The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum

Figures

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  FIGURE 1.. Example of tracing of papillary muscle contraction. The papillary muscle was electrically stimulated at 1 Hz with rectangular pulses of 4 ms. The stimulation strength was twice the threshold voltage. After a stabilization period of 60 minutes, 0.1 µM forskolin was added to the bathing solution after a further period of 30 minutes, milrinone was added to the bathing solution at increasing concentrations.

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  FIGURE 2.. Dosing schedule. The same color coding is used also in Figure 3.

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  FIGURE 3.. Positive inotropic effect of levosimendan (upper left panel, yellow hexagons), OR-1896 (upper right panel, green dots), OR-1855 (lower left panel, blue triangles), and milrinone (lower right panel, red squares) in the presence and the absence of forskolin (0.1 µM) in Guinea pig isolated papillary muscle. Shown are mean changes of twitch tension ± SEM from the baseline levels. An asterisk (*) indicates a statistical significant difference (P < 0.05) from the baseline level. A dagger (†) indicates a statistical significant difference (P < 0.05) between the groups with and without forskolin. Data were analyzed for statistical differences using two-way ANOVA followed by the Šídák test (Prism 9.1.0, GraphPad, CA). ANOVA, analysis of variance.