The effect of BIX02565 is mediated by inhibition of ribosomal S6 Kinase (RSK). A, Hearts isolated from dominant-negative (DN)-RSK transgenic mice (DN-RSK-Tg) and non-transgenic littermate control (NLC) mice were perfused with KH buffer for 20 minutes for stabilization. Hearts were perfused with KH buffer or BIX02565 (100 nmol/L) for 10 minutes, followed by global ischemia for 40 minutes and reperfusion for 60 minutes. Both BIX-treated NLC hearts and untreated DN-RSK-Tg have significant increase in left ventricular–developed pressure (LVDP) after ischemia/reperfusion (I/R). A, Measurements of LVDP. B, dp/dt max. C, Rate pressure product (RPP) before and during I/R in NLC and DN-RSK-Tg mouse hearts (shown as mean ± standard error of the mean [SEM], n = 6, *P < .01).