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(Circulation. 1996;93:135-142.)
© 1996 American Heart Association, Inc.

Articles

Ranolazine Stimulates Glucose Oxidation in Normoxic, Ischemic, and Reperfused Ischemic Rat Hearts

James G. McCormack, PhD, DSC; Rick L. Barr; Andrew A. Wolff, MD; Gary D. Lopaschuk, PhD

From the Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada (R.L.B., G.D.L.), Syntex Medical Research, Palo Alto, Calif (A.A.W.), and the Department of Pharmacology, Syntex Research Centre, Heriot-Watt University Research Park, Edinburgh, Scotland (J.G.M.).

Correspondence to Prof G.D. Lopaschuk, Cardiovascular Disease Research Group, Departments of Pediatrics and Pharmacology, 423 Heritage Medical Research Bldg, University of Alberta, Edmonton, T6G 2S2, Canada. E-mail glopasch@gpu.srv.ualberta.ca.

	Abstract

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Background Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts.

Methods and Results Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate); with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-³H/U-¹⁴C]-glucose and FA oxidation with the use of [1-¹⁴C]- or [9,10-³H]-palmitate. In working hearts, 10 µmol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low FA, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 µmol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O₂ use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis.

Conclusions Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O₂ and reduction in the buildup of H⁺, lactate, and harmful fatty acyl intermediates.

Key Words: glucose • glycolysis • ischemia • fatty acids • reperfusion

	Introduction

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Ranolazine [(±)-N-(2,6-dimethylphenyl)-4[2-hydroxy-3(2-methoxyphenoxy)-propyl]-1-piperazine acetamide; RS-43285] is a novel antiischemic agent that has demonstrated antiischemic effects in a number of in vivo^{1 2 3} and in vitro^{4 5 6} cardiac preparations, as measured by a variety of different indices of ischemic damage. In these studies, ranolazine appears to bring about its effects without altering hemodynamics or baseline contractile parameters. In patients with chronic stable angina, ranolazine at oral doses 240 mg significantly increased treadmill exercise times to angina and to 1-mm ST-segment depression.^{7 8 9 10} These improvements in treadmill exercise parameters were both comparable in magnitude⁹ and additive^{7 8 9 10} to those of ß-blockers and calcium channel antagonists and occurred in the absence of any change in heart rate or decrease in blood pressure. In one study, rate-pressure product at end-exercise was significantly increased by ranolazine; thus, with ranolazine the heart could achieve a higher workload before the onset of both subjective and objective evidence of myocardial ischemia.⁹ In contrast, ß-blockers, calcium antagonists, and nitrates prolong treadmill exercise times in angina patients by depressing blood pressure, heart rate, and/or contractility to decrease cardiac work.

Thus, ranolazine appears to act via a nonhemodynamic mechanism clearly different from those of other antianginal drugs. It has therefore been proposed that it may act as a metabolic modulator.^{1 2 3 4 5 6 7 8 9 10} In one study in which an isolated guinea pig heart model of low-flow ischemia was used,⁵ it was found that the antiischemic effects of ranolazine were associated with increases in the amount of the pyruvate dehydrogenase complex existing in its active, dephosphorylated form. Because this enzyme is thought to be the major control site in carbohydrate utilization,¹¹ this led to the suggestion that ranolazine may bring about its effects through the stimulation of glucose oxidation at the expense of fatty acid oxidation.⁵ Such a switch in substrate utilization, and in particular the ability to enhance glucose oxidation, appears to be associated with a number of advantages for the preservation of the ischemic and reperfused cardiomyocyte.^{5 12 13 14 15} This may thus offer an explanation for the antiischemic efficacy of the drug and hence may indicate a novel and effective nonhemodynamic approach to antianginal therapy.^{14 16 17 18}

The present studies were therefore undertaken to directly assess the effects of ranolazine on myocardial substrate utilization by the isolated rat heart. The studies were performed on hearts perfused under a variety of different conditions, including during normoxic perfusions, during low-flow ischemia, and during reperfusion after global ischemia. In all instances, evidence was obtained that ranolazine stimulates glucose oxidation.

Small parts of the present work have previously been reported briefly as meeting abstracts.^{19 20}

	Methods

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Materials
Ranolazine (dihydrochloride; RS-43285-193) was synthesized and supplied by Syntex Research. Radiolabeled substrates ([U-¹⁴C]-glucose, [5-³H]-glucose, [1-¹⁴C]-palmitate, and [9,10-³H]-palmitate) and hyamine hydroxide (methylbenzethonium; 1 mol/L in methanol) were purchased from New England Nuclear. Bovine serum albumin (fraction V) was obtained from Boehringer Mannheim. Dowex 1-X4 anion exchange resin was from BioRad Laboratories, and ACS aqueous counting scintillant was purchased from Amersham Canada Ltd. All other chemicals were reagent grade.

Heart Perfusions
Hearts were excised from sodium-pentobarbital–anesthetized male Sprague-Dawley rats (300 to 400 g); the aorta was cannulated, and a retrograde perfusion with Krebs-Henseleit buffer (pH 7.4, gassed with 95% O₂/5% CO₂) and containing 1.25 mmol/L CaCl₂ was initiated as previously described.^{15 21 22} During this initial perfusion, the hearts were trimmed of excess tissue and the pulmonary artery and opening to the left atrium were each cannulated before switching the heart perfusions to the working mode (in a closed system for CO₂ collection).^{15 21 22} This was carried out with an 11.5–mm Hg left atrial filling pressure and an 80–mm Hg hydrostatic aortic afterload in a recirculating buffer system (120 mL) containing 11 mmol/L glucose, 3% albumin, and with either 1.25 or 2.5 mmol/L CaCl₂, 0.4 or 1.2 mmol/L palmitate, and in the presence or absence of insulin (100 µU/mL), as is indicated in the figure and table legends. The palmitate was prebound to the albumin.

These different perfusate conditions were chosen to vary the contribution of glucose oxidation to overall ATP production in the hearts; 11 mmol/L glucose was chosen to saturate glucose uptake and maintain tissue glycogen levels. Hearts were paced (280 beats per minute) or unpaced as indicated. Heart rate, peak systolic pressure development, and developed pressure were monitored throughout with a Spectramed P 23XL pressure transducer in the aortic afterload line; signals were recorded with a Gould RS-3600 physiograph. The pulmonary artery was cannulated to allow O₂ consumption measurements; in addition Transonic flow probes and in-line micro O₂ electrodes were used for the O₂ measurements. Global no-flow ischemia was produced for a 30-minute period by clamping off both the left atrial and aortic flows; throughout this ischemic period, hearts were maintained at 37°C. Left atrial and aortic flows were then recommenced for the indicated times.

Attempts were made initially to make hearts ischemic while still in the working mode by using the one-way ball valve technique.²¹ Using this approach, we observed that in ranolazine-treated hearts a rapid cessation of fatty acid oxidation occurred after the onset of ischemia, with glucose oxidation rates being maintained (results not shown). However, it proved very difficult using this methodology to obtain the steady state conditions that were desired over the sample collection times for substrate utilization measurements (a progressive decline was seen, as assessed by O₂ consumption and functional parameters). Therefore, it was decided to switch to the Langendorff perfusion mode for studies on the effects of ranolazine during varying degrees of ischemia that were achieved by progressively lowering coronary flow from 15 mL/min (normoxia in this mode) to 7, 3, and 0.5 mL/min, with 30 minutes being spent at each flow rate to allow adequate sample collection. Functional parameters and O₂ consumption indicated that new steady states were achieved over these time periods at each flow rate. Therefore, for the low-flow ischemia experiments, a separate group of hearts were initially perfused under working normoxic conditions as described above before being switched to the Langendorff mode and perfused at the flow rates indicated. Ranolazine (at 1, 10, or 30 µmol/L as shown) was added to the appropriate buffers for the times indicated.

Measurements of Glycolysis, Glucose Oxidation, and Fatty Acid Oxidation
Glycolysis and glucose oxidation were measured simultaneously by perfusing hearts with buffers additionally containing tracer [5-³H/U-¹⁴C]-glucose as described previously.^{15 21 22} Fatty acid oxidation was similarly measured in separate but parallel experiments using either tracer [1-¹⁴C]palmitate or [9,10-³H]-palmitate as indicated.^{21 22} When assessed under identical conditions, the results obtained with either label were similar (results not shown). The specific activity of each of the radiolabels used in the perfusate was 600 000 disintegrations per minute/mL.

Steady state rates of glycolysis were determined by measuring tritiated water production (as released at the enolase step) after its separation from radiolabeled glucose using Dowex 1-X4 columns as described previously.^{15 21 22} Steady state rates of either glucose or palmitate oxidation were generally determined by measurement of ¹⁴CO₂ production in the closed perfusion system that allowed collection of both gaseous and perfusate CO₂ (which is released at the level of the pyruvate dehydrogenase complex and/or at the level of the Krebs Citric Acid Cycle), as described previously.^{15 21 22} In some experiments [9,10-³H]-palmitate was used, and oxidation rates were obtained by measuring perfusate ³H₂O production after its separation from the labeled precursor using a chloroform/methanol extraction as described previously.²² Samples were collected for analyses by collecting all effluent over 10 or 20 minutes (working preparation) or 10- or 30-minute periods (Langendorff preparation). All rates are expressed as either nanomoles or micromoles of substrate used per minute per gram of dry weight of tissue and were linear over the time periods measured. At the end of perfusions, hearts were quickly frozen with Wollenberger clamps cooled to the temperature of liquid N₂ and then processed and used to determine the wet-to-dry weight ratio as previously described.¹⁵

Statistical Analysis
The unpaired t test was used to determine statistical differences between two groups, and the paired t test was used to determine statistical differences between different conditions applied to the same hearts. For statistical comparision of three groups, ANOVA followed by the Neuman-Keuls test was used. A value of P<.05 was considered significant. All data are presented as mean±SE for the number of separate perfusions indicated.

	Results

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Effects of Ranolazine on Baseline Hemodynamics and Contractile Function
Ranolazine over the concentration range used in the present studies had no effect on a variety of (baseline) hemodynamic and contractile parameters measured during the course of the present studies on substrate oxidation. This is shown in Table 1 for the normoxic working heart perfused with either 1, 10, or 30 µmol/L ranolazine. These data serve as an illustration of this lack of effects and are from the hearts that were used in the low-flow studies described below. Essentially similar results were also obtained in other studies described in this article (results not shown), including those described in Table 2, that is, lack of effect of the drug on these baseline parameters in normoxic hearts.

View this table: [in this window] [in a new window]   Table 1. Mechanical Function in Normoxic Working Hearts Perfused in the Presence or Absence of Ranolazine

View this table: [in this window] [in a new window]   Table 2. Effects of Ranolazine on Substrate Utilization in Normoxic Working Rat Hearts Perfused Under a Variety of Conditions

Effects of Ranolazine on Glycolysis, Glucose Oxidation, and Fatty Acid Oxidation in Normoxic Working Rat Hearts
The first set of studies was carried out with normoxic working hearts perfused with 1.25 mmol/L calcium and 1.2 mmol/L palmitate together with 100 µU of insulin per milliliter of perfusate. The results in Table 2 (A) show that 10 µmol/L ranolazine significantly increased glucose oxidation under these conditions but did not affect the rates of either glycolysis or palmitate oxidation; 1 µmol/L ranolazine produced a smaller but still significant increase in glucose oxidation and did not affect the other rates. Under these conditions, the exogenously added palmitate accounts for the bulk of the fatty acid oxidation taking place.^{14 15 21 22} The rates of glycolysis obtained are 10-fold higher than the rates of glucose oxidation (Table 2, A) and suggest that the supply of pyruvate from glycolysis would not be limiting to support the rates of glucose oxidation observed. This also would suggest that the primary effect of ranolazine is to stimulate glucose oxidation at a postglycolytic step. The presence of insulin previously has been shown to stimulate glycolysis in fatty acid–perfused hearts but not to have any major effects on glucose oxidation.¹⁴ The rates obtained in these studies all appeared to be essentially linear over the 1-hour period of these studies (20-minute collection periods), indicating that steady state conditions were achieved and also that ranolazine appears to stimulate glucose oxidation rates to new steady states within the first 20-minute period.

In these first studies, the contribution of glucose oxidation in terms of overall substrate oxidation was rather low (see next section). However, in working hearts perfused under entirely different conditions designed to allow glucose oxidation to provide much more of the overall substrate utilization, the ability of ranolazine to enhance glucose oxidation rates was also clearly evident (Table 2, D). This was largely achieved by increasing the perfusate calcium concentration (to 2.5 mmol/L) and decreasing the perfusate palmitate concentration (to 0.4 mmol/L).^{14 15 21 22} Also, insulin was not present in these experiments and the hearts were paced. Under such conditions, a tendency toward a concomitant reduction in palmitate oxidation also could be observed (Table 2, D). Although this was not significant in this data set, significant decreases were observed in further experiments under conditions in which these variables ([calcium], [palmitate], ± pacing, ± insulin) were altered to produce a wide range of different relative substrate oxidation (see Table 2, B). The effects of ranolazine on glucose oxidation were significant under all conditions; this suggests that the primary effect of the drug is on this parameter and that under some circumstances, these other parameters (fatty acid oxidation, glycolysis) respond to this primary event.

These results show that ranolazine enhances glucose oxidation in working hearts perfused under each of several different sets of conditions in which the amount of glucose oxidized is markedly varied (Table 2) by up to 15-fold under basal conditions.

Effects of Ranolazine on Calculated Rates of ATP Production
The data obtained in Table 2 were used to calculate overall rates of ATP production from the metabolic pathways used by the exogenously applied substrates, as has been described previously.¹⁴ For each of the initial (basal) perfusion conditions described in Table 2, the contribution of glucose oxidation to the overall calculated rates of ATP production from the exogenous substrates varied widely and averaged 2.5% (A), 8.3% (B), 20.8% (C), and 44% (D). The presence of 10 µmol/L ranolazine clearly increased the percentage contribution of glucose oxidation under all of these markedly different basal conditions, giving averaged values of 7.1%, 18.6%, 33.3%, and 64.8%, respectively. In all instances, a decrease in the percentage contribution of fatty acid oxidation was observed, although this was most marked when glucose contribution was higher, averaging 95.2%, 87.4%, 72.2%, and 47.2%, respectively, in the absence of ranolazine and 90.1%, 76.3%, 58.3%, and 27.7%, respectively, in the presence of 10 µmol/L ranolazine. In these latter two cases (see Table 2, C and D), it would also appear that one result of the addition of ranolazine during high glucose use is to increase the overall rate of ATP production from the exogenous substrates (by 16% and 32%, respectively). Presumably with the assumption that the requirement of ATP by the heart is not altered by ranolazine, this would suggest that under such circumstances, endogenous substrate utilization (mostly triacylglycerol)²² will be correspondingly reduced. The percentage contribution of glycolysis to overall ATP production rates remained low under all of the conditions tested (range, 2% to 12%) and was not markedly or consistently affected by ranolazine.

These results indicate that ranolazine increases the percentage contribution of glucose oxidation to overall rates of ATP production under a wide range of conditions of differing substrate availability to the heart.

Effects of Ranolazine on Metabolic Substrate Utilization in Rat Hearts Subjected to Low-Flow Ischemia
These experiments were carried out in the presence of 2.5 mmol/L CaCl₂ and 0.4 mmol/L palmitate, and the hearts were paced. A wide variation in degree of ischemia and overall rates of O₂ consumption with this protocol were used (see "Methods"); O₂ consumption decreased as flow decreased; for example, in control hearts (n=15) from 78.5±7.0 µmol O₂ per gram dry weight per minute in the working mode to 30.2±4.2, 16.0±1.3, 8.1±0.5, and 1.5±0.1 µmol O₂ per gram of dry weight per minute in the Langendorff mode at 15, 7, 3, and 0.5 mL/min flow, respectively. Ranolazine at 1, 10, or 30 µmol/L did not have any apparent effect on O₂ consumption at any of the different flow rates. In contrast, the results shown in Fig 1 indicate that 10 µmol/L ranolazine had marked stimulatory effects on glucose oxidation at all of these flow rates. Addition of 1 µmol/L ranolazine did not result in a significant increase in glucose oxidation rates (data not shown). If 30 µmol/L ranolazine was present, the stimulation of glucose oxidation did not increase further, suggesting that 10 µmol/L already gives the maximal effect (data not shown).

View larger version (15K): [in this window] [in a new window]   Figure 1. Bar graphs showing rates of glucose oxidation by hearts initially perfused in the normoxic working mode (aerobic) and then in the Langendorff mode, sequentially at the different flow rates indicated and in the presence or absence of 10 µmol/L ranolazine. Perfusate contained 2.5 mmol/L calcium and 0.4 mmol/L palmitate (see "Methods"), and hearts were unpaced. Each perfusion condition was maintained for 30 minutes, and measurements were made at steady state. Values shown are mean±SE. Number of hearts used were control, 10; 10 µmol/L ranolazine, 7. *Significant difference from appropriate control value.

The results for simultaneous or parallel measurements of glycolysis and palmitate oxidation rates are given in Fig 2 for experiments conducted with 10 µmol/L ranolazine. Fig 2A indicates that glycolytic rates at most flow rates with 10 µmol/L ranolazine are similar to or slightly higher than those for the control. Overall, the glycolytic rates measured at the different flow rates did not change as dramatically as the other parameters measured. For instance, Fig 2B shows that palmitate oxidation decreases substantially as flow is decreased, but also that ranolazine did not have any apparent affects on palmitate oxidation rates at any of the different flow rates.

View larger version (22K): [in this window] [in a new window]   Figure 2. Bar graphs showing rates of (A) glycolysis and (B) palmitate oxidation in hearts perfused under conditions described in Fig 1. [1-14C]-palmitate was used in these experiments. Numbers of hearts used for A and B, respectively, were control, 10 and 8; 10 µmol/L ranolazine, 7 and 6. *Significant difference from appropriate control value.

All of these data (Figs 1 and 2) on substrate utilization under varying degrees of ischemia again suggest that the primary effect of ranolazine appears to be the promotion of glucose oxidation. The major effect of ranolazine, therefore, appears to be to increase the proportion that comes from glucose of the residual oxidation that is left under the low-flow conditions (compared with glycolysis and fatty acid oxidation).

In passing, it is worth noting the decline in all of the measured oxidation parameters when the hearts are switched from the working mode to even the well-oxygenated control condition in the Langendorff mode (Figs 1 and 2).

Effects of Ranolazine on Functional Recovery and on Substrate Oxidation on Reperfusion After a Period of Global No-Flow Ischemia
The effects of 10 µmol/L ranolazine were studied in the working heart preparation that was subjected to a 30-minute period of global low-flow ischemia followed by reflow for 1 hour; in these studies, ranolazine was only applied during the reperfusion period and rate measurements were made over 10-minute periods. A concentration of 1.2 mmol/L palmitate was chosen for these studies because higher concentrations of palmitate around this range are observed in the blood of patients after a myocardial infarct^{23 24} or after cardiac bypass surgery.²⁵ The calcium concentration was 2.5 mmol/L in these experiments.

Fig 3 (A and B) indicates that ranolazine (10 µmol/L) appears to afford some increased functional recovery of the hearts when added at the start of and throughout the reperfusion period; however, in these experiments the apparent increases in functional recovery observed in the presence of ranolazine did not reach statistical significance when compared with control values. In a later series of experiments, however, in which ranolazine was applied throughout the whole perfusion protocol, including a 30-minute period before the ischemic period, the increases in functional recovery observed with ranolazine in this instance did reach statistical significance compared with untreated controls (Fig 3, C and D). Oxidation rates, however, were not measured in this latter series of experiments, and the results on oxidation measurements now described below were obtained from hearts in which the drug was applied at the start of and throughout the reperfusion period.

View larger version (24K): [in this window] [in a new window]   Figure 3. Plots showing the effects of 10 µmol/L ranolazine added either at reperfusion (A and B) or before ischemia (C and D) on the recovery of cardiac rate-pressure product (A and C) and cardiac work (B and D) in working rat hearts subjected to a 30-minute period of global no-flow ischemia (indicated by bar) followed by a 60-minute period of aerobic reperfusion. In C and D the ranolazine was also present during the 30-minute period of aerobic perfusion before the ischemic period. Numbers of hearts used in A and B were for control, 20; ranolazine, 16; and in C and D control, 7; ranolazine, 7. co indicates cardiac output; psp, peak systolic pressure. *Significantly different from appropriate control values.

The results in Fig 4 show that the principal effect of ranolazine on substrate utilization would again appear to be the enhancement of glucose oxidation (see also Table 3). This effect is observed at the earliest measured time point (10 minutes) after the introduction of the drug at the start of the reperfusion period (Fig 4A). Glycolysis is only minimally affected by ranolazine under these circumstances, although statistically significant differences from values obtained in control perfusions were obtained at some later time points (Fig 4B and Table 3). This suggests that these increases in glycolysis obtained with the drug perhaps arise as a consequence of the increased glucose oxidation rates. An inhibition of fatty acid (for example, palmitate) oxidation is also observed over the reperfusion period (Fig 4C and Table 3); however, this again appears to be slower in onset compared with the glucose oxidation changes, suggesting that it too may follow or be the result of the increased glucose oxidation. The averaged results from these experiments are also compared in Table 3 with preischemic values for these flux parameters. These data indicate that an important consequence of the ranolazine stimulation of glucose oxidation may be to reverse the enhancement of fatty acid oxidation, which appears to form a major metabolic response of the reperfused heart but may be detrimental.^{5 12 13 14 15}

View larger version (17K): [in this window] [in a new window]   Figure 4. Plots showing the effects of 10 µmol/L ranolazine added at reperfusion (to hearts previously subjected to a 30-minute period of global ischemia) on rates of A, glucose oxidation; B, glycolysis; and C, palmitate oxidation. Palmitate oxidation was measured using [1-14C]-palmitate in these experiments. See Fig 3 for further details of the protocol and Table 3 for further numerical analyses of the data. Numbers of hearts involved for A and B were control, 8; ranolazine, 10; for C, control, 7; ranolazine, 8. *Statistically significant effect of ranolazine.

View this table: [in this window] [in a new window]   Table 3. Effects of Ranolazine (10 µmol/L) Added at Reperfusion to Hearts Previously Subjected to a 30-Minute Period of Ischemia on Steady State Rates of Glucose Oxidation, Glycolysis, and Palmitate Oxidation

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of the present work clearly show that ranolazine stimulates glucose oxidation in isolated rat hearts perfused under a variety of different conditions in either the working or Langendorff modes and in either normoxic conditions, ischemic conditions, or on reperfusion after global ischemia. Stimulation of glucose oxidation by ranolazine was observed under all of the conditions tested, whereas the effects observed on glycolysis (sometimes inhibited, sometimes stimulated, mostly unaffected) and palmitate oxidation (sometimes inhibited) were more modest in nature and not always observed. This may indicate that the primary effect of the drug is to stimulate glucose oxidation and that these other effects on glycolysis and/or palmitate oxidation could be brought about in a compensatory manner as the result of this primary event. The results of Fig 4 in particular offer possible time course evidence for this proposed scheme of events. Operation of the Randle "glucose–fatty acid cycle"¹¹ can account for the stimulation of glucose oxidation bringing about a concomitant decrease in fatty acid oxidation.

The mechanism whereby ranolazine promotes glucose oxidation is as yet unknown. As mentioned in the introduction, the drug has already been shown to increase the amount of active dephosphorylated pyruvate dehydrogenase in perfused guinea pig hearts subjected to low-flow ischemia.⁵ A more recent report has also described increases in the amounts of active enzyme as the result of application of the drug to normoxic rat hearts.²⁶ The pyruvate dehydrogenase complex occupies a key site in respiratory fuel selection and is thought to effectively dictate the rate of carbohydrate (and lactate when available) utilization.^{11 27} The fact that ranolazine stimulates glucose oxidation means that it must also enhance flux through this enzyme. Clearly, an increase in the amount of active enzyme is one way in which an increase in flux through the enzyme could be brought about; however, the catalytic activity itself is also subject to regulation, and presently there are few studies that directly address the relative contribution of each type of control of flux through the enzyme.^{11 27}

The enzyme complex is regulated both by end product inhibition of the active form of the enzyme (by acetyl CoA and NADH) and by a phosphorylation-dephosphorylation cycle, which interconverts the enzyme between inactive phosphorylated and active dephosphorylated forms.^{11 27} The enzyme complex and its interconverting (and specific) kinase and phosphatase are all exclusively intramitochondrial in mammalian tissues, suggesting that the site(s) of action of the drug might also be intramitochondrial.

The question of the importance of kinase and phosphatase in the regulation of pyruvate dehydrogenase activity raises the possibility that ranolazine may act by altering kinase and/or phosphatase activity directly. However, in our studies to date (unpublished work of J.G. McCormack and coworkers), we have been unable to observe any direct effects of ranolazine on either the kinase or phosphatase or on the catalytic activity of pyruvate dehydrogenase in either the absence or presence of other known effectors of these enzymes. This suggests that flux through the enzyme might be affected by the drug having a primary effect on another target(s), which then affect a regulator(s) of the pyruvate dehydrogenase system. This clearly warrants further study.

Notwithstanding, the present lack of a precise molecular target for ranolazine, the clearly demonstrable stimulation of glucose oxidation by the drug does offer a plausible means for explaining its antiischemic efficacy, which unlike many commonly prescribed antianginal agents (for example, ß-blockers, calcium channel blockers), is achieved without depressing blood pressure, heart rate, or contractility.^{1 2 7 8 9 10} The studies of the present work (see Table 1) also reenforce this lack of effect of the drug on baseline cardiac performance and give some indication of its antiischemic properties (Fig 3).

An increase in flux through pyruvate dehydrogenase and glucose oxidation would have a number of advantages under conditions of reduced oxygen availability. It may first result in reduced lactate production and release, which is observed with ranolazine,^{1 5} by diverting more lactate to be used as a substrate. The favoring of glucose oxidation at the expense of fatty acid oxidation allows the production of more ATP per O₂,^{14 28} and this would of course be most beneficial under times of O₂ limitation such as reduced coronary flow and/or increased work demand. This may thus account for the preservation of tissue ATP in ischemia, which is observed with the drug,^{4 5 6} and hence lower the delivered oxygen content at which the biochemical and mechanical evidence of ischemia develop.¹³ There also was some evidence to suggest increased sensitivity to the drug (in terms of glucose oxidation) at lower flow rates (Fig 1). This is of interest in consideration of the observation that, while left ventricular developed pressure was no different between perfusion of isolated rat hearts with glucose or hexanoate at physiological flow rates, it was increasingly better maintained with glucose compared with hexanoate as coronary flow was reduced.¹³ While ranolazine did not alter myocardial O₂ consumption, it does appear throughout that ranolazine may increase the amount of glucose utilization versus fatty acid utilization and thus the amount of ATP formed per O₂ consumed. Tissue ATP preservation and reduced lactic acidosis may then account for the observed preservation of cellular viability with the drug.^{4 5 6} Another potential beneficial consequence of the promotion of glucose oxidation at the expense of fatty acid oxidation under conditions of O₂ limitation might be the reduced accumulation of fatty acyl intermediates (for example, palmitoyl carnitine), which occurs in ischemia^{29 30} and is thought to bring about detrimental effects by the perturbation of ionic balance and other systems.^{29 30}

Other strategies to bring about a stimulation of flux through pyruvate dehydrogenase and glucose oxidation and/or a reduction in fatty acid oxidation also have been shown to have antiischemic efficacy in cardiac preparations. Dichloroacetate and carnitine have been shown to have antiischemic efficiency^{12 15} ; they also increase the amount of active pyruvate dehydrogenase, which leads to enhanced glucose oxidation.^{12 14 15 31} Dichloroacetate and carnitine are also thought to concomitantly bring about inhibition of fatty acid oxidation, first by operation of the glucose–fatty acid cycle, but also by an additional mechanism that involves an increase in cytosolic acetyl CoA leading to an increase in cytosolic malonyl CoA.³¹ Malonyl CoA is the potent physiological inhibitor of carnitine palmitoyl transferase I, the key regulatory and rate-limiting enzyme in fatty acid oxidation.³¹ It clearly would be of interest to determine whether ranolazine had any effects on acetyl CoA and malonyl CoA content of hearts.

The effects of ranolazine on glucose oxidation described in the present study broadly appear to be of similar magnitude to those reported for dichloroacetate^{12 14} and carnitine.¹⁵ However, ranolazine would appear to be much more potent than these two other agents because they each require a concentration of 1 mmol/L or greater to achieve their maximal effects, whereas ranolazine appears to achieve its maximal effect at 10 µmol/L (Fig 1).

An alternative approach to achieving the same desired switch in metabolic substrate utilization, via operation of the glucose–fatty acid cycle, is to inhibit fatty acid oxidation.^{31 32} Thus, inhibitors of carnitine palmitoyl transferase I also can lead to reductions in fatty acid oxidation and increases in glucose oxidation and can be shown to have antiischemic efficacy as a result.^{31 32 33} However, long-term administration of such agents has been found to be associated with toxicity problems and in particular their causing cardiac hypertrophy.^{32 34} Toxicological studies with ranolazine have not shown any similar findings (unpublished observations of Syntex Research), and the compound has now shown a good safety profile in several acute and chronic clinical studies.^{7 8 9 10} Also, recent evidence suggests that the major benefit to be realized with the use of carnitine palmitoyl transferaser I inhibition is rather the relief of the inhibition of glucose oxidation caused by high intracellular levels of fatty acid and their metabolites.^{31 35}

These and other observations have led to the concept that glucose oxidation is the key step to be influenced in a metabolic approach to the treatment of ischemia/reperfusion diseases such as angina.^{14 31} Thus, agents that lead to the stimulation of glycolysis alone (for example, insulin)¹⁴ may even exacerbate tissue damage, especially on reperfusion.^{14 31} This is largely because although a stimulation of glycolysis may allow more ATP production in ischemia, if this is not coupled to an enhancement of glucose oxidation, then an excess of protons and lactate will build up, and on reperfusion these will lead sequentially to Na⁺ and Ca²⁺ loading and tissue damage.³¹ It is of interest that ranolazine has been shown to prevent the calcium overload caused by ischemia/reperfusion in an isolated rabbit heart model.⁶ The cardioprotective properties of adenosine have been shown to be associated with a reduction in glycolytic rates and an enhancement of glucose oxidation.²² In the present study, ranolazine generally did not affect rates of glycolysis, and its major effect appears to be the promotion of glucose oxidation alone, although in the present low-flow ischemic study (Fig 2A), a concentration of 1 µmol/L ranolazine did appear to cause some inhibition of glycolysis.

Summary
Ranolazine brings about a clear enhancement of glucose oxidation in rat hearts perfused under a variety of conditions, including in ischemia and reperfusion. This effect of ranolazine may account, at least in part, for its anti-ischemic efficacy in the absence of hemodynamic effects.

	Acknowledgments

 
These studies were supported by an External Studies grant from Syntex Research.

Received November 29, 1994; revision received June 12, 1995; accepted August 8, 1995.

	References

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