Anesth Analg 2002;94:117-122
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Vecuronium Directly Inhibits Hypoxic Neurotransmission of the Rat Carotid Body
Ayuko Igarashi, MD*,
Sumio Amagasa, MD PhD
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Hideo Horikawa, MD PhD, and
Machiko Shirahata, MD DMSc
*Department of Anesthesiology, Shinjo Prefectural Hospital; Department of Anesthesiology and Resuscitation, Yamagata University, School of Medicine, Yamagata, Japan; and Departments of Environmental Health Sciences and Anesthesiology/Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland
Address correspondence to Dr. Machiko Shirahata, Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205. Address reprint requests to Ayuko Igarashi, MD, Department of Anesthesiology, Shinjo Prefectural Hospital, 12-25, Wakaba-chou, Shinjo, Yamagata, Japan, 996-0025.
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Abstract
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Previous studies have suggested that partial neuromuscular blockade by vecuronium may inhibit the chemoreceptor neural response to hypoxia. Because acetylcholine and its receptors are critically involved in the hypoxic neurotransmission of the carotid body, we examined whether vecuronium interferes with nicotinic processes in the carotid body and inhibits the chemoreceptor neural response to hypoxia. The carotid body was harvested from anesthetized adult Wister rats. Carotid sinus nerve activity (CSNA) was recorded in vitro, whereas the carotid body was perfused with Krebs solutions equilibrated with 5% CO2/air or 5% CO2/N2. Vecuronium (0.1, 0.5, and 5 µM) was administered via perfusion. Hypoxic perfusion increased CSNA and the response remained stable for two hours. With vecuronium 0.5 and 5 µM, the increase in CSNA (
CSNA) in response to hypoxia was significantly attenuated. The inhibitory effect of vecuronium was dose-related. Acetylcholine and nicotine increased CSNA, and the values of CSNA were significantly attenuated by vecuronium. These results indicate that vecuronium directly inhibits the carotid body neural response to hypoxia, possibly because of the inhibition of neuronal nicotinic receptors in the carotid body.
IMPLICATIONS: We investigated the effect of vecuronium on the chemoreceptor response to hypoxia with perfused rat carotid bodies. The results indicate that vecuronium significantly reduces carotid body neural responses to hypoxia, acetylcholine, and nicotine by inhibiting neuronal nicotinic receptors in the carotid body.
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Introduction
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Postoperative residual neuromuscular blockade is a significant risk factor for developing pulmonary complications (1). As an index for a sufficient recovery of respiratory functions, a train-of-four (TOF) ratio of 0.7 in the adductor pollicis muscle has been widely used. However, a TOF ratio of 0.7 may not always be associated with normal respiratory functions. For example, Eriksson et al. (2–4) have shown that partial neuromuscular blockade depressed the ventilatory response to hypoxia in humans. They suggested that commonly used muscle relaxants such as vecuronium may exclusively inhibit the peripheral chemoreceptor function. Their investigation was extended to studies using rabbits, and showed that the systemic administration of vecuronium impaired the hypoxic response of the carotid sinus nerve (5). These studies raise a question whether vecuronium affects nicotinic receptors in the carotid body. Vecuronium inhibits nicotinic receptors at the neuromuscular junction but not at the autonomic ganglia (6). However, Wada et al. (7) have shown that vecuronium inhibits the secretion of catecholamines from adrenal medullary cells, indicating that vecuronium has a strong affinity to neuronal nicotinic acetylcholine (ACh) receptors.
The roles of ACh and its receptors in the carotid body neurotransmission have long been overlooked. However, recent studies together with abundant previous data indicate that ACh and its receptors are critically involved in the excitation of the carotid body (8,9). Furthermore, two types of neuronal nicotinic receptor subunits have been localized in the cat carotid body (9,10).
The objectives of this study were to examine (a) the effect of vecuronium on the hypoxic neurotransmission of the carotid body and (b) the effect of vecuronium on nicotinic receptor excitation of the carotid body. By using an in vitro preparation, we could observe the direct effect of vecuronium on the carotid body. We have found that moderate-to-small doses of vecuronium (5, 0.5, 0.1 µM) depress hypoxic neurotransmission of the rat carotid body, possibly because of the inhibition of neuronal nicotinic ACh receptors in the carotid body.
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Materials and Methods
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After approval of our institutional animal care and use committee, experiments were performed on 24 adult Wister rats weighing 250–350 g. Rats were anesthetized with inhaled ether and 
-chloralose (100 mg/kg, intraperitoneally). The carotid bifurcation was exposed, and the conjunction of the carotid sinus nerve and the glossopharyngeal nerve was identified. After systemic heparinization (2000 IU/kg, IV), the rat was decapitated and the entire carotid bifurcation with the carotid sinus nerve was excised in one block. The tissue was immediately immersed into ice-cold Krebs solution equilibrated with 5% CO2/95% O2. The residual blood in the arteries was eliminated by flushing the common carotid artery with the same solution. Under a surgical microscope, the connective tissue around the carotid body was carefully removed and the sinus nerve was prepared for the nerve recording. The internal carotid artery and the occipital artery were ligated, and a snare was placed at the distal end of the external carotid artery to control the outflow. The common carotid artery was cut approximately 0.5 cm proximal to the bifurcation and attached to a stainless steel tubing in the recording chamber (Fig. 1). The perfusate was driven by a peristaltic pump to the tissue. By adjusting flow rate (5–6 mL/min) and the snare at the external carotid artery, the mean perfusion pressure was stably maintained at 104 ± 7.8 mm Hg (n = 24). The perfusate entered the common carotid artery through the stainless steel tubing and exited from the tissue to the recording chamber via the venous outflow of the carotid body and the external carotid artery. The perfusate was then drained out from two outflow channels at the bottom of the recording chamber. The temperature in the recording chamber was maintained at 35°C by circulating warm water in a water bath and a water jacket.
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Figure 1. A schematic diagram of the perfusion system. A carotid bifurcation was mounted in a recording chamber and immersed in Krebs solution which was covered with liquid paraffin (LP). The carotid sinus nerve (CSN) was lifted into the LP with bipolar platinum electrodes. Perfusates were equilibrated with gas mixtures in a thermo-controlled water tank (WT) and driven by a peristaltic pump (P) into the common carotid artery through a stainless steel tubing (shadowed area in the tubing). The perfusates exited from veins of the carotid body (CB) and the external carotid artery. Two outflow channels placed at the bottom of the recording chamber drained the perfusates from the recording chamber to an outer chamber. Drugs were administered from a three-way stopcock (T) into the perfusion line. Open arrows represent circulation of warm water from WT to the water jacket and the water bath. Closed arrows represent the direction of the perfusate. H = heater, Pr = pressure transducer, Tp = thermoprobe.
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The perfusate was the modified Krebs solution (composition in mM: NaCl 118, KCl 4.5, MgSO4 · 7H2O 1.2, Na2HPO4 1.2, EDTA 0.0016, CaCl2 2.4, NaHCO3 22, glucose 10, and choline chloride 30 µM) with or without vecuronium. The Krebs solutions in reservoirs were equilibrated with either 5% CO2/air (normoxic Krebs) or 5% CO2/95% N2 (hypoxic Krebs). A pressure transducer and a thermoprobe were installed in the perfusion line near the carotid artery for continuous monitoring of the perfusion pressure and temperature (Fig. 1). Samples of the perfusate were taken from a three-way stopcock in the perfusion line and analyzed for PO2, PCO2 and pH.
To record the chemoreceptor neural activity, we used conventional whole nerve recording techniques (11). Briefly, the whole carotid sinus nerve was placed on the bipolar platinum electrodes and lifted into liquid paraffin which covered the surface of the Krebs solution. The electrodes were connected to a biophysical amplifier. Amplified and filtered (bandwidth 300 Hz to 3 kHz) neural activity was fed to an oscilloscope. Neural discharge was counted by using a histogrammer. The neural discharge (raw and counted) and the perfusion pressure were recorded simultaneously with a multichannel thermal-pen recorder.
Vecuronium bromide was obtained from Organon (Osaka, Japan), prepared with distilled water (4 mg/mL), and diluted in the Krebs solution at appropriate concentrations (0.1, 0.5, 5 µM). These values are less than 50% effective concentration (EC50) for vecuronium (5.19 ± 1.17 µM; 3.31 ± 0.75 µg/mL) which was measured with the phrenic nerve-hemidiaphragm preparation in the rat (12). ACh and nicotine were obtained from Sigma Chemical Co. (St. Louis, MO). Stock solutions of ACh (10 mg/mL) and nicotine (1 mg/mL) were freshly prepared with distilled water, and they were diluted in the Krebs solution immediately before administration (1 mg/mL for ACh and 25–250 µg/mL for nicotine).
Initially the carotid body was perfused with the normoxic Krebs solution. To assess the neural response to hypoxia, the perfusate was switched to the hypoxic Krebs solution for 5 min. The perfusate was then returned to normoxic Krebs solution and normoxic perfusion was maintained for at least 5 min. The hypoxic challenge was repeated several times until the stable neural response was confirmed. Subsequently, vecuronium (0.1, 0.5, or 5 µM) was administered to the carotid body in normoxic Krebs solution for 30 min. Then the perfusate was changed to the hypoxic Krebs solution with vecuronium for 5 min followed by normoxic Krebs perfusion. One group of carotid bodies was not exposed to vecuronium (vecuronium 0 µM). In these preparations, the hypoxic exposure was repeated every 30 min for up to 2 h to test the stability of the preparation.
To examine the carotid body responses to ACh (100 µg) and nicotine (2.5–25 µg), these agents in a volume of 0.1 mL were administered from the three-way stopcock in the perfusion line during normoxic perfusion. The responses were measured before vecuronium administration and immediately after the carotid body was challenged with hypoxic perfusion containing vecuronium.
The baseline noise of the whole recording system was estimated at the end of each experiment. The carotid sinus nerve was cut from the carotid body and the activity generated by the disconnected carotid sinus nerve was considered the baseline noise level and was subtracted from all measurements. Steady-state carotid sinus nerve activity (CSNA) was quantified by averaging the counted activity for 10 s (impulses/s). The control values during normoxia were obtained immediately before the hypoxic challenges or ACh/nicotine administrations. The values during hypoxia were obtained between 4 min 50 s to 5 min after the hypoxic challenge was initiated. The differences between the values of CSNA during normoxia and hypoxia (CSNA) were considered as the carotid body neural response to hypoxia. The values of CSNA after vecuronium were also normalized in respect to those before vecuronium and expressed as percent to further assess the effect of vecuronium. Six carotid bodies from 6 rats were used for testing each dose of vecuronium (total 24 carotid bodies). In 12 preparations, the carotid body responses to ACh and nicotine were further investigated. The responses were quantified by subtracting values of CSNA before the agents from the peak values after the agents. The effect of ACh was tested before and with 0.5 µM (n = 3) or 5 µM (n = 3) vecuronium. All data were pooled. Similarly, the effect of nicotine was tested before and with 0.1 µM (n = 5) or 0.5 µM (n = 1) vecuronium, and the data were pooled.
The raw values of CSNA with or without vecuronium were analyzed by using Wilcoxon’s signed rank test. The normalized values of CSNA were compared with one-way analysis of variance followed by Bonferroni’s test. The CSNA values in response to ACh and nicotine were analyzed by using Wilcoxon’s signed rank test. All values were expressed as means ± SEM. A P value < 0.05 was considered significant.
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Results
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All carotid bodies (n = 24) responded to hypoxia and increased the CSNA (Fig. 2, left). Perfusion with normoxic Krebs solution containing 0.1, 0.5, or 5 µM vecuronium for 30 min did not change the baseline CSNA. However, the carotid body neural responses to hypoxia were reduced in all cases (Fig. 2, right).
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Figure 2. The representative carotid sinus nerve responses to hypoxic Krebs perfusion before and with vecuronium (VB). The records were obtained from three different preparations. Arrows indicate the start (on, downward arrows) and the end (off, upward arrows) of hypoxic perfusion. CSNA = carotid sinus nerve activity. A, The effect of VB 0.1 µM. CSNA increased in response to hypoxic Krebs perfusion (left). With VB 0.1-µM administration, the carotid body was again challenged with hypoxic Krebs (right). The increase in the CSNA was reduced. B, Hypoxic responses of a carotid body before and with VB 0.5 µM. C, Hypoxic responses of a carotid body before and with VB 5 µM.
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CSNA in response to hypoxia remained unchanged with time (vecuronium 0-µM group, Fig. 3A), but vecuronium administration decreased CSNA in a dose-related manner. The values of CSNA with vecuronium 0.5 µM and 5 µM were significantly reduced from each control. When the values of CSNA with vecuronium were normalized in respect to CSNA before vecuronium (Fig. 3B), the values for the 0.5- and 5-µM groups were significantly less than that for the 0-µM group. Furthermore, the value for the 5-µM group was significantly less than that for the 0.1-µM group.
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Figure 3. The effect of vecuronium (VB) on the carotid chemoreceptor neural response to hypoxia. Data were obtained from independent six rat carotid bodies for each concentration of VB. Data are mean ± SEM (n = 6 in each group). CSNA = a difference in values of carotid sinus nerve activity (CSNA) between normoxia and hypoxia. A, Carotid sinus nerve response to hypoxia before (control) and with VB (VB-treated). Values of CSNA in response to hypoxic perfusion were decreased with VB (0.1, 0.5, 5 µM), whereas without VB (VB 0 µM), values of CSNA were unchanged. *Significantly different from each control (P < 0.05). Statistical analysis was performed with Wilcoxon’s signed rank test. B, Normalized hypoxic response to hypoxia was calculated: (VB-treated CSNA/control CSNA) x 100 (%). VB 0.1, 0.5, 5 µM decreased the carotid sinus nerve hypoxic responses to 84.9% ± 4.8%, 78.0% ± 2.9%, and 58.5% ± 10.1%, respectively. *Significantly different from VB 0-µM group (P < 0.05); significantly different from VB 0.1-µM group (P < 0.05). Statistical analysis was performed with one-way analysis of variance followed by Bonferroni’s test.
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Samples of the perfusate were obtained from the three-way stopcock located near the common carotid artery, and PO2, PCO2, and pH were measured. Some materials in the perfusion line were gas permeable and Krebs solution was not anoxic at the entrance of the common carotid artery. The values of PO2, PCO2, and pH in the samples did not significantly vary among experiments. The addition of vecuronium did not change PO2, PCO2, and pH (Table 1).
The carotid sinus nerve responses to ACh and nicotine were tested in 12 preparations before and with vecuronium (Fig. 4). ACh (100 µg) or nicotine (2.5–25 µg) in 0.1 mL of Krebs solution increased the chemoreceptor neural activity, whereas Krebs solution 0.1-mL injection did not change the chemoreceptor activity (data for Krebs not shown).
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Figure 4. Representative carotid body responses to nicotinic agonists with or without vecuronium (VB). Acetylcholine (ACh) and nicotine were tested in different rat carotid bodies. A, A bolus administration of ACh 100 µg increased the carotid sinus nerve activity (CSNA) (left). With VB 0.5 µM, carotid sinus nerve response to ACh was decreased (right). B, The response to bolus administration of nicotine 2.5 µg was inhibited with VB 0.5 µM.
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The mean value of CSNA in response to ACh was 232 ± 43 impulses/s before vecuronium, and it was significantly reduced to 132 ± 39 impulses/s with vecuronium (Fig. 5). Also, vecuronium significantly decreased CSNA in response to nicotine from 230 ± 50 to 188 ± 52 impulses/s.
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Figure 5. The effect of vecuronium (VB) on the carotid body neural responses to acetylcholine (ACh) and nicotine. VB significantly decreased carotid body neural responses to ACh 100 µg (A) (n = 6) and nicotine 2.5–25 µg (B) (n = 6). *P < 0.05 by Wilcoxon’s signed rank test. CSNA = a difference in values of carotid sinus nerve activity between normoxia and hypoxia.
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The carotid body in the in vitro perfusion system maintained constant responses to both hypoxic stimulus and administrations of the nicotinic agents when vecuronium was not used. Neither adaptation nor deterioration of the CSNA was observed for 60 min after the perfusion was initiated, during which time the data collections were completed. The stability of the preparations in which vecuronium was not administered was further examined after the data collection (n = 3). The hypoxic response of those preparations remained stable for 2 to 3 h. However, in the preparations in which vecuronium was administered, the hypoxic response of the carotid body did not recover to the prevecuronium level for 30 to 60 min after termination of vecuronium perfusion.
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Discussion
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We found that vecuronium directly inhibited the hypoxic response of the rat carotid body. Furthermore, our study is the first to report that vecuronium attenuated the carotid body responses to nicotinic agents. These data suggest that the inhibition of neuronal nicotinic receptors in the carotid body is the underlying mechanism of the depressed chemoreceptor response to hypoxia after vecuronium.
Eriksson et al. (2–4) found that partial neuromuscular block by vecuronium, atracurium, and pancuronium impaired the hypoxic ventilatory response in nonanesthetized humans. Further, they measured the output of the phrenic nerve (13) and the carotid sinus nerve (5) in anesthetized rabbits, and found that vecuronium inhibited the hypoxia-induced increases in these nerve activities. Although their data indicate the inhibitory effect of vecuronium on the carotid body, the mechanism of the inhibition was not clear. The inhibitory effect of vecuronium on the carotid body may be exerted indirectly. For instance, the carotid chemoreceptor is influenced by efferent inputs from the carotid sinus nerve and the ganglioglomerular nerve, a branch of the cervical sympathetic ganglion. The effects of vecuronium on the petrosal ganglion, in which the cell bodies of carotid sinus nerve locate, or the cervical sympathetic ganglion could affect carotid chemoreceptor neural output. In addition, vecuronium may reduce the afferent input to the central nervous system from peripheral stretch receptors and muscle spindles, and in turn may change the efferent influence on the carotid body. In our in vitro preparation, the efferent inputs to the carotid body via the central nervous system, the petrosal ganglion, and the sympathetic cervical ganglion were eliminated. Thus, we were able to evaluate the direct effect of vecuronium on the carotid body. Our results were consistent with the data of Eriksson’s group and have clearly demonstrated that vecuronium has a direct inhibitory effect on the response of the carotid body to hypoxia.
Vecuronium inhibited the carotid sinus nerve responses to ACh and nicotine as well (Fig. 4, 5). Much data indicate that ACh works as an excitatory neurotransmitter in the carotid body, although controversy still exists (8). The presence of nicotinic receptors in the carotid body has been first indicated with [125I]-bungarotoxin binding technique (14,15). -Bungarotoxin binds to 1 subunit of muscle type nicotinic receptors and to 7, 8, and 9 subunits of neuronal nicotinic receptors. The carotid body is originated from the neural crest, and therefore the nicotinic receptors distributing in the carotid body are expected to be the neuronal type. Neuronal nicotinic receptor subunits 4 and 7 were localized in the cat carotid body (9,10). The fact that vecuronium inhibited the carotid body responses to ACh and nicotine suggests that the inhibition of neuronal nicotinic receptors in the carotid body is an underlying mechanism for vecuronium-induced depression of the carotid body response to hypoxia.
Neuronal nicotinic receptors differ from nicotinic receptors at the neuromuscular junction (16,17). The structure and function of neuronal nicotinic receptors have been extensively investigated in the last decade, but the effects of muscle relaxants on these receptors have not been well studied. However, a few reports have indicated that some muscle relaxants directly act on neuronal nicotinic receptors. For example, the adrenal chromaffin cells express neuronal nicotinic receptors in which activation triggers the release of catecholamines (18,19). Vecuronium, pancuronium, and d-tubocurarine inhibit catecholamine release from cultured bovine chromaffin cells (7), and the inhibition by vecuronium is 10-fold more potent than that by pancuronium and d-tubocurarine. Garland et al. (20) have shown that pancuronium and d-tubocurarine inhibit current via 4ß2 type neuronal nicotinic receptors. Therefore, vecuronium probably directly inhibits neuronal nicotinic receptors in the carotid body and induces the reduction of hypoxic ventilatory response.
In our preparation, we used 0.1, 0.5, and 5 µM of vecuronium. In all cases, vecuronium decreased the hypoxic response of the rat carotid body. Although the concentration of vecuronium at subparalyzing level (TOF 0.7) in rats is not known, the EC50 value for neuromuscular blockade in the Wister rat phrenic nerve-hemidiaphragm preparation was reported to be 5.19 ± 1.17 µM (3.31 ± 0.75 µg/mL) (12). A similar number was also found in a recent report (21). The EC50 value of vecuronium in the rat seems to be more than that of humans (0.15–0.17 µM; 0.094–0.11 µg/mL) (22,23). The plasma concentrations of vecuronium in humans were 0.11–0.16 µM (0.07–0.1 µg/mL) at 1 hour after a single IV dose (0.1 mg/kg) (23,24) or 1 µM (0.64 µg/mL) at 1 hour after a 0.25 mg/kg IV injection (25). In the latter case, 0.1 µM vecuronium was found even 3 hours after the injection. Therefore, it seems that vecuronium at a dose less than the paralyzing level of the neuromuscular junction can inhibit the hypoxic response of the carotid body. We also observed a poor recovery from the vecuronium-induced inhibition of the carotid body response to hypoxia. Even after 30 minutes washout with Krebs, the inhibitory effect of vecuronium on the carotid body response to hypoxia was not restored. This is not attributable to the deterioration of the preparation. When the carotid body was not exposed to vecuronium, the response to hypoxia was well maintained within this time frame. A similar slow recovery of the chemoreceptor response to hypoxia was observed in whole animal experiments: Wyon et al. (5) showed that the recovery of the carotid sinus neural response to hypoxia occurred 90 minutes after vecuronium administration. Although the mechanism of the slow recovery remained unsolved, the clinical implication may be important. The recovery of skeletal muscle constriction (TOF > 0.7) cannot be used as an indicator of the recovery of the hypoxic ventilatory response.
We conclude that vecuronium depresses the carotid body neural response to hypoxia and nicotinic agonists. The depression of the peripheral chemoreceptor response to hypoxia induced by vecuronium may be attributable to the inhibition of neuronal nicotinic receptors in the carotid body. This study together with previous studies suggest that even a small dose of vecuronium causes the depression of the chemoreceptor response to hypoxia.
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Acknowledgments
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Supported in part by NHLBI 61596 and by the Department of Anesthesiology and Resuscitation, Yamagata University, School of Medicine, Yamagata, Japan.
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References
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Accepted for publication August 28, 2001.
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Abstract
Introduction
