The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction

Abstract

Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na ϩ and Ca 2ϩ overload and cardiac dysfunction. This study determined whether ranolazine [(Ϯ)-1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]Ϫ] attenuates PC-induced Na ϩ current and ventricular contractile dysfunction of the isolated heart. PC (4 M, 30 min) increased late Na ϩ current by 1034 Ϯ 349% in guinea pig isolated ventricular myocytes; ranolazine (10 M) and tetrodotoxin (TTX, 3 M) significantly attenuated this effect of PC. PC increased left ventricular end-diastolic pressure (LVEDP), coronary perfusion pressure (CPP), wall stiffness, and cardiac lactate and adenosine release from the isolated heart. Ranolazine (10 M) significantly reduced the PC-induced increase in LVEDP by 72 Ϯ 6% (n ϭ 6, p Ͻ 0.001), reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 Ϯ 10% (n ϭ 6 -7, p Ͻ 0.05). Ranolazine (10 M) reduced the PC-induced increases of lactate and adenosine release by 70 Ϯ 8 and 81 Ϯ 5%, respectively (n ϭ 6, p Յ 0.05 for both). TTX (2 M) significantly (p Ͻ 0.05) reduced PC-induced increases of CPP and LVEDP. Pretreatment of isolated myocytes or hearts with the free radical scavenger tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid, disodium salt) (1 mM) significantly reduced the effects of PC to cause increases of late Na ϩ current and LVEDP, respectively, but unlike ranolazine or TTX, tiron did not reverse increases of late Na ϩ current and LVEDP caused by PC. In summary, ranolazine and TTX, inhibitors of the late Na ϩ current, attenuated the PC-induced ventricular contractile dysfunction and increase of coronary resistance in the guinea pig isolated heart. Long-chain acyl carnitines, including palmitoyl-L-carnitine (PC), are intermediates of fatty acid metabolism that accumulate rapidly during brief ischemia (Sobel et al., 1978;DaTorre et al., 1991), secondary to a reduction of tissue oxygenation and mitochondrial lipid oxidation. Hypoxia of 1-h duration was shown to increase the content of long-chain acylcarnitines in sarcolemmal membranes of cultured neonatal rat cardiac myocytes by 70-fold (Knabb et al., 1986). PC has been shown to cause metabolic, electrical, and mechanical cardiac malfunction (Corr et al

Identification of Minuscule Inward Currents as Precursors to Membrane Electroporation-Induced Currents: Real-Time Prediction of Pore Appearance

“…However, neither tetrodotoxin nor ranolazine produced any effects on PALCAR-stimulated I MEP found in these cells. Taken together, results from these observations lead us to propose that, in GH 3 cells, PALCAR has a stimulatory effect on I MEP , rather than on late Na + currents [21,28,29. ]…”

“…Previous work has demonstrated that PALCAR could reduce electrophoretic mobility of erythrocytes [16], elevate intracellular Ca 2+ in vascular endothelial cells [20] and increase the amplitude of late Na + current [21]. Therefore, we further investigated the biophysical properties of I MEP in cells exposed to PALCAR (3 µM) for 2 hours.…”

“…Earlier studies have shown that this compound could reduce electrophoretic mobility of erythrocytes [16], alter the vectorial transport in Caco-2 cell monolayers [17], elevate intracellular Ca 2+ in vascular endothelial cells and heart cells [18,19,20] and increase the amplitude of late Na + current [21]. However, the ability of this compound to interact with I MEP to influence the electrical behavior of I MEP is incompletely understood.…”

Old and New Intravenous Inotropic Agents in the Treatment of Advanced Heart Failure

“…However, its beneficial effects on LV diastolic function, likely mediated by the prevention of intracellular Ca 2+ overload, have also been shown. 56,57 It may, therefore, be potentially useful for the treatment of HF, also when caused by LV diastolic dysfunction. Beneficial effects on LV remodeling and myocardial fibrosis have also been shown in experimental models.…”

The late sodium current in heart failure: pathophysiology and clinical relevance

“…In several non-HF animal models, ranolazine reversed diastolic dysfunction (at least partially) during ischaemia and reperfusion, 159,160 in the presence of ischaemic metabolites such as ROS 92 or palmitoylcarnitine, 161 in induced hypertension 162 and in spontaneously hypertensive rats. 163 Interestingly, Lovelock et al 162 suggest that ranolazine can directly modulate myofilament calcium sensitivity besides the well-established ion channel effects.…”