Free
Meeting Abstracts  |   May 1996
Dose-dependent Increases in the Renal Sympathetic Nerve Activity during Rapid Increase in Isoflurane Concentration in Intact, Lower Airway-deafferented, and Baroreceptor-deafferented Rabbits
Author Notes
  • Received from the Department of Anesthesiology and Critical Care Medicine, Kyushu University, Fukuoka, Japan. Submitted for publication July 24, 1995. Accepted for publication January 11, 1996.
  • Address for correspondence to Dr. Hoka: Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
  • Address electronic mail to: ehoka@kuaccm.med.kyushu-u.ac.jp.
Article Information
Meeting Abstracts   |   May 1996
Dose-dependent Increases in the Renal Sympathetic Nerve Activity during Rapid Increase in Isoflurane Concentration in Intact, Lower Airway-deafferented, and Baroreceptor-deafferented Rabbits
Anesthesiology 5 1996, Vol.84, 1196-1204. doi:
Anesthesiology 5 1996, Vol.84, 1196-1204. doi:
Key words: Airway stimulation. Anesthetics, volatile: isoflurane. Central nervous system: excitation. Nerve: activity; recording. Reflexes: baroreceptor. Sympathetic nervous system: reflexes.
ISOFLURANE has been reported to increase the heart rate (HR) in animals [1,2] and humans. [3-7] The concomitant increases in plasma norepinephrine and epinephrine concentrations also have been reported, especially when the inhaled concentration of isoflurane is rapidly increased. [3,5,8-10] These findings suggest that isoflurane inhalation during a rapid change of concentration may stimulate the sympathetic nervous system. The origin of this potential stimulation due to the administration of isoflurane could be related to the stimulation of airway sensory afferents, [3-5] the baroreceptor reflex, [11,12] and/or the direct stimulation of the central nervous system. [5] This study was designed to document the presence and the time course of sympathetic activation of isoflurane by direct recordings of nerve outflow to the renal circulation and to dissect potential mechanisms by doing lower airway deafferentation and baroreceptor deafferentation in rabbits.
Methods and Materials
General Procedures
This study was approved by our institutional animal care committee. The experiments were performed on 20 Japanese white rabbits weighing from 2.7 to 3.8 kg. The animals were anesthetized initially with pentobarbital sodium (30 mg *symbol* kg sup -1). alpha-Chloralose (10 mg *symbol* kg sup -1 bolus and 10 mg *symbol* kg sup -1 *symbol* h sup -1) was given intravenously as basal anesthesia. After tracheostomy, the lungs were mechanically ventilated with a Harvard respirator (Mills, MA). A ligation of the trachea above the tracheostomy was performed to rule out the effect of isoflurane on the nasal mucosa, pharynx, and larynx. The arterial blood gases and pH were measured periodically to confirm appropriate ventilation. Body temperature was maintained above the 37 degrees C by a heating pad and a heating lamp. A 16-G double-lumen catheter was placed into the right femoral vein as a route for drug administration. An 18-G catheter was placed into the right femoral artery and connected to a pressure transducer (Uniflow, Baxter, CA) and a carrier amplifier (AP 601G, Nihon Kohden, Tokyo, Japan). HR was determined from the arterial pressure wave with a HR counter (AT 601G, Nihon Kohden).
Nerve Recording
The method for nerve recording has been reported. [13,14] Briefly, the left renal sympathetic nerves were exposed under a microscope, cut distally, and covered with warm mineral oil. The efferent renal sympathetic nerve activity (RSNA) was recorded with a bipolar stainless steel electrode. Impulses were amplified and fed into a oscilloscope (VC-10, Nihon Kohden), which was connected to a nerve spike counter (MET-1100, Nihon Kohden) with a window discriminator set just above the noise level. The spikes were counted and integrated at 2-s intervals. The raw electroneurogram, the output from the spike counter, HR, and arterial pressure, were displayed on a Macintosh-IISi computer (Apple, Cupertino, CA) through an analog-to-digital converter (Mac-Lab, Analog Digital Instruments, Castle Hill, Australia). Changes in RSNA were expressed as %RSNA, which was determined based on changes from the baseline level, designated as 100%.
Denervation
The vagi were exposed and cut through a mid cervical incision. Sinoaortic denervation was performed by making a bilateral section of the aortic nerves, interrupting all nerve fibers between the internal and external carotid artery, and stripping the adjacent adventitia in the region of the carotid sinus. The effectiveness of sinoaortic denervation was confirmed by the absence of a decrease in HR and RSNA after a phenylephrine-induced increase in arterial pressure.
Experimental Protocols
After the completion of surgical procedures, at least 1 h was allowed for the stabilization of hemodynamic variables and RSNA under basal anesthesia of alpha-chloralose. The study was divided into the following three groups.
Group 1. Isoflurane in Intact Rabbits (n = 6). Four concentrations of isoflurane--1%, 2%, 3%, and 4%--were randomly inhaled for 10 min in each animal, and changes in RSNA, HR, and mean arterial pressure (MAP) were examined. At least 1 h was allowed for the washout of isoflurane to be achieved after each change in the inspired concentration.
Group 2. Isoflurane in Baroreceptor-deafferented Rabbits (n = 9). After sinoaortic denervation and vagotomy, 1%, 2%, 3%, and 4% isoflurane were randomly inhaled for 5 min, and changes in RSNA, HR, and MAP were examined. One hour was allowed between each exposure.
Group 3. Isoflurane in Lower Airway-deafferented Rabbits (n = 5). After a bilateral vagotomy, 1%, 2%, 3%, and 4% isoflurane were randomly inhaled for 5 min, and the changes in RSNA, HR, and MAP were examined.
In a preliminary study, we demonstrated that MAP severely declined in the baroreceptor-deafferented rabbits if 4% isoflurane was administered for 10 min, whereas RSNA demonstrated a maximal change within 5 min. Therefore, the exposures to isoflurane in groups 2 and 3 were set for 5 min, rather than 10 min as in group 1. The vaporizer was calibrated over the appropriate range of concentrations using a gas analyzer (5250 RGM Ohmeda, Liberty Corner, NJ), and the ability of the vaporizer to maintain these concentrations over the course of the study was established. The end-tidal concentrations of isoflurane were measured in five rabbits of group 1.
Statistical Analysis
All data were expressed as the mean+/-SEM. Statistical comparisons of the baseline values, those of the maximum changes in %RSNA between different groups of rabbits, and those of the hemodynamic and %RSNA changes in repeated measures were performed with an analysis of variance, and post hoc analyses were performed with unpaired or paired t test followed by Bonferroni's correction. A value of P < 0.05 was considered statistically significant.
Results
(Figure 1) shows the time courses of end-tidal concentrations of isoflurane during 10 min inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations steeply increased for the initial 1-2 min and relatively reached a plateau at 3-5 min after the start of inhalation.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
×
(Table 1) shows the baseline values of HR, MAP, and RSNA in each group. HR in group 1 was significantly lower than that in groups 2 and 3, whereas MAP and RSNA in group 2 were significantly higher than those in groups 1 and 3.
Table 1. The Baseline Values of Heart Rate, Mean Arterial Pressure (MAP), and Renal Sympathetic Nerve Activity (RSNA) in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
Image not available
Table 1. The Baseline Values of Heart Rate, Mean Arterial Pressure (MAP), and Renal Sympathetic Nerve Activity (RSNA) in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
×
(Figure 2) shows the effects of isoflurane on MAP in the three groups. In groups 1 and 3, MAP initially decreased at 1 min, recovered or reached a plateau from 2 to 3 min, then decreased. In group 2, isoflurane decreased MAP, although the decrease during 3% and 4% isoflurane reached a plateau from 2 to 3 min.
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
×
(Figure 3) shows the effects of isoflurane on HR in the three groups. HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2.
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
×
(Figure 4) shows the effects of isoflurane on %RSNA in the three groups. Isoflurane increased %RSNA in a dose-related manner in the three groups within 5 min.
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
×
(Table 2) shows the maximum changes in %RSNA from the baseline values in response to the inhalation of 1%, 2%, 3%, and 4% isoflurane. Isoflurane dose-dependently increased %RSNA in the three groups. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas those in group 2 were significantly less than in groups 1 and 3.
Table 2. The Maximum Changes in the % RSNA from the Baseline Values in Response to 1%, 2%, 3%, and 4% Isoflurane Inhalation in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
Image not available
Table 2. The Maximum Changes in the % RSNA from the Baseline Values in Response to 1%, 2%, 3%, and 4% Isoflurane Inhalation in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
×
(Figure 5) shows the comparisons among maximum changes of MAP, HR, and %RSNA during inhalation of 2% and 4% in three groups. It appeared that the maximum decreases in MAP in group 2 were significantly greater than group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2 were less than those of groups 1 and 3.
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
×
(Figure 6), Figure 7, Figure 8show the representative tracings of responses in MAP and RSNA to 4% isoflurane in each group. In group 1 (Figure 6), RSNA increased gradually, reached a maximum, and gradually declined thereafter, whereas MAP initially decreased, recovered or even exceeded the baseline level, and then gradually but substantially decreased. In group 2 (Figure 7), RSNA increased and MAP began to decrease after the start of inhalation with a small notch. In group 3 (Figure 8), RSNA increased, and MAP slightly decreased, recovered, and substantially decreased thereafter.
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
×
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
×
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
×
Discussion
This study provided three principal findings. First, inhaled isoflurane caused a dose-dependent increase in RSNA in tracheally intubated rabbits. Second, the increase in RSNA was not attenuated in the lower airway-deafferented rabbits. Third, the increase in RSNA was attenuated but remained present in the baroreceptor-deafferented rabbits.
An increase in the sympathetic nerve activity during the inhalation of a high concentration of isoflurane has been postulated by many investigators. [3-5,8-10] An increase in HR often is seen during isoflurane anesthesia. [1-7] The plasma concentrations of norepinephrine and epinephrine have been reported to increase during acute exposure to 5% isoflurane. [3] On the other hand, Ebert and Muzi [15] were unable to demonstrate changes in sympathetic nerve activity directed to the vasculature of human skeletal muscles when isoflurane was increased from 1% to 1.8%, contrasted to a 2.5-fold increase in muscle sympathetic nerve activity during equipotent increases in the inspired desflurane inhalation. However, the same authors reported that a rapid exposure to a 5% inspired concentration of isoflurane caused a brief but substantial increase in muscle sympathetic nerve activity in humans. [16] In this study, we demonstrated using a direct recording of the renal sympathetic nerve that isoflurane-induced sympathetic activation occurred in a dose-dependent manner and reached a maximum of 1.5-, 2.1-, 2.8-, and 3.8-fold during the inhalation of 1%, 2%, 3%, and 4% isoflurane, respectively. These peak effects occurred 4 or 5 min after initiating the isoflurane at a time coincident with a significant decrease in blood pressure and a significant increase in HR. Our results about RSNA changes during 4% isoflurane inhalation in rabbits were similar to those of Ebert and Muzi [16] in terms of the time course and magnitude in which the skeletal sympathetic nerve activity increased with a maximum of 3.5-fold at 3-4 min after advancing the isoflurane vaporizer from 1.2% to 5%.
Regarding the mechanism of sympathoexcitation produced by inhalation of isoflurane, at least three possible causes are considered, including irritation of the airway, the baroreceptor reflex, and direct stimulation of the central nervous system. First, irritation of the airway by isoflurane inhalation may initiate reflex increases in sympathetic nerve activity. Isoflurane is a pungent anesthetic associated with laryngospasm and breath-holding during the induction of anesthesia. [17] We used rabbits with a tracheostomy and ligation of the trachea above the tracheostomy to rule out the effect of isoflurane on the nasal mucosa, pharynx, and larynx. Thus, the receptors of the upper airways were bypassed in this study, however, the receptors of the lower airways would be the site of irritation if the observed sympathoaugmentation is attributable to airway irritation. The vagus nerves supply the respiratory tract from the larynx down to the smallest airways and alveoli. [18] Irritant receptors connected with vagal myelinated nerve fibers and other receptors attached to vagal C-fibers are thought to be activated by mechanical stimuli, the inhalation of various irritant gases, such as cigarette smoke, sulfur dioxide, and ammonia, and other chemical mediators. [19-21] Coleridge et al. [22] showed that high concentrations of halothane, ether, chloroform, or trichloroethylene initially produce an excitation of pulmonary stretch receptors innervated by vagal fibers. Accordingly, a bilateral vagotomy appears to eliminate the conduction of sensory and/or afferent information from nerve receptors in the walls of the lower airways and lungs. [18] Therefore, the finding that the increases in %RSNA after exposure to isoflurane was not attenuated in the lower airway-deafferented rabbits (group 3) compared with the intact rabbits (group 1) suggests that airway stimulation is not the major source of the sympathoexcitation. However, our study could not exclude the possibility of different efferent pathways from the lungs other than those traveling in the vagus nerve as a possible source contributing to responses via lower airway stimulation.
Second, the unloading of baroreceptors in association with a reduction of blood pressure during isoflurane inhalation may result in a baroreflex-induced increase in sympathetic efferent nerve activity. Isoflurane decreases blood pressure by its direct depressant effect on the myocardium [23] and vascular smooth muscle. [24] Isoflurane has been reported to cause a lesser attenuation of baroreflex function than halothane or enflurane. [11,12,25] Thus, the isoflurane-induced increase in RSNA might be attributable to unloading of baroreceptors. To exclude the contribution of the baroreflex, we performed sinoaortic plus vagal deafferentation. The carotid sinus, aortic, and vagal nerves carry the afferent information from the carotid sinus baroreceptors, the aortic baroreceptors, and the cardiopulmonary baroreceptors, respectively. The elimination of the baroreflex was confirmed by a lack of decrease in HR and RSNA in response to an increase in the blood pressure by phenylephrine. Therefore, the finding that the increases in %RSNA regarding exposure to isoflurane were significantly attenuated in the baroreceptor-deafferented rabbits (group 2) compared to the intact rabbits (group 1) thus suggests that the baroreflex plays an important role in sympathoexcitation.
Third, isoflurane may directly stimulate the central nervous system. The finding that the increase in RSNA was observed even in the baroreceptor-deafferented rabbits (group 2) suggests a direct stimulating effect of isoflurane on the central nervous system. Volatile anesthetics, such as cyclopropane, [26] diethyl ether, [27] fluroxene, [28] halothane, [29] have been reported to cause direct central sympathetic excitation, in which inhalation of high concentrations of these anesthetics revealed an increase of cervical sympathetic activity in baroreceptor-denervated and decerebrated cats. The exact site of the sympathoexcitation in the central nervous system remains unclear, but the ventral medulla that regulates the tone of the sympathetic nervous system activity may be a candidate.
The baseline RSNA was significantly higher in group 2 than group 1 (Table 1), suggesting that the afferent input from baroreceptors exerts a tonic inhibition of RSNA. The maximum increases in %RSNA in groups 1 (intact) and 2 (baroreceptor-deafferented) during 4% isoflurane were 285% and 140% (Figure 4and Figure 5and Table 2), whereas the baseline values of RSNA were 72 versus 134 counts/s (Table 1). Accordingly, the maximum counts/second of RSNA in both groups were observed to be at almost equivalent levels. It is suggested that the sympathoexcitation of 4% isoflurane in intact rabbits may arise from the full unloading effects on the baroreceptor reflex plus the direct stimulation of the central nervous system. Figure 4shows that RSNA increases were equivalent in all three groups at 2 min, but baroreceptor-deafferented rabbits (group 2) did not increase further; in contrast, groups 1 and 3 continued to increase their RSNA thereafter. Thus, we can speculate that the early increase in RSNA at either 2 or 3 min after inhalation may be primarily due to central nervous system stimulation, whereas the later augmentation in RSNA may be largely due to the baroreflex.
We measured RSNA as a representative of regional sympathetic outflows. However, there is spatial and temporal differing control of regional sympathetic outflow. [30] It has been reported, for example, that an initial phase of sympathoexcitation in response to hemorrhage was unidirectional in renal, cardiac, liver, splenic, and adrenal sympathetic nerve activity, but a late phase of the changes was different among them. [30] Therefore, the increase of RSNA observed in this study could be considered to reflect qualitatively the overall sympathetic activation, but it should be taken into account that the extent and time course of sympathetic activation might be different among different organs.
In conclusion, this study indicates that inhalation of isoflurane is associated with increases in RSNA in rabbits. This response can be attributed to a baroreceptor reflex mechanism responding to the simultaneous hypotension or direct stimulation of the central nervous system. The response does not appear to be mediated by stimulation of airway receptors that mediate their effects via vagal mechanisms.
REFERENCES
Pagel PS, Kampine JP, Schmeling WT, Warltier DC: Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane, and enflurane in the chronically instrumented dog. ANESTHESIOLOGY 1991; 74:539-51.
Skovsted P, Sapthavichaikul S: The effects of isoflurane on arterial pressure, pulse rate, autonomic nervous activity, and barostatic reflexes. Can J Anaesth 1977; 24:304-14.
Yli-Hankala A, Randell T, Seppala T, Lindgren L: Increases in hemodynamic variables and catecholamine levels after rapid increase in isoflurane concentration. ANESTHESIOLOGY 1993; 78:266-71.
Ishikawa T, Nishino T, Hiraga K: Immediate responses of arterial blood pressure and heart rate to sudden inhalation of high concentrations of isoflurane in normotensive and hypertensive patients. Anesth Analg 1993; 77:1022-5.
Weiskopf RB, Moore MA, Eger EI, Noorani M, McKay L, Chortkoff B, Hart PS, Damask M: Rapid increase in desflurane concentration is associated with greater transient cardiovascular stimulation than with rapid increase in isoflurane concentration in humans. ANESTHESIOLOGY 1994; 80:1035-45.
Stevens WC, Cromwell TH, Halsey MJ, Eger EI, Shakespeare TF, Bahlman SH: The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. ANESTHESIOLOGY 1971; 35:8-16.
Graves CL, McDermott RW, Bidwai A: Cardiovascular effects of isoflurane in surgical patients. ANESTHESIOLOGY 1974; 41:486-89.
Randell T, Seppala T, Lindgren L: Isoflurane in nitrous oxide and oxygen increases plasma concentrations of noradrenaline but attenuates the pressor response to intubation. Acta Anaesthesiol Scand 1991; 35:600-5.
Balasaraswathi K, Glisson SN, El-Etr AA, Mummaneni N: Haemodynamic and catecholamine response to isoflurane anaesthesia in patients undergoing coronary artery surgery. Can J Anaesth 1982; 29:533-8.
Bernard JM, Pinaud M, Macquin-Mavier I, Remi JP, Souron R, Bainvel JV: Impact of surgical stress on the haemodynamic profile of isoflurane-induced hypotension. Acta Anaesthesiol Scand 1988; 32:248-52.
Seagard JL, Elegbe EO, Hopp FA, Bosnjak ZJ, von Colditz JH, Kalbfleisch, Kampine JP: Effects of isoflurane on the baroreceptor reflex. ANESTHESIOLOGY 1983; 59:511-20.
Kotrly KJ, Ebert TJ, Vucins E, Igler FO, Barney JA, Kampine JP: Baroreceptor reflex control of heart rate during isoflurane anesthesia in humans. ANESTHESIOLOGY 1984; 60:173-9.
Okamoto H, Hoka S, Kawasaki T, Sato M, Yoshitake J: Effects of CGRP on baroreflex control of heart rate and renal sympathetic nerve activity in rabbits. Am J Physiol 1992; 263:R874-9.
Okamoto H, Hoka S, Kawasaki T, Okuyama T, Takahashi S: L-arginine attenuates ketamine-induced increase in renal sympathetic nerve activity. ANESTHESIOLOGY 1994; 81:137-46.
Ebert TJ, Muzi M: Sympathetic hyperactivity during desflurane anesthesia in healthy volunteers: A comparison with isoflurane. ANESTHESIOLOGY 1993; 79:444-53.
Ebert TJ, Muzi M: Sympathetic activation with desflurane in humans, Anesthesia and Cardiovascular Disease: Advances in Pharmacology. Volume 31. Edited by Bosnjak ZJ, Kampine JP. San Diego, Academic, 1994, pp 369-78.
Lindgren L, Randell T, Saarnivaara L: Comparison of inhalation induction with isoflurane or halothane in children. Eur J Anaesth 1991; 8:33-7.
Widdicombe JG: Vagal reflexes in the airways, The Airways: Neural Control in Health and Disease. Edited by Kaliner MA, Barnes PJ. New York, Marcel Dekker, 1988, pp 187-202.
Mills JE, Sellick H, Widdicombe JG: Activity of lung irritant receptors in pulmonary microembolism, anaphylaxis and drug-induced bronchoconstrictions. J Physiol (Lond) 1969; 203:337-57.
Sellick H, Widdicombe JG: Stimulation of lung irritant receptors by cigarette smoke, carbon dust, and histamine aerosol. J Appl Physiol 1971; 31:15-9.
Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG: Bradykinin stimulates afferent vagal C-fibers in intrapulmonary airways of dogs. J Appl Physiol 1980; 48:511-7.
Coleridge HM, Coleridge JCG, Luck JC, Norman J: The effect of four volatile anaesthetic agents on the impulse activity of two types of pulmonary receptor. Br J Anaesth 1968; 40:484-92.
Bernard J-M, Wouters PF, Doursout M-F, Florence B, Chelly JE, Merin RG: Effects of sovoflurane and isoflurane on cardiac and coronary dynamics in chronically instrumented dogs. ANESTHESIOLOGY 1990; 72:659-62.
Sprague DH, Yang JC, Ngai SH: Effects of isoflurane and halothane on contractility and the cyclic 3',5'-adenosine monophosphate system in the rat aorta. ANESTHESIOLOGY 1974; 40:162-7.
Takeshima R, Dohi S: Comparison of arterial baroreflex function in humans anesthetized with enflurane or isoflurane. Anesth Analg 1989; 69:284-90.
Price HL, Warden JC, Cooperman LH, Millar RA: Central sympathetic excitation caused by cyclopropane. ANESTHESIOLOGY 1969; 30:426-38.
Skovsted P, Price HL: Central sympathetic excitation caused by diethyl ether. ANESTHESIOLOGY 1970; 32:202-9.
Skovsted P, Price HL: Central sympathetic excitation caused by fluroxene. ANESTHESIOLOGY 1970; 32:210-7.
Millar RA, Biscoe TJ: Postganglionic sympathetic discharge and the effect of inhalation anaesthetics. Br J Anaesth 1966; 38:92-114.
Koyama S, Sawano F, Matsuda Y, Saeki Y, Shibamoto T, Hayashi T Jr, Matsubayashi Y, Kawamoto M: Spatial and temporal differing control of sympathetic activities during hemorrhage. Am J Physiol 1992; 262:R579-85.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
Figure 1. Changes in end-tidal concentrations after the start of inhalation of 1%, 2%, 3%, and 4% isoflurane. The end-tidal concentrations of isoflurane at each inspired concentration caused a steep increase for the initial 2-3 min and then a gradual increase. Values are mean +/-SEM.
×
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
Figure 2. Effects of isoflurane on mean arterial pressure (MAP) in groups 1 (top), 2 (middle), and 3 (bottom). In groups 1 and 3, MAP initially decreased, recovered or reached a plateau, and finally decreased. In group 2, isoflurane decreased MAP in a dose-dependent manner. *P < 0.05 versus before inhalation. Values are mean+/- SEM.
×
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 3. Effects of isoflurane on the heart rate (HR) in groups 1 (top), 2 (middle), and 3 (bottom). HR increased during the inhalation of isoflurane in groups 1 and 3 but decreased in group 2. * P < 0.05 versus before inhalation. Values are mean+/-SEM.
×
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
Figure 4. Effects of isoflurane on changes in renal sympathetic nerve activity (%RSNA) in groups 1 (top), 2 (middle), and 3 (bottom). Isoflurane increased %RSNA in a dose-related manner in all three groups within 5 min. *P < 0.05 versus before inhalation. Values are mean+/-SEM.
×
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
Figure 5. Effects of 2% and 4% isoflurane on the maximum changes in mean arterial pressure (MAP, top), heart rate (HR, middle), and renal sympathetic nerve activity (%RSNA, bottom) in groups 1-3. The maximum changes in MAP in group 1 were not compared with those in groups 2 and 3, because those were largely influenced by the inhalation time. It appears that the maximum decreases in MAP in group 2 were significantly greater than in group 3. HR increased in groups 2 and 3 but decreased in group 2. The maximum increases in %RSNA in group 3 were similar to those in group 1, whereas in group 2, they were less than in groups 1 and 3. *P < 0.05 versus 2% isoflurane. #P < 0.05 versus group 1. &P < 0.05 versus group 2. Values are mean+/-SEM.
×
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
Figure 6. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 10 min in group 1 (an intact rabbit). RSNA began to increase at 1 min after the start of inhalation, reached the maximum at 4 min, and gradually declined thereafter, whereas MAP decreased at 1 min, recovered and even exceeded the baseline level at 3 min, and gradually decreased thereafter.
×
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
Figure 7. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 2 (a baroreceptor-deafferented rabbit). RSNA increased to a maximum at 2 min after initiating the inhalation of isoflurane, and then MAP began to decrease soon after the start of inhalation with a small notch at 2 min.
×
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
Figure 8. Responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to 4% isoflurane for 5 min in group 3 (a lower airway-deafferented rabbit). RSNA increased and reached a maximum at 5 min after isoflurane inhalation was initiated, whereas MAP slightly decreased at 1 min, recovered from 2 to 4 min, and decreased thereafter.
×
Table 1. The Baseline Values of Heart Rate, Mean Arterial Pressure (MAP), and Renal Sympathetic Nerve Activity (RSNA) in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
Image not available
Table 1. The Baseline Values of Heart Rate, Mean Arterial Pressure (MAP), and Renal Sympathetic Nerve Activity (RSNA) in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
×
Table 2. The Maximum Changes in the % RSNA from the Baseline Values in Response to 1%, 2%, 3%, and 4% Isoflurane Inhalation in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
Image not available
Table 2. The Maximum Changes in the % RSNA from the Baseline Values in Response to 1%, 2%, 3%, and 4% Isoflurane Inhalation in Intact Rabbits (G-1), Baroreceptor Deafferented Rabbits (G-2), and Lower-airway Deafferented Rabbits (G-3)
×