Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure.
OBJECTIVES
To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.


BACKGROUND
Ranolazine and mexiletine potently inhibit depolarizing late Na+ current (INa,late) and Na+ entry into cardiomyocytes. Blocking Na+ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca+2 load, further compromising systolic contraction during HF.


METHODS AND RESULTS
Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dtmax) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dtmax, LVSP, heart rate, maximal LV pressure fall rate (-dP/dtmax), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize INa,late. Patch-clamped HF cardiomyocytes confirmed drug-induced INa,late blockade.


CONCLUSIONS
Ranolazine or mexiletine blocking INa,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of INa,late by ranolazine or mexiletine may not exacerbate HF in patients.
['Goldstein|Robert E|RE|', 'Klein|Michael G|MG|', 'Ouimet|Sean P|SP|', 'Shou|Matie|M|', 'Hood|Maureen N|MN|', 'Flagg|Thomas P|TP|', 'Haigney|Mark C|MC|']
D000818:Animals D002317:Cardiovascular Agents D004195:Disease Models, Animal D018450:Disease Progression D004305:Dose-Response Relationship, Drug D016903:Drug Monitoring D006333:Heart Failure D006439:Hemodynamics D008801:Mexiletine D009200:Myocardial Contraction D000069458:Ranolazine D013552:Swine D061567:Voltage-Gated Sodium Channel Blockers D061566:Voltage-Gated Sodium Channels
Ranolazine mexiletine action potential systolic dysfunction