Abstract
Background: Palmitoyl‐L‐carnitine (PC), an ischemic metabolite, increases late Na+ channel current, causing cellular Na+ and Ca2+ overload and contractile dysfunction. Ranolazine (Ran) is a selective blocker of late sodium current. This study was conducted to determine whether Ran attenuates PC‐induced diastolic dysfunction.Methods: Guinea pig isolated hearts perfused at constant flow (Langendorff method) were used to study left ventricular end‐diastolic pressure (LVEDP), coronary perfusion pressure (CPP), ventricular wall stiffness, and cardiac lactate and adenosine release. Hearts were treated with 4 μM PC for 30 min followed by treatment with Ran or vehicle for 30 min.Results: PC significantly increased LVEDP, CPP, wall stiffness, and lactate and adenosine release. Ran (10 μM) significantly attenuated the PC‐induced increase in LVEDP by 61 ± 5 % (n=6, p<0.001), the PC‐induced increase of CPP by 27 ± 3% (n=6–7, p<0.05), and the PC‐induced increases of lactate and adenosine release by 50 ± 7 and 75 ± 4 %, respectively (n=6, p ≤0.05 for both). Ran reduced the PC‐induced increase of wall stiffness: LVEDP at all intraventricular volumes was lower in the presence of Ran + PC than in the presence of PC alone.Conclusion: Ran attenuated PC‐induced ventricular diastolic dysfunction, as indicated by reductions of LVEDP, ischemic metabolites, and CPP.
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