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Direct Comparative Effects of Isoflurane and Desflurane on Sympathetic Ganglionic Transmission

Boban, Natasa MD; McCallum, J. Bruce PhD; Schedewie, Heinrich K. MD, PhD; Boban, Mladen MD; Kampine, John P. MD, PhD; Bosnjak, Zeljko J. PhD

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Although the sympathetic ganglion is an important site of peripheral regulation, few studies have examined the effect of anesthetics on synaptic transmission.In the present study we compared the actions of desflurane with those of isoflurane on synaptic transmission and neurotransmitter release in the stellate ganglion. In the electrophysiologic group, 14 stellate ganglia were isolated from adult mongrel dogs after halothane anesthesia, desheathed, and superfused with Krebs' solution. Compound action potentials (CAP) were induced by supramaximal stimulation of the preganglionic T3-ramus at a low frequency of 0.4 Hz and were recorded from the postganglionic ventral ansa subclaviae. Each ganglion was exposed to two levels of anesthetics (equivalent to 1 and 2 minimum alveolar anesthetic concentration [MAC]), followed by an anesthetic-free washout period. While equianesthetic concentrations of isoflurane and desflurane caused essentially equipotent suppression of ganglionic transmission, desflurane was more efficacious than isoflurane, both with respect to the onset of and recovery from the inhibition of synaptic activity. In the electrochemical group, 25 ganglia were exposed to both anesthetics at a high concentration (equivalent to between 1.82 and 1.95 MAC) during maximal and submaximal current stimulations, and the release of actylcholine (ACh) in the superfusate was measured with liquid chromatography. Although desflurane and isoflurane caused a significant depression of CAP, neither anesthetic inhibited the release of ACh in the superfusate at either maximal or submaximal current stimulations. These results indicate that the suppression of ganglionic activity is equipotent for both anesthetics based on equivalent MAC values, but that desflurane is more efficacious than isoflurane with respect to onset and recovery at the higher concentrations of anesthetics. The source of impaired conduction appears to be a reduced sensitivity to neurotransmitter release in the postsynaptic neuron.

(Anesth Analg 1995;80:127-34)

Departments of Anesthesiology and Physiology, The Medical College of Wisconsin, Milwaukee, Wisconsin.

This work was supported by Janssen Pharmaceutica and Anesthesiology Training Grant GM 08377.

Accepted for publication August 26, 1994.

Address correspondence and reprint requests to J. Bruce McCallum, PhD, Medical College of Wisconsin, Anesthesia Research, MEB, 404, Milwaukee, WI 53226.

Desflurane has been proposed as attractive for clinical use because of its advantageous biophysical properties. These are, most notably, low blood solubility [1] and resistance to biodegradation [2,3]. Desflurane and isoflurane are structural analogs, and comparative studies of these two anesthetics have revealed similarities in their cardiovascular and hemodynamic effects [4].

Volatile anesthetics depress sympathetic nervous system activity and reflex control [5-8], which may obscure the direct effects of these anesthetics on visceral organs. Indeed, after pharmacologic blockade of the autonomic nervous system in vivo [9,10], the effects of isoflurane and desflurane on contractility and coronary flow differed from those in autonomically intact animals. Similar results were also observed in isolated hearts [11].

To what degree desflurane may affect sympathetic nervous system activity has not been described. The purpose of the present study was therefore to determine the effects of different concentrations of desflurane on sympathetic ganglionic transmission and neurotransmitter release in order to compare them with the effects of equianesthetic concentrations of isoflurane. Isolated stellate ganglia were chosen as the experimental model because the sympathetic ganglia play a significant role in processing and integrating the information arriving from the central and peripheral nervous systems and controlling the output to the target organs [12-14].

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Methods

After approval by our Animal Care and Use Committee, 39 mongrel dogs of both sexes weighing 20 to 25 kg were anesthetized with halothane. The chest was opened by median sternotomy, and the stellate ganglia were dissected from the prevertebral musculature. The excised ganglia were suspended in ice-cold Krebs' solution and carefully desheathed under an Olympus stereo zoom dissecting microscope in an atraumatic fashion as described previously [13]. The ganglia were allowed to equilibrate for 1 h after desheathing to compensate for the effects of halothane anesthesia and desheathing. Two separate groups of experiments were performed.

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Experimental Groups

Electrophysiologic Group To determine the electrophysiologic effects of anesthetics on ganglionic transmission, 14 ganglia were placed in a specially designed tissue bath consisting of two compartments. In the first compartment, the stellate ganglion body, sympathetic chain and preganglionic T2-T3 thoracic rami were pinned to the silastic rubber floor and superfused with a modified Krebs' solution (in mM: Na+ 137, K+ 4, Mg2+ 0.5, Cl- 134, HCO3 16, glucose 5.5, EDTA 0.05, and Ca2+ 2.5) equilibrated with a 97% O2-3% CO2 mixture of gas at pH 7.4 and 37 degrees C. The efferent ventral ansa subclaviae was tunneled through a separating silastic barrier into the second bath compartment, which contained warm mineral oil. The sympathetic chain and T2-T3 rami were wrapped around bipolar tungsten stimulating electrodes, while the ventral ansa was mounted on bipolar recording electrodes. Monophasic square-wave pulses with amplitude up to 10 mA, stimulus duration up to 1 ms, and a frequency of 0.4 Hz were generated by a constant current nerve stimulator to evoke a compound action potential (CAP) at two times the threshold required to produce maximal response to stimulation. Recording electrodes were connected to a high-input impedance preamplifier and filter amplifier. The CAP was displayed on a digital oscilloscope and recorded/processed with the help of an analog output MacADIOS Trademark IISE Superscope (GW Instruments, Somerville, MA) interfaced with a desktop computer. Each measurement represented the average of 10 consecutive CAP recordings. The magnitude of an averaged CAP was expressed in microvolts (mu V), and the signal conduction time from the stimulation artifact to the peak of each compound action potential was expressed in milliseconds (ms).

To administer anesthetics in the superfusate, liquid desflurane or isoflurane were aspirated anaerobically and injected immediately into a designated hermetically sealed 4-L bottle containing 1 L of oxygenated superfusate solution as previously described [11]. A 200-mL volume of 3% CO2, 97% O2 gas mixture was also injected into each sealed bottle to account for displacement of approximately 200 mL of solution during a 20-min period of ganglionic superfusion. The sealed superfusate was stirred continuously to facilitate equilibration of the anesthetics between the gas and liquid phases, and the superfusate was maintained at 37 degrees C. Isoflurane minimum alveolar anesthetic concentration (MAC) for dogs is 1.28 vol% [15], and the gas/solution partition coefficient in Krebs' solution is 0.55 at 37 degrees C and 1 atm [16]. To obtain a superfusate concentration of isoflurane equivalent to about 1 MAC, 170 micro Liter of liquid isoflurane was injected into the sealed bottle. The dog MAC for desflurane is 7.2 vol% [17], and the solution/gas partition coefficient for desflurane is 0.225 at 37 degrees C and 1 atm [1]. To obtain a superfusate concentration of desflurane equivalent to 1 MAC, 980 micro Liter of liquid desflurane was injected into the sealed bottle. To obtain the high concentrations (approximately 2 MAC), the volumes injected into the sealed bottle were doubled. At each increment of anesthetic administration, an 1-mL sample was collected from the organ bath and put immediately into sealed, 2-mL vials for a head-space analysis of anesthetic concentration by gas chromatography. Concentrations measured were 0.29 +/- 0.01 (low) and 0.54 +/- 0.04 mM (high) for isoflurane, and 0.62 +/- 0.03 (low) and 1.14 +/- 0.04 mM (high) for desflurane. Effective vapor concentrations were calculated as 1.3 and 2.5 vol% for isoflurane and 7.2 and 13.1 vol% for desflurane, which gave effective calculated MAC values of 1.05 and 1.95 for isoflurance and 1.0 and 1.82 for desflurane. Analysis of samples from the organ bath showed that the concentration of each anesthetic did not change during the 20-min period of continuous anesthetic superfusion.

Electrochemical Group To determine the electrochemical effects of anesthetics on ganglionic transmission, 25 ganglia were placed in a different, specially designed, water-jacketed glass tissue bath with a total internal volume of 4.71 cc. Superfusate in 1-mL amounts was exchanged periodically through an injection port from a prewarmed fluid reservoir, and fluid samples were withdrawn through the same port for analysis of acetylcholine (ACh) released in the superfusate. The sympathetic chain and preganglionic T3 thoracic ramus were wrapped around bipolar tungsten stimulating electrodes as before, but the ventral ansa was drawn into a glass micropipette monopolar suction electrode for recording. Neostigmine bromide (5 micro Meter) was added to the Krebs' solution to retard hydrolysis of the ACh. Temperature was monitored with a Type T thermocouple probe, and the superfusate in the chamber was equilibrated with a 97% O2-3% CO2 mixture of gas at pH 7.4 and 37 degrees C. CAP data were calculated as an integral (mV centered dot ms) of the area under the wave after subtracting the electrotonic baseline.

Liquid chromatography (LC) was used to determine the amount of ACh in the superfusate. Detection was performed using a BAS LC-4C electrochemical detector (Bioanalytical Systems, Inc., Lafayette, IN) with a platinum electrode held at +0.5 V versus an Ag/AgCl reference electrode. An immobilized enzyme reactor column supplied by BAS converted the ACh to hydrogen peroxide for oxidation at the detector cell. The circulating mobile phase was aqueous 0.07 M NaClO4 and 0.06 M Tris of pH 8.5 +/- 0.05. Pump pressure was kept between 1100-2000 psi at 1.0 mL/min. Retention time at these flows was approximately 5 min for ACh. Sensitivity for ACh was 39 nA/ng injected, and the minimum detectable amount injected was 0.75 pmol (137 pg). Sample loop size was 0.2 mL, and the chamber volume of the superfusate was 1 mL. At each step in the protocol, one sample was obtained at a resting frequency stimulation of 0.4 Hz for 5 min, followed by a second sample after a higher frequency stimulation of 5 Hz for 5 min. The resting frequency of 0.4 Hz corresponds to the spontaneous firing rate of mammalian sympathetic ganglion cells [18,19]. Preliminary data indicated that maximal release of ACh was achieved at 5 Hz for 5 min. At the end of each study the ganglia were weighed, and the distance between stimulating and recording electrodes was measured. All data were recorded on a strip chart recorder and scored manually against external standardized test injections of 15, 10, and 5 pmol ACh and choline.

Anesthetics were delivered to the tissue chamber using a modified Ohio DM 5000 (Ohmeda, Madison, WI) anesthesia machine, which was equipped with a temperature-controlled vaporizer designed to provide uniform, predictable rates of desflurane vapor administration. Carrier gases were a 97% O2-3% CO2 mixture at a flow of 100 mL/min. End-tidal anesthetic concentrations of desflurane and isoflurane were monitored between the common gas outlet and the tissue chamber, using an infrared anesthetic gas analyzer (Datex Capnomac, Helsinki, Finland), until effective vapor concentrations were reached, at which point the gas flow as redirected to the tissue chamber. Only the high concentrations of approximately 2 MAC were delivered to the ganglia since the purpose of this part the study was to determine the maximum effect of the anesthetics on neurotransmitter release. Fluid samples taken from the tissue bath for analysis by gas chromatography were replaced with equivalent volumes from a fluid reservoir preequilibrated for 30 min with the same anesthetic concentrations. Isoflurane concentrations were 0.54 +/- 0.03 mM in the tissue bath and the fluid reservoir, while concentrations for desflurane were measured at 1.13 +/- 0.02 mM in the tissue bath and 1.54 +/- 0.01 mM in the fluid reservoir. Effective vapor concentrations in the tissue bath were calculated as 2.5 vol% for isoflurane and 13.1 vol% for desflurane, which gave the calculated MAC values of 1.95 for isoflurane and 1.82 for desflurane.

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Protocol and Statistical Analysis

Electrophysiologic Group After stabilization of the CAP, each of the 14 stellate ganglia was exposed both to isoflurane and to desflurane in random order. One group of ganglia (n = 6) was exposed to the anesthetics for 10 min with 15-min anesthetic-free control periods between anesthetics. The second group (n = 8) was exposed to the anesthetics for 20-min followed by anesthetic-free control periods (up to 30 min) that allowed maximal recovery of CAP. The CAP amplitude was determined every 5 min. At the conclusion of every experiment, stellate ganglia were exposed to hexamethonium chloride (25 mM) to verify the synaptic nature of the CAP.

Electrochemical Group The 25 ganglia were allowed to equilibrate for 1-2 h after a CAP was evoked until a steady state was achieved (< 5% change in evoked potential). Two groups of experiments were performed. In one group, 15 ganglia were exposed to a supramaximal stimulation current as determined by the peak response in CAP to stimulus. Within this group, eight ganglia received desflurane and seven received isoflurane. In another group, 10 ganglia underwent submaximal stimulation defined as <50% of the current which produced the maximum response to stimulation. Within this group, six received desflurane and six received isoflurane. Two ganglia from this group were exposed to both anesthetics to eliminate differences between ganglia. The ganglia were allowed to equilibrate for 15 min in the presence of the anesthetic before the initiation of measurements. Fluid samples for LC analysis were drawn after a 5-min stimulation and injected immediately into the chromatograph. At the end of each submaximum stimulation experiment, a final sample was taken for analysis by LC during maximum stimulation to verify the current-dependent nature of ACh release.

All data are expressed as means +/- SEM. Statistical differences for values obtained over the time course were determined by two-way analysis for variance with repeated measures. Mean values were considered significantly different at P < 0.05.

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Results

Electric stimulation of the T3 ramus produced a complex wave form with three components Figure 1. The first component was a short latency, nonsynaptic spike representing the activity of preganglionic axons extending across the stellate ganglion. These fibers were not blocked by the administration of hexamethonium at the end of the study. The second component was a spike potential with a single peak lasting approximately 10-15 ms. This second spike represents the summation of all axonal action potentials arising from the responsive ganglion cells at the tip of the recording electrode. Excitation of these cells was blocked by the administration of hexamethonium at the end of the study. The third component consists of the late negative portion of the synaptic potential. Since the focus of this study was the effect of anesthetics on the fast-acting nicotinic action potential, only the second synaptic response was examined. The amplitude of the potential was measured from the electrical baseline to the peak height, while the area under the peak was measured from the lowest value at the first nonsynaptic spike to the point where the after-potential crossed the electrical baseline in a negative direction after the second spike.

Figure 1

Figure 1

In the electrophysiologic group, in an initial group of six ganglia, isoflurane and desflurane had indistinguishable effects on all observed variables of ganglionic transmission when given equianesthetic concentrations for up to 10 min Figure 2. At the lower anesthetic level isoflurane and desflurane equally decreased CAP (22% and 23%, respectively), and this equal suppression was also observed at higher doses (48% and 49%, respectively). Desflurane and isoflurane at both anesthetic levels did not affect the nonsynaptic CAP or the conduction velocity of synaptic transmission.

Figure 2

Figure 2

However, when the duration of anesthetic exposure was doubled, and when washout periods of up to 30 min were allowed for maximum recovery of CAP, isoflurane and desflurane caused a dose-dependent decrease of the synaptic CAP Figure 3. At the lower anesthetic concentration, synaptic CAP decreased equally for both drugs, and the rate of recovery was also similar Figure 3A. At the higher anesthetic concentration, however, exposure to desflurane resulted in a greater decrease of the synaptic CAP than that caused by an equianesthetic dose of isoflurane Figure 3B. During the washout period after exposure to desflurane, the synaptic CAP recovered significantly faster to the control levels than after exposure to isoflurane Figure 3B. Desflurane and isoflurane at both anesthetic levels did not affect the nonsynaptic CAP amplitude Table 1, Figure 1 or the conduction velocity of synaptic or nonsynaptic signal transmission Table 2, Figure 1.

Figure 3

Figure 3

Table 1

Table 1

Table 2

Table 2

In the electrochemical group, stellate ganglia maintained at a resting frequency of 0.4 Hz remained stable throughout the study, as shown by the return to basal evoked potentials in all studies. Small amounts of ACh were released at this resting frequency. Table 3 depicts the amount of ACh released as a function of frequency stimulation before, during, and after anesthetic administration. No differences were observed between the amounts of neurotransmitter released during low-frequency stimulations (0.4 Hz, 5 min) despite the increase in current. However, the amount of neurotransmitter released during the high-frequency stimulations (5 Hz, 5 min) did increase between submaximum and maximum stimulation currents. Therefore, the amount of ACh released at low frequencies was subtracted from the amount released during high frequencies. The net difference represents the rate of dispersion of neurotransmitter during high-frequency stimulations. The dispersion rate at high frequencies was used to evaluate the effect of anesthetics. The wet weight of the ganglia ranged from 62 +/- 5 mg for the high-current isoflurane group to 70 +/- 8 mg for the low-current desflurane group. The amounts of neurotransmitter released in picograms of ACh/mg tissue weight at both maximum and submaximum current stimuli are depicted in Table 3.

Table 3

Table 3

(Figure 4) compares the effect of desflurane on CAP and ACh release during maximum stimulation versus the effect during submaximum stimulation. The high dose of desflurane suppressed CAP irrespective of the current used to evoke the potential response. At the high concentration, almost no electrical activity could be observed. However, the amount of neurotransmitter released remained essentially unchanged during desflurane administration for both high- and low-current stimuli. Maximum current applied at the end of the submaximum current studies evoked a significant increase in both CAP and ACh release.

Figure 4

Figure 4

The effect of isoflurane was similar to desflurane. Figure 5 compares the effect of isoflurane on CAP and ACh release during maximum and submaximum stimuli. The high dose of isoflurane inhibited the evoked potential response to maximum and submaximum stimuli. However, neurotransmitter release in response to maximum and submaximum stimuli did not change during isoflurane administration. At the end of studies with submaximum stimulation, a maximum stimulation produced a significant increase in ACh release and CAP.

Figure 5

Figure 5

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Discussion

The principal finding of our study is that desflurane and isoflurane produce an equipotent, dose-dependent depression of synaptic ganglionic transmission in the isolated stellate ganglion, but that desflurane is significantly more efficacious at higher doses than isoflurane, both in onset and recovery. Potency in this case refers to the time-independent effects of the anesthetics, while efficacy signifies the time-dependent effects [20]. When ganglia were exposed to equianesthetic concentrations of volatile anesthetics for 10 min, no differences were observed between isoflurane and desflurane. However, when the ganglia were exposed to the same concentrations for 20 min, the higher concentration of desflurane achieved significantly more suppression of synaptic activity than isoflurane in a shorter period of time and recovered more quickly. This finding suggests that the duration of exposure is the most significant factor in differentiating the effects of isoflurane and desflurane on ganglionic transmission. Furthermore, although depression of synaptic transmission is common to other currently used volatile anesthetics [5,7,8], the exact mechanism of action underlying these effects still remains unclear. Despite the decrease in synaptic transmission during isoflurane and desflurane administration, no corresponding decrease in neurotransmitter release was observed at either maximum or submaximum current stimulations. This finding suggests that these anesthetics alter the sensitivity of the postjunctional neuron. Finally, while effectively depressant on synaptic ganglionic transmission, the concentrations of desflurane and isoflurane used in this study did not alter the nonsynaptic CAP and did not interfere with the conduction of nerve impulses along nerve fibers. This finding indicates that synaptic transmission through sympathetic ganglia is much more sensitive to general anesthetics than conduction of impulses along nerve fibers.

The most notable difference between desflurane and isoflurane in this study was that after exposure to the higher dose of desflurane, recovery of the synaptic CAP during the washout period was faster than after exposure to the corresponding dose of isoflurane. This finding is expected, because it has been shown that desflurane solubility in different tissues is significantly lower than that of other volatile anesthetics [21]. Similarly, studies in vivo have shown that rates of elimination of desflurane from rabbit brain were significantly faster than those of isoflurane and halothane [21]. In human clinical studies, after discontinuation of the volatile anesthetics, patients receiving desflurane react to standard stimuli in about half the time required by those receiving isoflurane [22,23].

The amount of ACh recovered using LC techniques ranged from 25.6 pg centered dot mg-1 centered dot min-1 during maximum current stimulation at 5 Hz down to 6.2 pg centered dot mg-1 centered dot min-1 during submaximum stimulation at 5 Hz. This compares favorably with the amounts detected in studies using radiolabelled techniques [24,25]. Perhaps the sensitivity of LC accounts for the higher levels of ACh at submaximum stimulation during anesthetic administration observed in this study compared to earlier studies of the effect of anesthetics on ACh release [26]. However, the focus of this study was primarily on the effect of anesthetics during high-frequency stimulation. Most nerve transmission in the sympathetic ganglion is achieved by the action of ACh on fast nicotinic receptors on the postganglionic neuron. The release of ACh requires the influx of extracellular calcium into presynaptic endings [27,28]. Electrical stimulation transiently increases the influx of calcium, which facilitates the release of ACh [29]. Continuous trains of electrical stimulations may consequently mask the preganglionic inhibition of neurotransmitter release through slower acting muscarinic receptors during submaximum stimulations. Several studies have indicated the presence of preganglionic muscarinic receptors which function as a negative feedback loop for the release of ACh [30]. Future study of the effect of anesthetics on preganglionic release of ACh may require intracellular recordings or patch clamp techniques [31].

Although the results of this study show that differences between desflurane and isoflurane action on the isolated stellate ganglion are not dramatic, they may be important in attenuating the effects of these drugs on the cardiovascular system in vivo. The stellate ganglion integrates and controls neural output to target organs, not only from the central nervous system, but is also independently involved in a peripheral reflex that may act to increase sympathetic efferent discharge or to prevent a decrease in sympathetic efferent activity [13]. The role of sympathetic ganglia in the control of reflex responses requires further observation in anesthetic administration and recovery. For example, the sympathetic ganglia could attenuate the reflex increase in sympathetic nerve activity in response to the hypotension associated with higher doses of desflurane [31]. Moreover, the large reservoirs of unbound ACh observed in the synaptic cleft in this study may represent an inhibition of the reuptake mechanism. Presumably, postsynaptic receptors could become hypersensitized to residual amounts of ACh after the cessation of anesthetic administration. Extrapolation of these results to in vivo conditions should be done with caution, however, because of the limitations of the preparation. Although our results suggest that comparison of isoflurane and desflurane in vitro on a MAC basis is reasonable, their direct effects in isolated tissue still may not be proportional to their anesthesia effects in vivo.

In summary, our study indicates that desflurane and isoflurane at the given concentrations cause an equipotent, dose-dependent depression of synaptic ganglionic transmission in the isolated stellate ganglion. However, after adequate length of exposure and concentration, desflurane produces a more efficacious depression of synaptic CAP and a faster recovery during anesthetic washout than equianesthetic concentrations of isoflurane. Overall, the described effects of desflurane and isoflurane are compatible with the effects of these two anesthetics on cardiovascular responses in vivo.

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