Department of Anaesthesiology and Intensive Care, University Hospital, SE-221 85 Lund, Sweden
Corresponding author. E-mail: mikael.bodelsson@anest.lu.se
Accepted for publication: February 19, 2003
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Abstract |
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Methods. Segments of arteries and veins were exposed to sevoflurane 1%, 2% and 4% (corresponding to approximately 0.5, 1 and 2 MAC in humans, respectively). The vessels were studied in vitro to determine the effects on (i) isometric contraction during electrical field stimulation (EFS) or in the presence of exogenous norepinephrine (NE); (ii) electrical field stimulated release of [3H]-NE from vessel segments previously incubated with [3H]-NE; (iii) uptake of [3H]-NE.
Results. In artery segments, sevoflurane 4% attenuated the contraction induced by both EFS and exogenous NE. In vein segments, sevoflurane 4% attenuated only the EFS-induced contractions. Sevoflurane 1% and 2% had no effect. The release of [3H]-NE was inhibited by sevoflurane 2% and 4% in arteries and by sevoflurane 1%, 2% and 4% in veins. Sevoflurane had no effect on the uptake of [3H]-NE in either vessel.
Conclusions. Sevoflurane depresses sympathetic neuromuscular transmission in human omental vessels by reducing neuronal NE release and NE sensitivity in arteries and by reducing NE release in veins. This could contribute to the hypotension seen during sevoflurane anaesthesia, at least at concentrations above 1 MAC.
Br J Anaesth 2003; 90: 76673
Keywords: anaesthetics volatile, sevoflurane; arteries, omental; nerve, transmission; sympathetic nervous system, norepinephrine; veins, omental
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Introduction |
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In dogs, isoflurane and desflurane depress sympathetic transmission in the stellate ganglion11 and the same has been demonstrated for halothane in guinea pigs.12 In particular, isoflurane, but also halothane and enflurane, reduce the contractile response to endogenous release of NE from sympathetic nerves by electrical field stimulation (EFS).13 As with other inhalation anaesthetic agents, sevoflurane diminishes baroreflex function.14 By measuring the transmembrane potential in vascular smooth muscle cells in situ in rat mesenteric artery and vein, Yamazaki and colleagues4 demonstrated that sevoflurane induces a hyperpolarization, which is attenuated by local sympathetic denervation. They concluded that sevoflurane inhibits both sympathetic neural and non-neural mechanisms involved in regulation of vessel tone. It has not yet been clarified how sevoflurane influences the sympathetic nervous system in the periphery. Furthermore, the effects of sevoflurane on vascular sympathetic activity in man are unknown.
The aim of the present study was to investigate the effects of sevoflurane on the function of perivascular sympathetic nerves in isolated human omental arteries and veins focusing on: (i) smooth muscle contraction in response to EFS and exogenous NE; (ii) electrical field stimulated release of neuronal NE; and (iii) effects on the neuronal reuptake of NE.
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Methods |
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Sevoflurane administration
Sevoflurane was vaporized by calibrated Sigma Elite vaporizers and administered via the carbon dioxide/oxygen mixture aerating the organ baths. The surface of the fluid in the organ baths was open to the atmosphere. The concentration of a gas dissolved in the fluid of such an organ bath depends on the solubility of the gas in the fluid (i.e. the fluidgas partition coefficient) and the partial pressure of the dissolved gas. The latter factor is in turn dependent on the balance between the rate of bubbling of the gas through the organ bath and the rate of evaporation of the gas from the surface of the organ bath into the atmosphere. We found that the use of a gas mixture containing 8% carbon dioxide enabled us to easily adjust the rate of the bubbling to achieve a steady state carbon dioxide partial pressure (PCO2) of 5 kPa in the KRS. This results in a pH value of 7.4 in a solution with the composition used.
Sevoflurane was administered to the organ baths via the gas bubbling mixture. Thus, the constant bubbling rate gave a stable and predictable partial pressure of sevoflurane dissolved in the KRS affected only by the amount of sevoflurane in the carbon dioxide/oxygen mixture. In addition, the sevoflurane concentration was regularly confirmed with gasliquid chromatography.
Gasliquid chromatography
In brief, 1.5 ml KRS was transferred to 4.75 ml gas-tight vials with a gas-tight syringe. After 30 min equilibration at 37 °C, 50 µl headspace gas was injected into a Perkin-Elmer 3920 gasliquid chromatograph.15 In initial experiments, 1 ml equilibrated KRS was transferred to a new 4.75 ml vial and after another 30 min the headspace was analysed. This enabled calculation of the gasKRS partition coefficient, as described by Smith and colleagues.16 The mean gasKRS partition coefficient was 0.38 (SD 0.04; n=23) and was unaffected by the sevoflurane concentration in the range 0.150.75 mM. This gasKRS partition coefficient is similar to the previously reported mean watergas (0.36 [0.01])17 and salinegas (0.37[0.016])18 partition coefficients.
The content of sevoflurane in the carbon dioxide/oxygen mixture was analysed by direct injection into the gasliquid chromatograph and adjusted to achieve a sevoflurane concentration in the KRS of 0.15, 0.30 or 0.60 mM. These concentrations correspond to equilibrated alveolar concentrations of 1%, 2% and 4%, respectively. For the sake of clarity and to make it easier to compare these in vitro concentrations with the in vivo situation, we hereafter express the organ bath concentrations as 1%, 2% or 4%. The minimum alveolar concentration (MAC) for sevoflurane in adults is 1.482.52%.19 The MAC value is age dependent, with lower values for elderly patients. Consequently, the sevoflurane concentrations used in the present study are equivalent to 0.40.7, 0.81.4 and 1.62.7 MAC, respectively. Considering that the mean age of the patients was 68 yr, the concentrations used correspond to MAC levels at the higher end of these ranges. The sevoflurane concentration in KRS reached steady state within 2 min of the start of sevoflurane administration.
Measurement of smooth muscle force
Vessel segments were cut into 24-mm long ring segments and placed into 2-ml tissue baths on two steel rods through the lumen. One of the rods was attached to a Grass FTO3C forcedisplacement transducer for measurement of isometric force. The force was recorded on a Grass polygraph model 7D (Grass Medical Instruments, Quincy, MA, USA). Six segments in separate organ baths were run in parallel. The temperature in the baths was thermostatically maintained at 37 °C and the KRS in the baths was continuously aerated with carbon dioxide/oxygen 8/92% at a rate giving PCO2 5 kPa and pH 7.4. The vessel segments were gradually stretched to a stable resting force of 6 mN during an equilibration period of 6090 min to obtain the optimal tension.20 Then KCl 90 mM was added and the resulting contraction registered. The KCl was then washed out by repeated changes of the KRS, during which the contraction was allowed to return to baseline.
Electrical field stimulation (EFS)
Linear wire platinum electrodes were mounted on each side of the vessel segment with 4 mm between the electrodes.21 The electrodes were connected to a custom-made square-wave stimulator and the wave pattern and the amplitude was continuously monitored with an oscilloscope (Tektronix UK Ltd). Stimulation pulses were 0.1 ms long and 12 V for the artery segments and 8 V for the vein segments;21 30 s pulse trains were used and a 4.5 min resting period allowed between stimulations. One vessel segment treated with the neuronal blocker tetrodotoxin (TTX) 1 µM was always run in parallel to exclude the possibility that the resulting contraction was the result of direct smooth muscle stimulation.
First, EFS was performed at frequencies of 1, 2, 4, 8, 16 and 32 Hz. The resulting vessel contraction was registered and the greatest contraction achieved for each segment (always at 32 Hz) was used as a neurogenic reference response. After this frequencyresponse series, the KRS was changed and the endogenous NE stores were replenished by adding exogenous NE cumulatively in log10 units to achieve organ bath concentrations of 1 nM100 µM.22 After the concentrationresponse series, which took 15 min to complete, the organ baths were washed several times until the tension returned to the baseline level. The segments were then randomized to be treated with sevoflurane 0, 1%, 2% or 4%. After 10 min pre-exposure to sevoflurane, frequencyresponse experiments with EFS were performed as above but in the presence of sevoflurane. The EFS-induced contractions are expressed as percentage of the neurogenic reference response in order to correct for differences in size and neuronal density between the specimens obtained from different patients.
Contraction in response to exogenous norepinephrine
In a second series of experiments performed on separate vessel segments, cocaine 100 µM was added to the organ baths. After 10 min, NE was added cumulatively in log10 units to achieve organ bath concentrations of 1 nM100 µM. The greatest contraction elicited was used as an exogenous NE reference response for each segment. The segments were randomized to be treated with sevoflurane 0, 1%, 2% or 4%.
Following washout, sevoflurane and cocaine were administered and exogenous NE was added cumulatively after 10 min. The resulting contractions are expressed as percentage of the exogenous NE reference response. Cocaine was present during these experiments to prevent any possible influence of the neuronal uptake on the contraction induced by the exogenous NE. We chose not to use the neuronal uptake inhibitor desipramine because of its antagonistic effects on -adrenoceptors.23
Measurement of [3H]-NE release
Artery and vein segments (12 cm in length) from each patient were pre-incubated in aerated KRS (at 37 °C, pH 7.4) with the extraneuronal amine uptake inhibitor normetanephrine 100 µM for 30 min.24 The vessel segments were then incubated with [3H]-NE 0.1 µM and normetanephrine for 40 min. They were rinsed four times over 50 min in KRS containing normetanephrine and the neuronal NE uptake inhibitor desipramine 0.6 µM.23 Each vessel segment was placed in an organ chamber (Ohmeda Comp Adapter Male/Male; volume 190 µl). Six organ chambers were run in parallel and the chambers were connected to a multichannel roller pump (PumpPro MPL Watson-Marlow WPI, Stevenage, UK), which continuously delivered aerated superfusion fluid (KRS with desipramine and normetanephrine) at a rate of 0.325 ml min1. The chambers and the superfusate were thermostatically maintained at 37 °C. EFS was applied via spiral-wire platinum electrodes placed 10 mm apart on each side of the vessel segment. The stimulation pulses were 0.2 ms long and 15 V for both artery and vein segments, which in pilot experiments had been shown to give a submaximal release of [3H]-NE; 30 s pulse trains were used and an 11.5 min resting period was allowed between stimulations. Each segment was stimulated four times. The superfusate was collected as 4-min fractions into scintillation vials. The radioactivity was determined in a liquid scintillation counter after addition of 2.8 ml Optiphase 3 scintillation fluid. The background radioactivity was estimated in vials with 2.8 ml Optiphase 3 added to 1.3 ml KRS.
Experimental protocol
First, all segments were stimulated with EFS at 32 Hz. The resulting release of [3H]-NE was used as a reference for each segment. After randomization, sevoflurane 0, 1%, 2% or 4% or TTX 1 µM was administered to the superfusate and EFS was sequentially delivered at 2, 8 and 32 Hz. The resulting release of [3H]-NE is expressed as percentage of the reference release.
Measurement of [3H]-NE uptake
Artery and vein segments (0.51 cm in length) were mounted on stainless steel wires (0.4 mm cross-sectional diameter) and placed in aerated KRS at 37 °C for 30 min equilibration. They were then randomly exposed to sevoflurane 0, 1%, 2% or 4% or desipramine 0.6 µM during a 15 min pre-incubation period in KRS with normetanephrine 10 µM. The vessel segments were then incubated for 15 min in vials containing identical medium as during the pre-incubation with [3H]-NE 0.1 µM. After incubation, the uptake of [3H]-NE was stopped by placing the vessels in KRS at 4 °C for 5 min. Eventually, the segments were blotted onto filter paper, weighed on a piece of aluminium foil, placed into scintillation vials and hydrolysed in 0.25 ml Optisolve for 120 min at 50 °C; 2.5 ml Optiphase 2 scintillation fluid was then added for determination of the radioactivity taken up into each segment. The background radioactivity was estimated in vials containing 2.5 ml Optiphase 2 added to 0.25 ml Optisolve.
Drugs
The following compounds were used: sevoflurane (Abbott Scandinavia AB, Solna, Sweden), L()-norepinephrine bitartrate (RBI/Sigma, St Louis, MO, USA), L -[2,5,6-3H]-norepinephrine (DuPont NEN, Boston, MA, USA; activity: 2.1 TBq mmol1), tetrodotoxin citrate, desipramine hydrochloride, DL-normetanephrine hydrochloride, disodium- calcium EDTA (all four from Sigma, St Louis, MO, USA) cocaine hydrochloride (Apoteket AB, Kungens Kurva, Sweden), Optisolve and Optiphase 2 and 3 (Wallac, Turku, Finland). All substances were dissolved and/or diluted in distilled water except L()-NE bitartrate and L-[2,5,6-3H]-NE, which was dissolved in NaCl 0.9 g litre1 with EDTA 0.024 mM to minimize oxidation.
Statistical analysis
In experiments of the release and uptake of [3H]-NE, background radioactivity was subtracted before analysis and presentation. Values are expressed as mean (SD). When values from more than one similar experiment were obtained from the same individual, the mean was calculated before further analysis and presentation. Thus, the number of determinations (n) equals the number of individuals. In the preparation of the tables and figures, all available data from similar experiments were pooled. Therefore, n may vary between the groups in the tables and figures. The log10 of the NE concentration required to elicit half-maximum response (pEC50) was determined by linear interpolation based on the concentrationresponse data. Concentration response and frequencyresponse curves, as well as the data from the release experiments, were analysed with respect to the factors concentration/frequency and sevoflurane treatment using two-way repeated-measures ANOVA after logarithmic transformation of the data to correct for inequality of the variances. When appropriate, this was followed by Dunnetts post hoc test comparing the different levels of sevoflurane with control. The uptake of [3H]-NE was analysed with one-way repeated-measures ANOVA, followed by Dunnetts post hoc test. The pEC50 values were compared using Students two-tailed t-test for unpaired data. All statistical calculations were performed using SPSS Sigma Stat Version 2.03 (SPSS Science, Chicago, IL, USA). A P value less than 0.05 was considered statistically significant.
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Results |
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Discussion |
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The action of sevoflurane found in the present study could be mediated via an influence on several mechanisms. The efficiency of EFS to elicit vascular constriction depends on three main factors: (i) the sensitivity of the smooth muscle cells to NE; (ii) the amount of NE released from the vascular sympathetic nerves upon stimulation; (iii) the rate of NE reuptake into the nerves. The balance between release and reuptake of NE determines the level of NE present in the neuromuscular cleft.
In the present study, arterial smooth muscle contraction in response to exogenously added NE was lower in the presence of sevoflurane 4% compared with control. This is consistent with results from previous studies in resistance arteries in rabbit57 and rat,8 9 which have also revealed a weaker contraction in response to NE in the presence of sevoflurane. In rat mesenteric artery the inhibitory effects of sevoflurane on NE contractions seems to be the result of an inhibition of voltage-gated calcium influx and inhibition of the myofilament calcium sensitivity.9 Our results suggest that sevoflurane-induced depression of EFS contraction in arteries is at least in part the result of a decreased NE sensitivity of the smooth muscle cells. However, this mechanism cannot explain sevoflurane-induced depression of the response to EFS in veins because the contraction in response to exogenous NE was not affected by sevoflurane in these vessels.
Differences in adrenergic mechanisms in arteries and veins could explain their different sensitivities of NE-induced contractions to sevoflurane in the present study. A mixture of post-junctional 1- and
2-adrenoceptors mediates smooth muscle contraction in human omental arteries and veins.26 Alpha1-adrenoceptors predominate in the arteries and
2-adrenoceptors in veins. The present results could indicate that
1-adrenoceptor-mediated contraction is more susceptible to the inhibitory action of sevoflurane, but this remains to be confirmed. We found a significantly higher pEC50 value for NE in the veins than in the arteries, as demonstrated previously.26 This could indicate a receptor reserve for NE in the veins.27 A depressant action of sevoflurane on the contractile machinery may well be overcome by the excess contractile stimulus produced by a venous receptor reserve. However, confirming the existence of a venous receptor reserve requires experiments with irreversible adrenoceptor antagonists such as phenoxybenzamine, which were not used in the present study.
The depolarization of a sympathetic nerve opens voltage-dependent calcium channels in the neuronal varicosities, which triggers the exocytosis of transmitter-containing vesicles.28 In order to determine the effect of sevoflurane on this process, we loaded the nerves with radioactive NE and measured the release of radioactivity upon EFS. We found a frequency-dependent release that was depressed by sevoflurane 2% and 4% in the artery segments and sevoflurane 1%, 2% and 4% in the vein segments. This indicates that sevoflurane blocks the depolarization of the nerves and/or the process of NE exocytosis. We have previously reported that propofol has a similar effect.21 Venous sympathetic nerves seem to be more sensitive to sevoflurane than those of the arteries. The exact site of action of sevoflurane in the release process remains to be investigated further and might also elucidate the mechanism of some of the central effects of this anaesthetic.29
Reuptake of NE into sympathetic nerve endings is an active process mediated by a specific transporter protein driven by the simultaneous cellular influx of sodium ions along their concentration gradient.30 31 In the present study we did not find any significant effect of sevoflurane on the uptake of [3H]-NE. This contrasts to the inhibitory action of propofol on neuronal NE uptake in human omental arteries21 and rat femoral arteries.32 Tas and colleagues33 reported profound effects of volatile anaesthetics on neuronal uptake processes but the present results suggest that sevoflurane does not possess such properties, at least not in human omental arteries and veins.
Collectively, in human omental vessels sevoflurane will decrease the concentration of NE in the neuromuscular cleft since it reduces NE release without affecting reuptake. This explains the reduced smooth muscle contraction in response to EFS in veins. Furthermore, depressed NE release could contribute to reduced contractile responses to EFS in arteries, but in these vessels the decreased smooth muscle NE sensitivity also observed seems to be important as well. Significant reductions of NE release were found with sevoflurane 2% and 4% in arteries and sevoflurane 1%, 2% and 4% in veins. However, the reduction had an impact on the EFS-induced contraction only with sevoflurane 4%. The present results do not provide any explanation for this discrepancy. Perhaps reduced NE release is not sufficient to reduce contraction upon EFS and an additional decrease in NE-induced contraction is also required, though not significant for the veins in the present study.
The net effect of sevoflurane anaesthesia on arterial pressure depends on the sum of the simultaneous actions of the anaesthetic on, for example, central cardiovascular regulatory mechanisms, sympathetic neuromuscular transmission, vascular smooth muscle and endothelium, as well as direct actions on myocardial contractility. The present results suggest that a partial impairment of sympathetic neuromuscular transmission in blood vessels could contribute, at least at sevoflurane concentrations above 1 MAC.
In conclusion, we have demonstrated that sevoflurane depresses the sympathetic neuromuscular transmission in human omental vessels by lowering neuronal NE release and the magnitude of the NE-induced contractions in arteries and by lowering NE release in veins.
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Acknowledgements |
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References |
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