To evaluate possible treatment-related hemodynamic changes, we administered ranolazine (Ran) or mexiletine (Mex) to swine with heart failure (HF) and controls (C).Ran and Mex potently inhibit depolarizing late Na current (I) and Na entry into cardiomyocytes Blocking Na entry may increase forward-mode Na/Ca exchange and reduce cellular Ca load, further compromising systolic contraction during HF.Anesthetized tachypaced HF swine received Ran (n=9) or Mex (n=7) as boluses then infusions; same experiments for 10 non-paced C. HF swine had characteristic elevated left ventricular (LV) end-diastolic pressure (LVEDP) and reduced maximal LV pressure rise (+dP/dt) and LV peak systolic pressure (LVSP). No significant change occurred after Ran dosing for any parameter: LVEDP, +dP/dt , LVSP, heart rate, maximal LV pressure fall rate (-dP/dt), or time constant for isovolumic relaxation. Similar results seen in additional HF swine: 7 given Mex and 7 others having Ran after 27% rate decrement to maximize I . Patch clamped HF cardiomyocytes confirmed drug-induced I blockade.Ran or Mex blocking I neither worsened nor improved hemodynamics during advanced HF. While results must be clinically confirmed, they suggest inhibition of I by Ran or Mex may not exacerbate HF in patients.