title: Distinct patterns of calcium transients during early and delayed afterdepolarizations induced by isoproterenol in ventricular myocytes.
abstract: 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.
  
  
  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+ transient 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.
authors.affiliation: CMBM, Centro Materiali e Biofisica Medica, Povo, Trento, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: De Ferrari
authors.forename: M C
authors.initials: MC
authors.lastname: Viola
authors.forename: E
authors.initials: E
authors.lastname: D'Amato
authors.forename: R
authors.initials: R
authors.lastname: Antolini
authors.forename: S
authors.initials: S
authors.lastname: Forti
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004594:Electrophysiology; D005456:Fluorescent Dyes; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects*; D014966:Xanthenes
chemical_list: D000814:Aniline Compounds; D005456:Fluorescent Dyes; D014966:Xanthenes; C059715:Fluo-3; D007545:Isoproterenol; D002118:Calcium