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Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
Submitted 7 June 2006 ; accepted in final form 4 August 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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150 Torr and PO2 90 Torr), conduction time, duration, and amplitude were measured before and during perfusion with therapeutic dosages of the drug or vehicle. Hypoxia-induced catecholamine secretion within the carotid body was measured using amperometry. With the use of whole body plethysmography, respiration was measured in unanesthesized rats while breathing room air, 12% O2, and 5% CO2, before and after intraperitoneal administration of amiodarone, lamotrigine, phenytoin, or vehicle. Lamotrigine (10 µM) and phenytoin (5 µM), but not amiodarone (5 µM), decreased chemoreceptor AP frequency without affecting other AP parameters or magnitude of catecholamine secretion. Similarly, lamotrigine (5 mg/kg) and phenytoin (10 mg/kg) blunted the hypoxic but not the hypercapnic ventilatory response. In contrast, amiodarone (2.5 mg/kg) did not alter the ventilatory response to hypoxia or hypercapnia. We conclude that lamotrigine and phenytoin at therapeutic levels impair peripheral chemoreceptor function and ventilatory response to acute hypoxia. These are consistent with INaP serving an important function in AP generation and may be clinically important in the care of patients using these drugs. carotid body; persistent sodium current; anticonvulsants; petrosal neurons
The mechanism by which hypoxia leads to AP generation is not well resolved. The glomus cell, a secretory cell presynaptic to the afferent nerve endings, is generally accepted to play a central role. Hypoxia impairs a number of K+ currents (45, 46) expressed in glomus cells, which leads to a rise in intracellular calcium (3, 5, 26) and secretion of various purported transmitters, including acetylcholine and ATP (6, 54, 60, 63). This release, in turn, is speculated to give rise to AP generation (31). The APs are then transmitted to the brain stem, where they are processed and integrated, leading to an increase in minute ventilation (
E) (10).
It is generally believed that the glomus cell secretion drives the generation of the neuronal APs. Although this is speculated to take the form of an episodic synaptic depolarizing potential (SDP) (e.g., neuromuscular junction) (31), recent results from our laboratory suggested that voltage changes in the nerve terminals are of small amplitude, high frequency, and not high amplitude, low frequency. This characteristic is inconsistent with SDPs but consistent with channel flicker or noise generated from channel transitions (19). Since the spike generation process is highly sensitive to changes in extracellular Na+ (19) and relatively insensitive to K+ channel blocking agents (16, 18, 39), we speculated that the channel noise leading to AP generation is due to Na+ channels.
Previous work from our laboratory demonstrated that rat petrosal chemosensory neurons express primarily tetrodotoxin-sensitive (TTX-S) currents of, at least, two isoforms based on the kinetics of recovery from inactivation (12). The rat nerve cells are of small diameter and have a conduction velocity under 1 m/s (20). This is in contrast to cat chemosensory neurons, which express both TTX-S and TTX-resistant currents (2) and have a higher conduction velocity, characteristic of A
neurons.
Several TTX-S isoforms carry a persistent inward current around resting potential, which plays an important role in determining cellular excitability. This current is postulated to be due to transitions from the inactive to open states of the Na+ channel (58) and may be reduced with drugs, which stabilize the inactive state. One drug, riluzole, has been widely used to inhibit this persistent Na+ current (INaP) and was useful in demonstrating an important role of INaP in the neurogenesis of gasping (15, 47, 49) and neuron bursting behavior in the hippocampus (29), suprachiasmatic nucleus (37), and hypothalamus (33). Previously, we demonstrated that riluzole decreases spiking activity in isolated chemoreceptors and reduces the ventilatory response to acute hypoxia but not to acute hypercapnia (25).
Riluzole is clinically used to treat spasticity in amyotrophic lateral sclerosis patients (40, 41), which is a relatively small patient potential. This led us to ask whether other widely used clinically therapeutic agents that stabilize the inactive state of the Na+ channel would also impair the functioning of peripheral chemoreceptors. In this study, we address the possible actions of therapeutic doses of the antiarrhythmic amiodarone and the anticonvulsants lamotrigine and phenytoin (8, 36, 53) on the peripheral chemoreceptor response to hypoxia in vitro and the respiratory response to hypoxia and hypercapnia in vivo.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Chemoreceptor isolation and single-unit recordings. Spiking activity of rat chemoreceptors, in vitro, was recorded from the soma of petrosal neurons with projections to the carotid body (20). For this preparation, rat pups were euthanized using 100% CO2 and then decapitated. The peripheral chemoreceptor complex consisting of the carotid body, sinus nerve, part of the glossopharyngeal nerve, and the petrosal ganglion was harvested in toto. The complex was exposed to a dilute mixture of collagenase (Boehringer type P, 1 mg/ml; Boehringer-Mannheim, Mannheim, Germany) and protease (Sigma type IX, 0.2 mg/ml; Sigma-Aldrich, St. Louis, MO) for 30 min at 36°C to aid in the removal of surrounding connective tissue. The complex was transferred to a recording chamber (model RC21C; Warner Instruments, Hamden, CT) mounted on the stage of an inverted microscope and superfused with Ringer solution (in mM: 120 NaCl, 3 KCl, 2 CaCl2, 1 Na2HPO4, 24 NaHCO3, 2 MgSO4, and 10 glucose) oxygenated with 21% O2–5% CO2–N2 balanced gas mixture at a rate of 3 ml/min. The temperature in the recording chamber was kept at 36–37°C by an inline heater (model TC-344B; Warner Instruments).
Single-unit activity was recorded using a glass suction electrode advanced into the petrosal ganglion. To facilitate unit identification and for measurement of nerve conduction time, a glass pipette filled with 1 N NaCl (1 M
impedance) was placed in the center of the carotid body, and a cathodal electrical stimulus (100 µA, 0.1-ms duration, 1/s) was delivered through the pipette to evoke orthodromic APs. Once an evoked AP was detected, stimulus was removed and observed for spontaneous activity. Discharge activity was continuously acquired and then digitized using Axoscope (Axon Instruments, Foster City, CA) at a sampling rate of 10 kHz (Figs. 1 and 2, A–D).
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150 Torr) was recorded for 1 min. Response to hypoxia was then tested by superfusing the preparation in Ringer solution equilibrated with 12% O2–5% CO2–balance N2 for 2 min, resulting in a chamber PO2 90 Torr, followed by a return to normoxia.
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Catecholamine secretion. To assess elements that are presynaptic to the afferent nerve fibers, hypoxia-induced catecholamine secretion was measured using amperometry. Catecholamines are a major component of the dense-cored secretory granules contained in the glomus cells, and kinetics of catecholamine release have been used as an index of hypoxic responsiveness of these cells (45, 46). Electrodes were 5-µm carbon fibers polypropylene insulated except for the tip (proCFE; Dagan, Minneapolis, MN), which were dip-coated in an ion exchange resin (Nafion; Sigma-Aldrich). The resin discriminated against negatively charged moieties (e.g., ascorbate) (17). Electrodes were polarized to +200 mV against a Ag-AgCl reference electrode and advanced into the carotid body under visual observation. Current changes were acquired and digitized (Axopatch 1D and Axoscope; Axon Instruments) at a sampling rate of 10 kHz (Fig. 4, A–D).
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Ventilation measurement. Breathing was measured in unanesthetized, unrestrained rats using whole body plethysmography (21). Rat pups were placed in a 0.5-liter cylindrical Plexiglas chamber (Buxco Electronics, Troy, NY) with a bias flow of 1 l/min. Pressure changes within the chamber were measured with the accompanying transducer (model TRD5700; Buxco Electronics). Chamber temperature and relative humidity were measured using a flow-through probe (Humidity and Temperature Voltage Output System, model HTM 2500; Humirel, Phoenix, AZ), while carbon dioxide tension in the chamber was analyzed via Capstar-100 carbon dioxide analyzer (CWE, Ardmore, PA). Calibrations of all instruments were done daily before the start of the experiment. Data were continuously acquired at a sampling rate of 200 Hz and digitized using Digidata 1320A and Axoscope acquisition program (Figs. 5, A–D, and 6, A–D).
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Experimental protocol for respiratory measurements.
On the morning of the day of study, animals were weighed, and body temperature was measured using a small, flexible temperature probe (YSI 451; YSI, Yellow Springs, OH). The rat was then allowed to acclimate to the plethysmograph for 
15 min or until the rat ceased exploratory behavior. A 5-min recording was taken during room air breathing followed by 10 min of hypoxia (12% O2). Based on the flow rate and chamber size, steady-state inspired O2 fraction levels were achieved in 40 s (2 time constants). After the hypoxia period, rats were allowed to recover in room air for 5 min and then rechallenged with hypercapnia, 5% CO2 in air, for 10 min. The rats were then removed from the chamber and transferred to their respective cages.
The rats were randomly assigned to the amiodarone, lamotrigine, phenytoin, or vehicle group. Rats in the drug-treated group were administered with either amiodarone at 2.5 mg/kg, lamotrigine at 5 mg/kg, or phenytoin at 10 mg/kg, dissolved in DMSO intraperitoneally. These doses were based on usual human doses and prior dose-determining experiments (7, 22). The rats randomized to the vehicle group were given similar volumes (1 ml/kg) of vehicle. After a minimum of 30-min incubation, body temperature was taken before replacing the rats in the plethysmograph. Experiments were initiated at least 45 min after drug administration.
Once the experiments were completed, the rats were killed, and blood was sent to the Clinical Chemistry Laboratory of Yale New Haven Hospital, where drug serum levels were measured using high-performance liquid chromatography. Blood samples were extracted 90 min after drug administration. The timing of the drug levels is similar to what is done clinically (7, 22).
Data analysis. AP occurrence times were detected and recorded using FETCHAN 6 (Axon Instruments), which also recorded the peak (extracellular) voltage excursion during an AP. Single-unit recording was confirmed by the unimodal histogram of AP amplitude events. AP occurrence times were converted to frequency (Hz) and plotted using Origin 7.5 (Microcal Software, Northampton, MA). The average frequencies of the spontaneous discharge activity over 30 s during normoxia and 2 min of hypoxia were obtained and used for comparison.
APs were also detected using Minianalysis (Synaptosoft, Decatur, GA). The program determined the time between spikes, the height of each spike, and the start and end of an AP. The data were entered into a customized Microsoft Excel (Microsoft, Redmond, WA) program, which averaged the conduction times, AP amplitudes, and durations. Nerve conduction time was measured on all orthodromically evoked spikes following an electrical stimulus delivered to an electrode placed in the carotid body, while the amplitude and duration of AP were recorded from all spontaneous APs during normoxia (Fig. 3A). The conduction time was based on the time lapse from the stimulus artifact to the arrival of the somal AP. Conduction time, amplitude, and duration of the AP were normalized to values measured during superfusion with Ringer solution.
Tissue catecholamine secretion was calculated based on the increase in the carbon-fiber electrode current during hypoxia (Fig. 4A). Since catecholamine stores within glomus cells in the preparation are limited, the magnitude of release generally decreases with multiple stimulus presentations (17). Thus the data were expressed as the magnitude of release following treatment with drug or vehicle compared with the magnitude of initial release.
Ventilatory pressure traces were analyzed using Minianalysis, which was used to detect the start and peak of the respiratory waveforms. Ten sequential breaths were quantified during room air breathing and at the start of each minute of the hypoxia or hypercapnia period. The pressure signal was corrected for the filtering characteristic of the chamber and used to calculate tidal volume (VT) based on the equation of Drorbaugh and Fenn (21). The product of the VT and respiratory rate (fR) provided the E, which was also normalized to carbon dioxide production (CO2). Both E and CO2 were computed as milliliters per minute per 100 g, and as such E/CO2 is unitless. Calculation of CO2 was based on the chamber CO2 tension and the known bias flow through the chamber. Recordings during normoxia showed stable CO2 tension, implying no build-up of CO2.
The average E, E/CO2, fR, and VT were calculated for each time point. Based on preliminary studies in our laboratory using unmedicated rats, peak changes in ventilation during hypoxia occurred within 1 min of the hypoxic challenge before declining to a lower level by the end of 10 min of hypoxia. Hypercapnia, in contrast, causes a slow increase in breathing, which plateaus around 5 min.
All values were expressed as means ± SE. Student’s t-test was used to compare the different AP parameters and catecholamine secretion between identical doses of the vehicle and vehicle + drug. Similarly, pairwise comparisons were made between vehicle-treated and each of the drug-treated ventilation measures at the different specified time points. Comparisons of ventilation between vehicle-treated and drug-treated rats were made at baseline normoxic, normocapnic breathing, at the start of hypoxia, at the end of the hypoxic challenge, at the middle of hypercapnia, and at the end of hypercapnia using Student’s t-test. Body temperature, pre- and postdrug administration, was compared using paired t-test. Since time-dependent changes or comparison among drugs was not considered, ANOVA was not employed. A level of 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The inhibitory actions of phenytoin and lamotrigine appeared to be specific to spike generation frequency. None of the agents or vehicle altered nerve conduction velocity, AP amplitude, or AP duration (Fig. 3).
Hypoxia-induced catecholamine release was measured in 35 carotid body preparations harvested from 20 rat pups in which catecholamine secretion was measured before and during vehicle or drug treatment (vehicle, n = 8; amiodarone, n = 9; lamotrigine, n = 8; and phenytoin, n = 10). In contrast to the effects on nerve spiking activity, none of the drugs at the lower drug concentration significantly altered the magnitude of hypoxia-induced catecholamine release compared with vehicle-treated samples (Fig. 4). At the higher drug concentration, lamotrigine and phenytoin did not affect hypoxia-induced catecholamine release (Fig. 4E). However, peak secretion with amiodarone (5 µM) was significantly lower compared with treatment with vehicle (P = 0.04).
Lamotrigine and phenytoin reduce the ventilatory response to acute hypoxia but not to acute hypercapnia. Ventilation was measured using whole body plethysmography, in vivo, in 39 rat pups following treatment with vehicle or drug (vehicle, n = 8; amiodarone, n = 11; lamotrigine, n = 10; and phenytoin, n = 10). Age, weight, body temperature, and ventilatory values before drug administration were statistically similar between vehicle and each of the drug-treated groups (Table 1, Figs. 5, E–H, and 6, E–H).
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E to 502.9 ± 40.0 ml·min–1·100 g–1 after 1 min and 197.5 ± 18.2 ml·min–1·100 g–1 at the end of the 10 min from a baseline of 120.7 ± 17.2 ml·min–1·100 g–1 (Fig. 5, A and E). Lamotrigine and phenytoin slightly, but significantly, reduced baseline ventilation to 48.4 ± 6.5 ml·min–1·100 g–1 (P < 0.01) following lamotrigine administration and 80.9 ± 10.3 ml·min–1·100 g–1 (P = 0.03) following phenytoin treatment (Fig. 5, C–E). At 1 min of hypoxia, E was 117.8 ± 15.5 ml·min–1·100 g–1 (P < 0.01) with lamotrigine and 270.3 ± 54.0 ml·min–1·100 g–1 (P < 0.01) after phenytoin injection. After 10 min of the challenge, only lamotrigine at 129.1 ± 22.1 ml·min–1·100 g–1 (P = 0.02) was lower than the vehicle-treated group. Amiodarone did not significantly affect the hypoxic ventilatory response (Fig. 5, B and E).
All drug-treated groups evidenced a decrease in body temperature. In the lamotrigine and phenytoin groups, temperature decreased from 34.8 ± 0.1 to 31.8 ± 0.6°C (P < 0.01) and from 34.8 ± 0.1 to 32.0 ± 0.4°C (P < 0.01), respectively. No drop was seen in the vehicle-treated group. Since ventilation can be affected by body temperature, E was normalized to CO2, with the latter as a gauge of metabolic activity, and then compared between the vehicle and the two drugs (Fig. 5F). Despite the normalization, E at room air and during hypoxia remained depressed after treatment with the anticonvulsants. E/CO2 at room air and at 1 and 10 min of hypoxia after vehicle administration was 22.8 ± 2.3, 95.1 ± 7.8, and 51.6 ± 7.2, respectively. Corresponding values after intraperitoneal injection of lamotrigine were 10.3 ± 1.1 (P < 0.01), 36.2 ± 7.3 (P < 0.01), and 29.9 ± 5.6 (P = 0.01), while, after phenytoin, they were 14.6 ± 1.7 (P < 0.01), 51.2 ± 6.9 (P < 0.01), and 40.1 ± 7.1 (P = 0.14).
Comparison of fR and VT between rats treated with vehicle and with lamotrigine or phenytoin showed a significant depression in fR following drug treatment and during hypoxia (Fig. 5, G and H). With vehicle, fR increased from 124.9 ± 4.5 breaths/min to 199.0 ± 2.0 breaths/min at 1 min and 159.3 ± 6.6 breaths/min at 10 min of hypoxia (Fig. 5G). At each of these time points, fR was significantly lower than vehicle-treated rats at 81.0 ± 7.9 breaths/min (P < 0.01), 117.8 ± 15.5 breaths/min (P < 0.01), and 103.7 ± 10.5 breaths/min (P < 0.01), respectively, after administration of lamotrigine. Similarly, after injection with phenytoin, fR was decreased at 103.1 ± 5.7 breaths/min (P < 0.01), 133.3 ± 11.7 breaths/min (P < 0.01), and 123.7 ± 7.3 breaths/min (P < 0.01), respectively.
VT at room air breathing after vehicle was 0.96 ± 0.14 ml/100 g, rising to 2.46 ± 0.19 ml/100 g at 1 min of hypoxia before going down to 1.24 ± 0.13 ml/100 g at the end of the hypoxic challenge (Fig. 5H). Unlike fR, VT after lamotrigine injection was lower than vehicle only during room air (0.58 ± 0.03 ml/100 g; P < 0.01) and at the start of hypoxia (1.43 ± 0.15 ml/100 g; P < 0.01). After phenytoin treatment, VT was depressed only at 1 min of the challenge (1.87 ± 0.20 ml/100 g; P = 0.02).
In contrast to their depressive action on the hypoxic ventilatory response, none of the drugs altered the magnitude of the ventilatory response to acute hypercapnia (Fig. 6). Following vehicle administration, hypercapnia increased E to 358.1 ± 54.7 ml·min–1·100 g–1 and 392.2 ± 44.8 ml·min–1·100 g–1 5 and 10 min into the hypercapnic period, respectively (Fig. 6, A and E). A similar ventilatory response during hypercapnia was observed following amiodarone, lamotrigine, and phenytoin treatment (Fig. 6, B–E). Values for E, E/CO2, fR, and VT were not different between vehicle treatment and drug treatment following administration of amiodarone, lamotrigine, and phenytoin (Fig. 6, E–H).
Serum drug levels of the active agents were generally within the therapeutic range. Therapeutic levels were achieved in 8 of 11 amiodarone-treated rats, 6 of 10 lamotrigine-treated rats, and 8 of 10 phenytoin-treated rats. Mean serum concentrations were amiodarone of 1.7 ± 0.1 µg/ml, lamotrigine of 14.8 ± 1.8 µg/ml, and phenytoin of 13.6 ± 1.5 µg/ml. As expected, serum levels of the three drugs were below the limits of detection in the vehicle-treated group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In a previous study, we used patch-clamp recordings to demonstrate that INaP is present in petrosal chemoreceptor neurons and is inhibited by low doses of riluzole (25). Riluzole at the same dosage reduced AP activity in isolated chemoreceptors and the ventilatory response to hypoxia, in vivo, without affecting other AP parameters or hypoxia-induced catecholamine release (25). INaP is a subthreshold, noninactivating Na+ current that, despite comprising a small amount of the Na+ influx, plays a significant role in the control of neuronal excitability at near firing threshold (59). The current is postulated to result from brief transitions of the fast Na+ channel from the inactive to the open state and from sustained openings of the Na+ channel that temporarily fail to inactivate (1). The current is postulated to raise the membrane potential to the brink of firing threshold, enhancing the ability of excitable cells to fire repetitively.
Lamotrigine and phenytoin are Na+ channel blockers with increased affinity to the inactive state of the Na+ channel (8, 38, 62). Phenytoin, in particular, is 100 times more effective in binding to the inactive compared with the resting state (8). The ability of these drugs to antagonize INaP contributes to their anticonvulsant effect by decreasing membrane excitability and preventing the spread of the AP from the epileptogenic focus (8, 42). Interestingly, the affinity of both anticonvulsants to the inactive state of the Na+ channel increases with repeated depolarizations (8, 62), a situation similar to the repetitively firing petrosal chemoreceptor neurons.
At therapeutic drug concentrations, lamotrigine and phenytoin produced results similar to riluzole administration. The spiking activity of isolated chemoreceptors and the respiratory response to acute hypoxia were significantly reduced by the two anticonvulsants. In contrast, neither drug affected the hypercapnic ventilatory response. This suggests that agents that inhibit INaP, as a class, may impair the functioning of peripheral chemoreceptors and, hence, the ability to detect a period of desaturation. While the impairment is likely to be graded, and perhaps small, it may potentially interact with other factors that can modulate the ability to respond to a hypoxic insult and lead to a potentially vulnerable condition.
In addition to reducing the ventilatory response to hypoxia, lamotrigine and phenytoin depressed ventilation during room air breathing, which may be largely attributed to the loss of peripheral chemoreceptor drive during room air breathing. The drop-off is somewhat larger than the typical 15% thought to be contributed by peripheral chemoreceptors to resting ventilation (4). However, this magnitude may be developmentally related, as the ventilatory response to surgical removal of carotid body input may be significantly greater in the young compared with the adult (32, 52).
All of the agents used in the present study have other actions in addition to inhibition of the INaP. Lamotrigine and phenytoin can affect other substates of the Na+ channel and certain types of K+ and Ca2+ channels known to exist within the peripheral chemoreceptor complex (24, 30, 55). For instance, both drugs show voltage-dependent inhibition of Na+ currents and block delayed rectifier K+ currents, while lamotrigine antagonizes L-type Ca2+ currents and phenytoin inhibits Ca2+-activated K+ currents (13, 14, 56, 62). However, these actions generally occur at supratherapeutic concentrations and are higher than those tested in the study (14, 44, 56, 62). Furthermore, AP parameters, other than AP frequency (i.e., conduction time, amplitude, and duration), were not significantly affected, suggesting that currents determining spike duration and transmission were not broadly altered (30, 48, 55). Thus a general inhibition of Na+, K+, or Ca2+ channels by the drugs is unlikely to have occurred.
The site of action of lamotrigine and phenytoin is likely at the nerve terminals. Rat glomus cells, the element presynaptic to the nerve terminals, do not contain fast Na+ channels (27) and should not be affected by changes in INaP (25). Although catecholamine release, per se, may not be responsible for excitatory transmission between glomus cells and nerve endings (17, 57), it may serve as a proxy for all purported transmitters contained within the dense-cored granules. Since neither lamotrigine nor phenytoin altered the magnitude of hypoxia-induced catecholamine release, their actions were likely directed solely to the postsynaptic site.
Lamotrigine and phenytoin are widely used for the treatment of epilepsy, which is reported to occur in as many as 1% of children worldwide with the greatest mortality and morbidity in the same age group (28). Epilepsy is generally treated with pharmacological agents, which reduce neuronal excitability. While both agents are effective in the treatment of epilepsy, phenytoin is a first-line drug in managing status epilepticus, an uncontrolled generalized seizure (61). On the other hand, lamotrigine is a treatment of choice for bipolar disorder aside from epilepsy (62).
Since lamotrigine and phenytoin are in widespread clinical use, results of the present study may have significant clinical implications. In our rats, acute treatment with therapeutic dosages of the drugs impaired room air ventilation and the hypoxic ventilatory response after presentation as a bolus. Phenytoin, in particular, is also given as a bolus for the treatment for status epilepticus and presented at doses similar to that used in the present study (22, 23, 61). If the drug caused impairment of ventilatory control or an impaired ability to maintain adequate oxygenation, then serious consequences to the developing brain may result, which would be exacerbated by the increased oxygen requirement associated with seizure activity. Lamotrigine, unlike phenytoin, is given orally, with doses increased over weeks (11), and it is currently unclear whether impaired oxygen sensing would occur following this presentation. A further examination of the issue appears warranted.
The reason that amiodarone did not impair peripheral chemoreceptor function in vitro or the hypoxic ventilatory response in vivo is, at present, unclear. Amiodarone is an anti-arrhythmic drug recommended in the treatment of life-threatening supraventricular and ventricular arrhythmias in children (43). Its action appears to be directed, at least partially, to INaP, which has been demonstrated to be present in heart muscle (34, 35, 50, 51). Similar to lamotrigine and phenytoin, the drug has a high affinity to the inactive state of the Na+ channel (36). However, the Na+ channel isoforms expressed in the heart differ from those expressed in peripheral ganglia (9), and the isoforms may potentially differ in their sensitivity to amiodarone. In the only report studying the effect of amiodarone on cortical neurons, a significant inhibition of the INaP was demonstrated (53), but the dosage (10 µM) was approximately double that used in our study. While higher dosages of amiodarone might impair chemoreceptor function, these were not tested due to the restriction of staying within the range of therapeutic concentrations.
In summary, the present study demonstrates that therapeutic concentrations of lamotrigine and phenytoin impair peripheral chemoreceptor activity in vitro and the ventilatory response to acute hypoxia in vivo. Since both agents are established to inhibit INaP, we speculate that INaP plays a critical role in spike generation at the afferent nerve terminal. The effect of the drugs on room air ventilation and the hypoxic ventilatory response may be clinically significant in the care of patients receiving these drugs.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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  D. F. Donnelly Spontaneous action potential generation due to persistent sodium channel currents in simulated carotid body afferent fibers J Appl Physiol, May 1, 2008; 104(5): 1394 - 1401. [Abstract] [Full Text] [PDF]
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P < 0.05; 
P < 0.01.
