Slow inactivation of a tetrodotoxin-sensitive current in canine cardiac Purkinje fibers

Gintant, Gary A.; Datyner, N B; Cohen, Ira S.

doi:10.1016/s0006-3495(84)84187-9

Cited by 127 publications

(76 citation statements)

References 28 publications

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“…Ranolazine and lidocaine both interact with Na ϩ channels at the same site on domain IV S6 (Fredj et al, 2006) and preferentially block the late Na current (Wasserstrom and Salata, 1988;An et al, 1996;Dumaine and Kirsch, 1998;Antzelevitch et al, 2004b). Because late I Na plays a prominent role in determining APD (Gintant et al, 1984;Carmeliet, 1987;Kiyosue and Arita, 1989;Maltsev et al, 1998;Sakmann et al, 2000) and a facilitating role in EAD formation, particularly under conditions in which I Kr and I Ks are reduced (Clancy and Rudy, 1999;Antzelevitch, 2000;Song et al, 2004;Fedida et al, 2006;Orth et al, 2006), it is reasonable to attribute the antiTdP effect of ranolazine to its late I Na blockade. By this hypothesis, blocking late I Na with ranolazine and lidocaine offsets the prolongation of ventricular repolarization by the I Kr blocker clofilium and thereby inhibits clofilium-induced TdP.…”

Section: Discussionmentioning

confidence: 99%

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

Wang

Robertson²,

Dhalla³

et al. 2008

J Pharmacol Exp Ther

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Ranolazine [Ranexa; (Ϯ)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] is novel anti-ischemic agent that has been shown to inhibit late I Na and I Kr and to have antiarrhythmic effects in various preclinical in vitro models. This study was undertaken to investigate the effects of ranolazine on drug-induced Torsade de Pointes (TdP) in vivo. TdP was induced by an I Kr blocker, clofilium, in anesthetized, ␣ 1 -agonist-sensitized rabbits. Clofilium prolonged QT interval corrected for heart rate (QTc) (52 Ϯ 9%) and monophasic action potential duration (MAPD) 90 (56 Ϯ 9%) and caused TdP in eight of eight rabbits. Pretreatment with ranolazine (480 g/kg/min) or lidocaine (200 g/kg/min) reduced the clofilium-induced prolongation of QTc (15 Ϯ 3 and 19 Ϯ 3%, respectively, p Ͻ 0.001 versus vehicle) and MAPD 90 (21 Ϯ 4 and 20 Ϯ 2%, respectively, p Ͻ 0.001 versus vehicle) and prevented the occurrence of TdP (zero of eight and zero of eight, respectively). Administration of ranolazine after the first episode of TdP terminated TdP and prevented its recurrence (zero of four versus vehicle, four of four). To rule out an ␣ 1 -adrenoceptor antagonistic activity of ranolazine, we compared the effects of ranolazine on blood pressure with those of the ␣ 1 -antagonist, prazosin. Although prazosin (10 g/kg/min) markedly shifted the phenylephrine (␣ 1 -agonist) dose-response curve to the right, it did not have any effect on clofilium-induced prolongation of QTc and MAPD 90 (43 Ϯ 7 and 53 Ϯ 9%, respectively) or the occurrence of TdP (seven of eight). In contrast, ranolazine completely suppressed TdP but did not cause any shift in the phenylephrine dose-response curve at the highest dose tested (480 g/kg/min). We conclude that ranolazine antagonizes the ventricular repolarization changes caused by clofilium and suppresses clofilium-induced TdP in rabbits.Ranolazine (Ranexa) is a novel anti-ischemic agent that does not cause clinically significant hemodynamic effects (i.e., hypotension) and bradycardia (Chaitman et al., 2004). Results of nonclinical electrophysiological studies revealed that ranolazine affects various ion currents in cardiomyocytes. Within the therapeutic plasma concentration range (2-8 M), the electrophysiological effects of ranolazine are probably due to the inhibition of late I Na and I Kr with potencies (IC 50 values) of 6 and 12 M, respectively. At a higher concentration (IC 50 ϭ 50 M), ranolazine also reduces late I Ca,L (Antzelevitch et al., 2004b). In atrial myocytes, inhibition of peak I Na probably contributes to the electrophysiological effect of ranolazine (Burashnikov et al., 2007). In ventricular myocytes from an LQT-3 mouse with mutant (⌬KPQ) Nav1.5 channels, ranolazine was found to be approximately 9 times more potent at blocking late Na ϩ than peak Na ϩ current (Fredj et al., 2006), whereas in canine ventricular myocytes from failing hearts, the late versus peak I Na selectivity was 38-fold (Undrovinas et al., 2006).Inhibition of pharmacologically or pathologically en...

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Section: Discussionmentioning

confidence: 99%

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

Wang

Robertson²,

Dhalla³

et al. 2008

J Pharmacol Exp Ther

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“…They could inactivate with time constants of several hundred msec and be particularly sensitive to TTX. This suggestion is supported by demonstration of a small, slowly inactivating component of Na + current in rabbit Purkinje strands (Gintant et al, 1984;Carmeliet, 1984). Second, there might be voltagedependent, time-independent Na + channels that provide inward current at plateau voltages (Attwell et al, 1979).…”

Section: Late Na + Currentsmentioning

confidence: 90%

New studies of the excitatory sodium currents in heart muscle.

Fozzard¹,

January²,

Makielski³

1985

Circulation Research

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After decades of frustration with inadequate methods, cardiac electrophysiologists have developed new techniques for superior control of membrane potential by use of single cells, and they have begun careful study of cardiac Na+ currents. Direct recordings of the behavior of single Na+ channels have been made by the newly developed patch clamp technique. Biochemists have made excellent progress purifying and characterizing the Na+ channel proteins, and there has been some initial success in reconstituting these partially purified channels into lipid bilayers, where their function can be studied. Even at this early stage of development of these new techniques, several conclusions are warranted: The cardiac Na+ currents are not accurately described by the original Hodgkin-Huxley mathematical formulation, making undesirable the further use of this model for study of cardiac excitation and conduction. We need to keep an open mind as to the kinetic behavior of Na+ channels, until the newer experimental techniques provide a more complete picture. Although the cardiac Na+ channel strongly resembles Na+ channels in other excitable tissues, important differences remain, reinforcing the idea that the detailed molecular structure of the cardiac Na+ channel will be different from its close relatives in other excitable cells. The density of Na+ channels in heart cell membranes is much less than in nerve and fast twitch skeletal muscle. The Na+ channels are the focus of action of many drugs and pathological processes. The tools are at hand for a complete description of the Na+ channel, including its gating and its molecular structure. We can expect considerable progress in this decade.

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“…A component of slowly inactivating Na+ current (Gintant et al 1984;Carmeliet, 1985) will, however, remain M. R. BO YETT, G. HART AND A. J. LEVI at 0 mV since the peak amplitude of this current lies at around -10 mV (Carmeliet, 1985).…”

Section: The Na+ Currentmentioning

confidence: 99%

Factors affecting intracellular sodium during repetitive activity in isolated sheep Purkinje fibres.

Boyett

Hart

Levi

1987

The Journal of Physiology

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SUMMARY1. Intracellular Na+ activity (a'a) was measured using neutral-carrier Na+-sensitive micro-electrodes in voltage-clamped sheep Purkinje fibres during and after 4 min sequences of depolarizing pulses applied to around 0 mV, at a rate of 2-5 Hz. After trains of pulse duration 50 ms the mean increase in aka was 0-65 + 0-3 mM (mean+ S.D., n = 18) whereas with longer pulse durations this rise became progressively smaller. At pulse durations of 300 ms a fall in aka was usually found.2. Recovery of aka after a pulse sequence followed a roughly exponential time course. The half-time of decline after a rise in aNa using 50 ms pulses was 111+ 52 s (n = 10), compared with a half-time of 318+ 116 s (n = 6) for recovery from a fall in aka during a sequence of 300 ms pulses.3. Application of 2 mM-Cs+ to block the pace-maker current (it) resulted in a decrease in resting aia by 0-85 + 0-45 mm (n = 6) and an outward current shift. Na+ loading during a depolarizing pulse train was greaterjn 2 mM-Cs+ than in control solution. The rise in aiNa produced by a train of 50 ms pulses in Cs+ was 1-15 + 0 4 mm (n = 10). At short pulse durations in the presence of Cs+, Na+ loading at the end of a pulse train increased as a function of pulse duration, becoming maximal at a duration of approximately 50 ms and then diminishing at longer pulse durations.4. Application of 2S5 x 10-5 M-tetrodotoxin (TTX) produced a fall in resting aNa of 0-55 + 0-2 mm (n = 6) and an outward current shift, suggesting that a TTXsensitive component of steady-state Na+ current exists at potentials in the region -65 to -80 mV.5. TTX greatly reduced the rise in a'a during a depolarizing pulse train at all pulse durations tested. A fall in aia was now found after trains of shorter pulse duration than in control solution. Similar results were obtained in the absence of TTX if the pulse train was initiated from a holding potential which was positive to the Na+ current (iNa) threshold. When iNa had been blocked, using either TTX or a low holding potential, the mean rise in aka after a train of 50 ms pulses was 0-25 + 0-2 mM (n= 8).6. The component of Na+ loading remaining at short pulse durations in the presence of TTX was abolished by 9-6 x 10-6 M-gallopamil (D600). The fall in aNa * Correspondence to Dr G. Hart, Cardiac Department, John Radcliffe Hospital, Oxford OX3 9DU.M. R. BOYETT, G. HART AND A. J. LEVI at the end of a pulse train in the presence of TTX and gallopamil increases at longer pulse durations.7. Na+ loading in TTX was unchanged or only slightly reduced by 5 mm-Mn2+. 8. The increment in aka during a pulse train was greater if the membrane was hyperpolarized during the interpulse interval.9. These results show that during repetitive activity mechanisms operate which tend to reduce aNa, namely a diminished leak current and deactivation of if, together with mechanisms which increase aka, i.e. the fast Na+ current and a second route for Na+ entry which is resistant to TTX but sensitive to gallopamil. We suggest that the TTX-insensitive component of Na+...

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Slow inactivation of a tetrodotoxin-sensitive current in canine cardiac Purkinje fibers

Cited by 127 publications

References 28 publications

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

New studies of the excitatory sodium currents in heart muscle.

Factors affecting intracellular sodium during repetitive activity in isolated sheep Purkinje fibres.

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