Affiliation:
1. From the Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Japan.
Abstract
Intracellular Ca
2+
waves (CaWs) of cardiomyocytes are spontaneous events of Ca
2+
release from the sarcoplasmic reticulum that are regarded as an important substrate for triggered arrhythmias and delayed afterdepolarizations. However, little is known regarding whether or how CaWs within the heart actually produce arrhythmogenic membrane oscillation because of the lack of data confirming direct correlation between CaWs and membrane potentials (
V
m
) in the heart. On the hypothesis that CaWs evoke arrhythmogenic oscillatory depolarization when they emerge synchronously and intensively in the heart, we conducted simultaneous fluorescence recording of intracellular Ca
2+
([Ca
2+
]
i
) dynamics and
V
m
of ventricular myocytes on subepicardial surfaces of Langendorff-perfused rat hearts using in situ dual-view, rapid-scanning confocal microscopy. In intact hearts loaded with fluo4/acetoxymethyl ester and RH237 under perfusion with cytochalasin D at room temperature, individual myocytes exhibited Ca
2+
transients and action potentials uniformly on ventricular excitation, whereas low-K
+
–perfused (2.4 mmol/L) hearts exhibited CaWs sporadically between Ca
2+
transients without discernible membrane depolarization. Further [Ca
2+
]
i
loading of the heart, produced by rapid pacing and addition of isoproterenol, evoked triggered activity and subsequent oscillatory
V
m
, which are caused by burst emergence of CaWs in individual myocytes. Such arrhythmogenic membrane oscillation was abolished by ryanodine or the Na
+
–Ca
2+
exchanger inhibitor SEA0400, indicating an essential role of CaWs and resultant Na
+
–Ca
2+
exchanger–mediated depolarization in triggered activity. In summary, we demonstrate a mechanistic link between intracellular CaWs and arrhythmogenic oscillatory depolarizations in the heart. Our findings provide a cellular perspective on abnormal [Ca
2+
]
i
handling in the genesis of triggered arrhythmias in the heart.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
112 articles.
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