How Does the Ca<sup>2+</sup>-paradox Injury Induce Contracture in the Heart?—A Combined Study of the Intracellular Ca<sup>2+</sup> Dynamics and Cell Structures in Perfused Rat Hearts—
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The calcium (Ca<sup>2+</sup>)-paradox injury of the heart, induced by restoration of extracellular Ca<sup>2+</sup> after its short-term depletion, is known to provoke cardiomyocyte contracture. However, undetermined is how the Ca<sup>2+</sup>-paradox provokes such a distinctive presentation of myocytes in the heart. To address this, we imaged sequential intracellular Ca<sup>2+</sup> dynamics and concomitant structures of the subepicardial ventricular myocytes in fluo3-loaded, Langendorff-perfused rat hearts produced by the Ca<sup>2+</sup> paradox. Under rapid-scanning confocal microscopy, repletion of Ca<sup>2+</sup> following its depletion produced high-frequency Ca<sup>2+</sup> waves in individual myocytes with asynchronous localized contractions, resulting in contracture within 10 min. Such alterations of myocytes were attenuated by 5-mM NiCl<sub>2</sub>, but not by verapamil, SEA0400, or combination of ryanodine and thapsigargin, indicating a contribution of non-specific transmembrane Ca<sup>2+</sup> influx in the injury. However, saponin-induced membrane permeabilization of Ca<sup>2+</sup> showed no apparent contracture despite the emergence of high-frequency Ca<sup>2+</sup> waves, indicating an essential role of myocyte-myocyte and myocyte-extracellular matrix (ECM) mechanical connections in the Ca<sup>2+</sup> paradox. In immunohistochemistry Ca<sup>2+</sup> depletion produced separation of the intercalated disc that expresses cadherin and dissipation of <font face="roman">β</font>-dystroglycan located along the sarcolemma. Taken together, along with the trans-sarcolemmal Ca<sup>2+</sup> influx, disruption of cell-cell and cell-ECM connections is essential for contracture in the Ca<sup>2+</sup>-paradox injury.
- ACTA HISTOCHEMICA ET CYTOCHEMICA
ACTA HISTOCHEMICA ET CYTOCHEMICA 48(1), 1-8, 2015
JAPAN SOCIETY OF HISTOCHEMISTRY AND CYTOCHEMISTRY