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(Circulation. 1995;91:2510-2515.)
© 1995 American Heart Association, Inc.

Articles

Distinct Patterns of Calcium Transients During Early and Delayed Afterdepolarizations Induced by Isoproterenol in Ventricular Myocytes

Gaetano M. De Ferrari, MD; MariaCristina Viola, MS; Elvira D'Amato, MS; Renzo Antolini, MS; Stefano Forti, MS

From CMBM (S.F., M.C.V., R.A.), Centro Materiali e Biofisica Medica, Povo, Trento; Dipartimento di Fisica (E.D., M.C.V., R.A., E.D.), Università degli Studi di Trento, Povo, Trento; Centro di Fisiologia Clinica e Ipertensione (G.M.D.), Università degli Studi di Milano (Italy); and Divisione di Cardiologia (G.M.D), IRCCS Ospedale Maggiore Policlinico, Milano, Italy.

Correspondence to Stefano Forti, Biofisica Medica, CMBM-ITC, 38050 Povo, Trento, Italy.

Background The relation between early afterdepolarizations (EADs) and changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i) is still unclear. In the present study, we compared spatiotemporal changes in [Ca²⁺]_i related to EADs and delayed afterdepolarizations (DADs) induced by isoproterenol.

Methods and Results Isolated patch-clamped guinea pig ventricular myocytes, loaded with fluo-3 acetoxymethyl ester (fluo-3 AM), were paced at 0.1 to 2 Hz. Isoproterenol (100 nmol/L) caused alterations in both phase 2 and phase 4 of the action potential (AP), consistent with EADs and DADs, respectively. During EADs (n=16), similar to driven APs, increases in [Ca²⁺]_i occurred simultaneously throughout the cell, whereas during DADs (n=25), they originated in discrete cell sites and propagated as a wave. This difference was confirmed by analysis of eight EADs and DADs coupled to the same beat. Ca²⁺ transients linked to EADs reached a peak relative fluorescence level (expressed as percentage of the maximal level reached during the last stimulated beat) that was always higher than that reached during the DADs (77±3% versus 64±2%, P<.001). Spatial heterogeneity of Ca²⁺ transients was assessed by the maximal time interval between peaks monitored in different cell regions; this time lag was always greater during DADs than during EADs (290 versus 40 milliseconds, P=.006).

Conclusions The present study had two main findings. First, even very modest notches occurring during the plateau of the AP may be accompanied by a marked secondary increase in [Ca²⁺]_i. Second, these Ca²⁺ transients occurring during EADs are synchronous throughout the cell and differ significantly from those observed under identical conditions during DADs.

Key Words: calcium • isoproterenol • myocytes • afterdepolarizations

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