Anesth Analg 2003;96:125-131
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Effects of Volatile Anesthetics on Nonadrenergic, Noncholinergic Depressor Responses in Rats
Daisuke Yoshikawa, MD*,
Masataka Kuroda, MD*,
Hiroshi Tsukagoshi, MD
,
Ken-ichiro Takahashi, MD*,
Shigeru Saito, MD*,
Koichi Nishikawa, MD*, and
Fumio Goto, MD*
*Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, Maebashi, Japan; and Department of Anesthesiology, Kameda General Hospital, Kamogawa, Japan
Address correspondence and reprint requests to Daisuke Yoshikawa, MD, Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Address e-mail to yosikawa{at}med.gunma-u.ac.jp
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Abstract
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The effects of volatile anesthetics on nonadrenergic, noncholinergic (NANC) transmission mediated by calcitonin gene-related peptide (CGRP) are unclear. We studied the effects of isoflurane, halothane, and sevoflurane on NANC depressor responses to electrical spinal cord stimulation in pithed rats whose mean arterial blood pressure was maintained near 120 mm Hg by continuous infusion of methoxamine. Autonomic outflow was blocked by hexamethonium. After 30 min of inhalation of different concentrations of anesthetics, spinal cord stimulation at the lower thoracic level (10 V at 4 Hz; duration, 1 ms) was applied for 30 s to induce a NANC depressor response. Isoflurane at 2% and halothane at 1.5% attenuated NANC depressor responses significantly, whereas isoflurane at 1%, halothane at 0.75%, and sevoflurane at 2% or 4% did not. Volatile anesthetics did not attenuate the release of CGRP after spinal cord stimulation, whereas isoflurane at 2% and halothane at 1.5% significantly inhibited depressor responses to exogenously administered CGRP. Sevoflurane at 4% did not significantly affect CGRP-induced depressor responses. Thus, isoflurane and halothane at large concentrations attenuate NANC depressor responses by attenuating the depressor action of CGRP, not CGRP release.
IMPLICATIONS: The anesthetics isoflurane and halothane attenuate nonadrenergic, noncholinergic depressor responses mediated by calcitonin gene-related peptide in the rat without affecting the release of the peptide.
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Introduction
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Smooth muscle tone in peripheral blood vessels is maintained primarily by sympathetic adrenergic nerves via release of the neurotransmitter noradrenaline. However, nonadrenergic nerves innervate regional vascular beds, and nonadrenergic vasodilation has been observed in various species (1). Perivascular nerve stimulation in vitro causes neurogenic vasodilation in the perfused rat mesenteric vascular bed; this effect is mediated by nonadrenergic, noncholinergic (NANC) nerves (2), which exert cardiovascular actions by releasing neuropeptides stored in their terminals (3,4).
Primary afferent neurons, originating from the dorsal root ganglia, provide a perivascular network of fibers surrounding the arterial system throughout the body. Stimulation of these fibers causes NANC vasodilation via the release of calcitonin gene-related peptide (CGRP) (3,4). CGRP, a 37-amino acid peptide translated from the calcitonin gene (5), is a potent vasodilator (6,7) that is distributed widely in perivascular nerves throughout the vascular system (8,9). The distribution and vascular activity of CGRP suggest that this peptide is an important endogenous neurotransmitter for neural regulation of the cardiovascular system.
Kawasaki et al. (2) reported that mesenteric resistance blood vessels are innervated by NANC vasodilator nerves and that vascular tone is controlled not only by sympathetic adrenergic nerves, but also by NANC vasodilator nerves. Taguchi et al. (10) have reported an in vivo model of the NANC depressor response. In this model, a NANC depressor response is induced by electrical stimulation of the spinal cord in the pithed rat. These authors found that spinal cord stimulation causes NANC vasodilation mediated by endogenous CGRP.
Whether volatile anesthetics affect CGRP-mediated NANC depressor response is uncertain. Because in vitro studies do not provide information on the integrated response of blood vessels under normal physiologic conditions in vivo, this study in pithed rats was designed to investigate the effects of volatile anesthetics on this response and to clarify underlying mechanisms.
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Methods
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All surgical procedures and experimental protocols were approved by the Gunma University Institutional Animal Care and Use Committee. Male Wistar rats (300–340 g) were anesthetized with 4% isoflurane in oxygen. The animals were ventilated artificially by using a Harvard respirator (Harvard Apparatus, South Natick, MA) via a tracheal cannula at a rate of 50–60 breaths/min with a stroke volume of 1 mL/100 g body weight. Rate was adjusted to maintain arterial PaCO2 at 35–40 mm Hg. The mean arterial blood pressure (MAP) was recorded with a Gould (Cleveland, OH) pressure transducer connected to the left carotid artery via a cannula (PE-50) containing heparinized saline. The output from the pressure transducer was displayed on a chart recorder (Nihon Koden, Tokyo, Japan). The carotid arteries were ligated, and both vagus nerves were severed in the neck. The rats were pithed by inserting a stainless steel rod (diameter, 1.5 mm) through the right orbit and foramen magnum down the spinal canal to its sacral terminus (11). This procedure destroys the entire central nervous system but leaves emerging nerve trunks intact. The tip of the rod then was withdrawn to the level of the lower thoracic vertebrae (T10/T11). Isoflurane anesthesia was discontinued immediately after pithing. Both jugular veins were cannulated with polyethylene tubing (PE-50) for the administration of hexamethonium and methoxamine. A 24-gauge Teflon cannula (Angiocath; Desert Medical, Sandy, UT) was placed in the tail vein for the administration of CGRP. Body temperature was maintained between 36°C to 37°C by using a heated blanket placed beneath the animal and controlled by a rectal thermistor probe (CMA/150; Stockholm, Sweden).
Rats were allowed to stabilize for 30 min before any experimental intervention. Mean blood pressure was then increased and maintained at a level of approximately 120 mm Hg by continuous in-fusion of the 
1-adrenoceptor agonist methoxa-mine (4–10 µg · kg-1 · min-1). Hexamethonium (2 mg · kg-1 · min-1) also was infused to block autonomic outflow. To prevent skeletal muscle contraction, d-tubocurarine was injected (1 mg/kg).
The pithing rod was insulated except for 1 cm at the tip and served as the stimulating electrode. The level of spinal cord stimulation was determined by varying the insertion depth of the rod. The position of the rod within the vertebral canal was verified by radiography in some rats and was determined on the basis of the length of the rod. A second stainless-steel rod was inserted under the skin of the back, parallel to the vertebral column, to serve as an indifferent electrode. In a preliminary experiment, depressor responses to spinal cord stimulation were shown to be dependent on voltage, frequency, and pulse duration of the stimulus. Higher voltages (25–50 V) and pulse duration (2–8 ms) caused twitching of skeletal muscles despite the presence of d-tubocurarine. The depressor response induced by 10 Hz was smaller than responses induced by 4 and 6 Hz. Thus, the optimum frequency, voltage, and pulse duration were 4–6 Hz, 10 V, and 1 ms, respectively.
One hour after pithing, electrical stimulation was applied to induce a NANC depressor response. Rectangular pulses were given over a total interval of 30 s (10 V at 4 Hz; duration, 1 ms) with an elec-tronic stimulator (SEN 3301; Nihon Koden). After recording of the baseline NANC depressor response, continuous infusion of human CGRP (8-37) (60 nmol · kg-1 · min-1) was started. In a preliminary experiment, CGRP(1 µg/kg IV) caused hypotension to the same extent as the electrical stimulation. Human CGRP (8-37) (60 nmol · kg-1 · min-1) blocked this response almost completely. The second electrical stimulation was applied to induce an NANC depressor response during continuous infusion of human CGRP (8-37).
One hour after pithing, electrical stimulation was applied to induce a NANC depressor response. Rectangular pulses were given over a total interval of 30 s (10 V at 4 Hz; duration, 1 ms). After recording of the baseline NANC depressor response, rats were assigned randomly to experimental groups (n = 6 each) or a control group (n = 6). In the experimental groups, a volatile anesthetic (1% isoflurane, 2% isoflurane, 2% sevoflurane, 4% sevoflurane, 0.75% halothane, or 1.5% halothane) was administered for 30 min. Concentrations of inspired anesthetics were measured continuously by a well calibrated gas monitor (Capnomac Ultima; Datex, Helsinki, Finland). In the control group, no volatile anesthetic was administered. Each rat in the experimental groups was given only one concentration of anesthetic. After 30 min of anesthetic inhalation, the NANC depressor response was reinduced and recorded. Then the administration of the volatile anesthetic was discontinued; NANC depressor responses were induced every 30 min to observe the recovery of responses after discontinuation of anesthetics.
As for the above experiment, MAP was maintained at 120 mm Hg by continuous infusion of methoxamine. Hexamethonium also was infused, to block autonomic outflow. To prevent skeletal muscle contraction, d-tubocurarine was injected. Rats were randomly assigned to the experimental groups (n = 6 each), the control group (n = 6), or an unstimulated sham group (n = 6). One hour after pithing, a volatile anesthetic (2% isoflurane, 4% sevoflurane, or 1.5% halothane) was administered for 30 min in the experimental groups. In the control and sham groups, no volatile anesthetic was administered. The NANC depressor response was induced by electrical stimulation (10 V at 4 Hz; duration, 1 ms) over a total interval of 30 s. In the sham group, no electrical stimulation was applied. Thirty seconds after termination of electrical stimulation, blood samples (2 mL) were collected from the carotid arterial catheter into polypropylene test tubes containing EDTA (1 mg/mL blood) and aprotinin (Trasylol, 500 kallikrein-inhibiting units per milliliter of blood; Bayer, West Haven, CT). Plasma was separated from blood by centrifugation (3000 rpm, 4°C, 20 min) and stored frozen in another polypropylene tube at -80°C until purification and analysis for the CGRP assay.
A radioimmunoassay (RIA) kit (Peninsula Laboratories, Belmont, CA) was used for the CGRP assay. Extraction of plasma samples was performed according to the general protocol for this RIA kit. Briefly, plasma samples were acidified by adding 2 mL of 1% trifluoroacetic acid (TFA) and centrifuged (12,000g, 4°C, 20 min). The supernatant fractions were applied to columns (SEP Columns; Waters Corp., Milford, MA). After the columns were washed with 1% TFA, plasma CGRP was eluted from the columns by using 60% acetonitrile in 1% TFA. The eluate was collected, lyophilized, and redissolved in RIA buffer.
CGRP standard and extracted samples (100 µL) were incubated for 24 h at 4°C with 100 µL of anti-CGRP antibody (rabbit anti-CGRP serum). Then, 100 µL of 125I-labeled CGRP in RIA buffer was added and incubated for 20 h at 4°C; next, 100 µL of goat anti-rabbit immunoglobulin G and 100 µL of normal rabbit serum were added and incubated for 90 min at room temperature. An additional 0.5 mL of RIA buffer was added, and samples were centrifuged (1700g, 4°C) for 20 min. After removal of the supernatant, 
radioactivity in the RIA test tube was measured. A 50% displacement point on the displacement curve corresponded to a 30 to 40 pg per tube CGRP standard.
Thirty minutes after pithing, the MAP of pithed rats was increased to 120 mm Hg with continuous infusion of methoxamine. Hexamethonium was infused to block autonomic outflow. Rats were assigned randomly to experimental groups (n = 6 each) or a control group (n = 6). One hour after pithing, a volatile anesthetic (2% isoflurane, 4% sevoflurane, or 1.5% halothane) was administered for 30 min in the experimental groups; in the control group, no volatile anesthetic was administered. During the inhalation of anesthetics, MAP was maintained near 120 mm Hg by continuous infusion of methoxamine. CGRP (0.1, 0.3, 1.0, 3.0, and 10 µg/kg) was administered IV for 30 s in increasing doses in 0.1 mL of saline. Injection of saline vehicle alone showed no effect. These experiments were performed in paired animals (one control, one experimental). The same dose of CGRP was injected in both control and experimental animals at essentially the same time point.
NANC depressor responses in each group were assessed by using an analysis of variance for repeated measures. When differences were significant, multiple intragroup comparisons were performed with the Scheffé test. Plasma concentrations of CGRP and the methoxamine administration rate were analyzed with analysis of variance. When differences were significant, multiple intergroup comparisons were performed with the Scheffé test. Data concerning blood pressure changes induced by exogenously administered CGRP were analyzed with a Student’s t-test. A P value <0.05 was considered to indicate significance.
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Results
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As shown in Figure 1, spinal cord stimulation caused a prolonged depression in MAP without changes in heart rate (HR). Continuous infusion of human CGRP (8-37) (60 nmol · kg-1 · min-1), a specific CGRP receptor antagonist, completely inhibited the depressor response to spinal cord stimulation (10 V, 4 Hz, 1 ms).
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Figure 1. Typical recording of a NANC depressor response induced by spinal cord stimulation in a pithed rat. Triangles indicate spinal cord stimulation. Electrical stimulation (4 Hz, 10 V, 1-ms duration) produced a NANC depressor response. No change in HR was seen. A CGRP-1 receptor antagonist, CGRP (8-37), completely inhibited this response. NANC = nonadrenergic, noncholinergic; CGRP = calcitonin gene-related peptide; BP = blood pressure; HR = heart rate; C6 = hexamethonium.
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MAP and HR of the pithed rats were 55 ± 3.6 mm Hg and 325 ± 15 bpm, respectively. MAP was increased to 123 ± 6.3 mm Hg by continuous infusion of methoxamine. Because inhalation of volatile anesthetics decreased MAP, the infusion rate of methoxamine was increased to maintain MAP near 120 mm Hg. MAP and methoxamine infusion rates just before the induction of each NANC depressor response are shown in Table 1. MAP did not differ between groups. In the 2% isoflurane group, the infusion rate of methoxamine at 30 min was significantly faster than in the control group (P = 0.020). Although infusion rates of methoxamine in other anesthetic groups at 30 min were faster than in the control group, these differences did not attain significance. Inhalation of 2% isoflurane and 1.5% halothane for 30 min significantly attenuated the NANC depressor response (Fig. 2). The attenuation was still evident in the 2% isoflurane group 30 min after discontinuation of the anesthetic (i.e., 60 min after anesthetic initiation). Inhalation of 1% isoflurane (P = 0.101), 2% sevoflurane (P = 0.603), 4% sevoflurane (P = 0.111), and 0.75% halothane (P = 0.697) did not show a significant effect on the NANC depressor response. After discontinuation of anesthetics, the NANC depressor response gradually increased and recovered to the baseline response 60 min after discontinuation of anesthetics (i.e., 90 min after anesthetic initiation).
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Table 1. Mean Arterial Blood Pressure (MAP) Just Before Electrical Stimulation and Methoxamine Administration Rate
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Figure 2. Effect of volatile anesthetics on NANC depressor responses. Columns indicate changes in mean arterial blood pressure after spinal cord stimulation at various time points. The magnitude of NANC depressor responses was not altered after repeated stimulation in the control group (A). In the volatile anesthetic groups, after the baseline response was measured at 0 min, anesthetics were administered from 0 to 30 min. Isoflurane 2% (B) and halothane 1.5% (D) attenuated the NANC depressor response significantly compared with each baseline response. The response recovered to the baseline level 30 to 60 min after discontinuation of anesthetics. **P < 0.01 vs 0 min; *P < 0.05 vs 0 min. Data are mean ± SD; n = 6. NANC = nonadrenergic, noncholinergic.
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As shown in Figure 3, plasma CGRP in the sham group was 28.3 ± 7.5 pg/mL. In the control group, electrical stimulation increased plasma CGRP to 68.5 ± 11.3 pg/mL. Plasma CGRP after electrical stimulation in anesthetic groups was 54.8 ± 12.4 pg/mL, 60.7 ± 13.8 pg/mL, and 62.9 ± 14.0 pg/mL in the 2% isoflurane, 4% sevoflurane, and 1.5% halothane groups, respectively. Thus, volatile anesthetics did not significantly attenuate CGRP release.
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Figure 3. Effects of volatile anesthetics on the release of CGRP after spinal cord stimulation. In the sham group, no spinal cord stimulation was applied. In the control group, no volatile anesthetic was administered. In the anesthetic groups, spinal cord stimulation was applied after 30 min of inhalation of each anesthetic. Data are mean ± SD (n = 6). Cont = control group; Iso 2% = isoflurane 2%; Sev 4% = sevoflurane 4%; Hal 1.5% = halothane 1.5%; CGRP = calcitonin gene-related peptide.
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Slow IV infusion of CGRP for 30 s produced a transient pressor response followed by persistent hypotension. The maximal CGRP-induced increase and the decrease in MAP from the preadministration value are shown in Figure 4. Halothane (1.5%) and sevoflurane (4%) inhibited the increase in MAP significantly. Although isoflurane at 2% tended to attenuate the increase in MAP, significance was not attained. Isoflurane (2%) and halothane (1.5%) significantly attenuated CGRP-induced depressor responses.
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Figure 4. Effect of volatile anesthetics on changes of mean arterial blood pressure (MAP) in response to exogenously administered CGRP. Upper panel, increase in MAP; lower panel, decrease in MAP. Open column, no anesthetic; closed columns, volatile anesthetics. **P < 0.01 versus no anesthetic; *P < 0.05 versus no anesthetic. Data are mean ± SD; n = 6. CGRP = calcitonin gene-related peptide.
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Discussion
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Using a pithed rat model, we examined the effects of volatile anesthetics on NANC depressor responses in vivo. Major findings of this study were as follows. First, isoflurane and halothane attenuated the NANC depressor response in a dose-related fashion. Second, the depressor responses recovered to baseline by 30 to 60 minutes after discontinuation of anesthetics. Third, isoflurane, halothane, and sevoflurane did not affect the release of CGRP after spinal cord stimulation. Forth, isoflurane and halothane attenuated the depressor response to exogenously administered CGRP. Taken together, these data indicate that isoflurane and halothane inhibit the NANC depressor response by attenuation of the depressor effect of CGRP, but not by inhibition of CGRP release.
The pithed rat model has been used to investigate cardiovascular responses mediated by autonomic outflow from the spinal cord in vivo (11). Taguchi et al. (10) showed that spinal cord stimulation at the lower thoracic level (T9 to T12) in pithed rats with artificially increased MAP and autonomic outflow blockade caused a long-lasting depressor response. Because atropine and propranolol did not affect the depressor response, the depressor response to spinal cord stimulation was judged to be NANC in nature. Furthermore, because either the neurotoxin tetrodotoxin or CGRP (8-37), a CGRP-1 receptor antagonist, inhibited the depressor response (10), the depressor response to spinal cord stimulation could be attributed to endogenous CGRP released from CGRP-containing nerves. As shown in Figure 1, we also demonstrated that CGRP (8-37) completely blocked the depressor response to spinal cord stimulation, indicating that this response is mediated by the CGRP-1 receptor.
There is no previous report demonstrating an effect of volatile anesthetics on the NANC nerve stimulation mediated by CGRP, although effects of volatile anesthetics on the response to NANC nerve stimulation mediated by nitric oxide (NO) have been studied. In isolated porcine trachea, Lindeman et al. (12) found that halothane does not affect NANC nerve-mediated relaxation of isolated porcine tracheal smooth muscle precontracted with carbachol. In their experiment, halothane had no effect on NANC nerve-mediated relaxation of isolated trachea; however, they did not study the effect of halothane at concentrations larger than 1.0%. Yamamoto et al. (13) have investigated the effects of halothane and isoflurane on the relaxation responses of isolated canine cerebral arteries to NANC nerve stimulation mediated by an NO/cyclic guanosine monophosphate pathway. Halothane at 2.3% and isoflurane at 2.3% and 3.5% significantly attenuated these relaxation responses to NANC nerve stimulation. Although halothane at 1.5% also inhibited the relaxation response in that model, significance was noted only for the concentration of 2.3%. In this study, halothane at 1.5% and isoflurane at 2% significantly attenuated the NANC depressor response. Smaller concentrations of anesthetics (halothane 0.75% and isoflurane 1%) did not show a significant effect on the NANC depressor response. Taken together, these data suggest that large concentrations of volatile anesthetics may be needed to inhibit NANC nerve-mediated responses.
CGRP, among the most potent vasodilating substances known, also exerts positive inotropic effects (14). These biological responses are mediated by specific cell-surface receptors predominantly coupled to the activation of adenylyl cyclase (14). CGRP-mediated vasorelaxation involves multiple second messengers, including cyclic adenosine monophosphate, NO/cyclic guanosine monophosphate, and K+ channels (14), whereas CGRP-mediated inotropic action is mediated mainly by an increase in cyclic adenosine monophosphate. In this experiment, volatile anesthetics attenuated both pressor and depressor responses after CGRP administration, suggesting that these drugs may attenuate both inotropic and vasodilatory actions of CGRP. Volatile anesthetics are suggested to have diverse effects on the signal transduction system regulating vascular tone (15,16). Halothane and isoflurane attenuated vasodilation and also blunted the intracellular [Ca2+] decrease induced by isoproterenol (16). These anesthetics interfered with ß-adrenoceptor-mediated responses in the rat aorta at a point downstream from agonist-receptor binding but upstream to adenylyl cyclase activation (16). Although precise mechanisms of actions of volatile anesthetics are unclear, such attenuation of ß receptor-mediated responses may contribute to the effects of volatile anesthetics on CGRP receptor-mediated responses.
The mechanism of the vasodilator effect of CGRP is not fully understood. CGRP has been reported to activate adenosine triphosphate-sensitive K+ (K+ATP) channels in arterial smooth muscle (17,18). Glibenclamide, a blocker of K+ATP channels, antagonized CGRP-induced hypotension in rabbits (19). Interactions between volatile anesthetics and K+ATP channels in various tissues have been described. Seki et al. (20,21) and Nakayama et al. (22) demonstrated by long-term invasive monitoring in dogs that the pulmonary vasodilator response to the K+ATP channel was attenuated during halothane, enflurane, and desflurane anesthesia, whereas sevoflurane did not attenuate the response. Halothane and isoflurane attenuated the endothelially dependent pulmonary vasorelaxation response to K+ATP channel activation (23). These data are consistent with our findings.
In this experiment, we measured only MAP; individual physiologic variables that affect MAP, such as venous return, cardiac output, and vascular resistance, have not been studied. Volatile anesthetics depress myocardial contraction and dilate vascular smooth muscle to different extents. Although at 30 minutes, significance was noted only in the 2% isoflurane group in this experiment, infusion rates of methoxamine to maintain an approximate MAP of 120 mm Hg were very different within and between groups. These data suggest that vascular tone before spinal cord stimulation may differ from that after such stimulation. These differences may affect depressor responses after spinal cord stimulation. Further studies examining changes in vascular tone are needed to confirm the effect of volatile anesthetics on NANC vasodilation.
In summary, halothane and isoflurane attenuated the NANC depressor response in vivo. Volatile anesthetics attenuated this response through inhibition of the depressor effect of CGRP, not inhibition of CGRP release after NANC nerve stimulation.
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Acknowledgments
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Supported by Grant-in-Aid 11671478 for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan.
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Footnotes
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Presented in part at the annual meeting of the Japan Society of Anesthesiologists, Sapporo, Japan, May 26–28, 1999.
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Accepted for publication September 18, 2002.
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M. Kuroda, D. Yoshikawa, K. Nishikawa, S. Saito, and F. Goto
Volatile Anesthetics Inhibit Calcitonin Gene-Related Peptide Receptor-Mediated Responses in Pithed Rats and Human Neuroblastoma Cells
J. Pharmacol. Exp. Ther.,
December 1, 2004;
311(3):
1016 - 1022.
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Abstract
Introduction
