Figure 7.
(A) Epac-induced wave of elevated cytosolic [Ca2+] ([Ca2+]i) shown in 41.0 × 20.5 µm confocal microscope fluo-3 images taken in successive 65 ms intervals within isolated ventricular myocyte. (B, C) Families of loose-patch clamp ionic current densities in a ventricular preparation; pulse protocol investigating Na+ channel activation and inactivation as in Figure 5A. Na+ currents in response to (B) activation by depolarization to level V1 and (C) following their inactivation, to final level V2 following their inactivation at level V1. Recordings made (a) before pharmacological challenge, (b) in the presence of 8-CPT (1 µM) alone or (c) following further addition of dantrolene, (d) after adding dantrolene alone or (e) combined with 8-CPT. (D) Corresponding dependences of Na+ current activation (top row) and inactivation (bottom row) (mean ± SEM) upon voltage V1 (a) before (open squares) and following introduction of 8-CPT (filled triangles) and 8-CPT and dantrolene combined (filled circles), (b) before (open squares) and following introduction of dantrolene (filled diamonds), (c) before (open squares) and following introduction of a combination of 8-CPT and dantrolene (filled circles).((A) From Figure 8 by permission (Hothi et al. [45]); (B), (C) from Figure 2 and (D) from Figure 4 by permission (Valli et al. [76]).
Na+ current reduction in native murine cardiomyocytes by altered Ca2+ homeostasis following ryanodine receptor (RyR) activation by the Epac activator 8-CPT, abrogated by dantrolene mediated RyR antagonism.

(A) Epac-induced wave of elevated cytosolic [Ca2+] ([Ca2+]i) shown in 41.0 × 20.5 µm confocal microscope fluo-3 images taken in successive 65 ms intervals within isolated ventricular myocyte. (B, C) Families of loose-patch clamp ionic current densities in a ventricular preparation; pulse protocol investigating Na+ channel activation and inactivation as in Figure 5A. Na+ currents in response to (B) activation by depolarization to level V1 and (C) following their inactivation, to final level V2 following their inactivation at level V1. Recordings made (a) before pharmacological challenge, (b) in the presence of 8-CPT (1 µM) alone or (c) following further addition of dantrolene, (d) after adding dantrolene alone or (e) combined with 8-CPT. (D) Corresponding dependences of Na+ current activation (top row) and inactivation (bottom row) (mean ± SEM) upon voltage V1 (a) before (open squares) and following introduction of 8-CPT (filled triangles) and 8-CPT and dantrolene combined (filled circles), (b) before (open squares) and following introduction of dantrolene (filled diamonds), (c) before (open squares) and following introduction of a combination of 8-CPT and dantrolene (filled circles).((A) From Figure 8 by permission (Hothi et al. [45]); (B), (C) from Figure 2 and (D) from Figure 4 by permission (Valli et al. [76]).

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