Differences in Functional Expression of Connexin43 and Na V 1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart.

Class-selective histone deacetylase (HDAC) inhibitors were designed to improve safety profiles and therapeutic effectiveness in the treatment of multiple cancers relative to pan-HDAC inhibitors. However, the underlying mechanisms for their therapeutic and cardiotoxic potentials remain poorly understood. Cardiac sodium currents (I-Na) and gap junction conductance (g(j)) were measured by whole cell patch clamp techniques on primary cultures of neonatal cardiomyocytes. Cardiac Na(V)1.5 sodium channel and connexin43 (Cx43) gap junction protein levels were assessed by Western blot analyses. Panobinostat produced concentration-dependent reductions in ventricular g(j), peak I-Na density, and Na(V)1.5 protein expression levels. Membrane voltage (V-m)-dependent activation of I-Na was shifted by +3 to 6 mV with no effect on inactivation. Entinostat (1 mu M) did not affect ventricular g(j), peak I-Na density, or I-Na activation. However, the I-Na half-inactivation voltage (V-1/2) was shifted by -3.5 mV. Ricolinostat had only minor effects on ventricular g(j) and I-Na properties, though I-Na activation was shifted by -4 mV. Cx43 and Na(V)1.5 protein expression levels were not altered by class-selective HDAC inhibitors. The lack of effects of class-selective HDAC inhibitors on ventricular g(j) and I-Na may help explain the improved cardiac safety profile of entinostat and ricolinostat.