RNA were subjected to different numbers (22)(23)(24)(25)(26)(27)(28)(29)(30) of cycles to establish the linear range of amplification.…”

“…To discriminate effects on Ca 2+ homeostasis from effects on contractile function, we evaluated the response to preload reduction and to nifedipine. The preload dependence of contraction is chiefly due to variations in the Ca 2+ sensitivity of contractile proteins, particularly of troponin C (1, 21-23), although modulation of nonselective stretch-activated channels may play an ancillary role (24). Nifedipine reduces contractile performance by antagonizing DHPR-mediated Ca 2+ entry, leading to a secondary decrease in SR Ca 2+ release.…”