Anesth Analg 2004;99:752-757
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132695.77191.F3
ANESTHETIC PHARMACOLOGY
The Soluble Guanylyl Cyclase Inhibitor ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, Dose-Dependently Reduces the Threshold for Isoflurane Anesthesia in Rats
Sylvia Cechova, PhD, and
Thomas N. Pajewski, PhD MD
Department of Anesthesiology, University of Virginia Health System, Charlottesville
Address correspondence and reprint requests to Thomas Pajewski, PhD, MD, Department of Anesthesiology, University of Virginia, Health System, Box 800710, Charlottesville, VA 22908-0710. Address e-mail to tnp9s{at}virginia.edu
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Abstract
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Nitric oxide (NO), a cell messenger for activating soluble guanylyl cyclase, is produced by activation of the enzyme NO synthase (NOS) in a wide variety of tissues, including the central nervous system. We have previously demonstrated that inhibition of NOS decreased the minimum alveolar anesthesia concentration (MAC) for isoflurane anesthesia. Moving more distally in the NOS-guanylyl cyclase signaling pathway, we investigated the effects of the specific soluble guanylyl cyclase inhibitor ODQ, 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one, on anesthetic requirements. The effect of ODQ on the MAC of isoflurane anesthesia was investigated in Sprague-Dawley rats while concurrently monitoring the their arterial blood pressure and heart rate. After determining control MAC, ODQ 20–500 mg/kg was administered intraperitoneally 30 min before re-determining MAC in the presence of the soluble guanylyl cyclase inhibitor. In one series, the effect of 250 mg/kg of ODQ on neuronal cyclase guanosine monophosphate production was determined by microdialysis. ODQ produced a statistically significant, dose-dependent decrease from isoflurane control MAC (maximal effect 52.4% ± 2.7%). No ceiling effect was observed over the dose-range studied. This reduction in isoflurane MAC was not accompanied by changes in either heart rate or blood pressure. Inhibition of the NOS-guanylyl cyclase signaling pathway decreased the MAC for isoflurane, which suggests that inhibition of this pathway may play a role in the anesthetic state. The MAC reduction by the soluble guanylyl cyclase inhibitor ODQ was devoid of any significant hemodynamic effects. The current findings, along with the previous observations that structurally distinct NOS inhibitors and the nonspecific soluble guanylyl cyclase inhibitor methylene blue decrease the MAC for volatile anesthetics, support that this is an effect specific to the NOS-guanylyl cyclase signaling pathway.
IMPLICATIONS: The nitric oxide-guanylyl cyclase signaling pathway has been proposed to be involved in sedation, analgesia, and anesthesia. Specific inhibitors of the enzyme nitric oxide synthase resulted in a reduction in the anesthetic requirements (MAC) for isoflurane. In the present study, we demonstrate that ODQ, a specific inhibitor of soluble guanylyl cyclase, was also capable of reducing the MAC for isoflurane anesthesia in the rat.
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Introduction
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The diffusible second messenger, nitric oxide (NO), is recognized as the transduction mechanism responsible for activating soluble guanylyl cyclase. A wide variety of tissues synthesize NO (1). Immunohistochemical localization studies indicate that the constitutive (endothelial and neuronal) NO synthases (NOS) are concentrated in endothelial, neuronal, and secretory tissues (2). A third isoform of this enzyme, inducible NOS, has also been described. NO mediates the increase in cerebellar cyclic guanosine monophosphate (cGMP) content in response to activation of glutamate receptors or other stimuli that increase cytosolic Ca2+ concentrations (3,4). Neuronal NOS activity has been demonstrated not only in the spinal cord but also in several brain regions, including the cerebellum, hypothalamus, midbrain, striatum, and hippocampus (5,6).
Inhaled anesthetics inhibit NO production in vascular endothelium, decrease cGMP content, and modify synaptic transmission in specific brain regions (7–9). In addition, halothane depresses synaptic transmission by L-glutamate-stimulated cortical neurons and N-methyl-D-aspartic acid (NMDA)-stimulated CA-1 neurons of the hippocampus (10,11). These observations suggested the hypothesis that inhibition of the L-arginine to NO pathway in the central nervous system (CNS) may result in a sedative, analgesic, or anesthetic effect (12). Subsequent studies revealed that inhibition of NOS activity using structurally distinct inhibitors reduced the threshold for isoflurane anesthesia in rats (13). Whereas the minimum alveolar anesthetic concentration (MAC)-reducing effect associated with NOS inhibition provided additional evidence that the NO-guanylyl cyclase signaling pathway was involved in the anesthetic state, inhibition of site(s) distal to NOS in this pathway might also result in MAC reduction. Methylene blue, a nonspecific inhibitor of guanylyl cyclase, has been reported to reduce cGMP concentrations and the MAC of sevoflurane anesthesia in the rat after intracerebroventricular injection (14). The availability of a specific inhibitor of soluble guanylyl cyclase, 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), allowed for further investigation of this pathway (15). Having previously shown that inhibition of the NO-guanylyl cyclase signaling pathway at the level of NOS decreased MAC, in the present study, we investigated the efficacy of ODQ, a specific inhibitor of soluble guanylyl cyclase, as an agent capable of reducing MAC for isoflurane anesthesia in the rat.
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Methods
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After obtaining institutional animal care committee approval, 28 male Sprague-Dawley rats (311 ± 4 g) were each placed in a clear plastic cone and anesthetized with 5% isoflurane (Ohmeda; Liberty Corner, NJ) and oxygen for 3 to 5 min. The inspired isoflurane concentration was reduced to 2%, and the rat was allowed to breathe spontaneously until cannulation of a femoral artery and vein with a 24-guage polyethylene catheter (Johnson and Johnson Medical Inc, Arlington, TX) had been accomplished. The trachea was then intubated with a 16-gauge polyethylene catheter (Johnson and Johnson Medical). The isoflurane concentration was decreased further to 1.5%, and ventilation was controlled with a Harvard animal respirator using measurement of arterial blood gases to maintain normal PO2, PCO2, and pH value. Alveolar isoflurane concentrations and end-tidal CO2 measurements were obtained using a Datex Engstrom Capnomac gas monitor (Helsinki, Finland). Heart rate and systolic and diastolic blood pressures were monitored and recorded using an AD Instruments MacLab (Mountain View, CA) data recording system. Temperature was measured using a Yellow Springs (Yellow Springs Instrument Company, Inc, Yellow Springs, OH) thermistor and maintained at normothermia with a heating blanket and warning lights. MAC, under control conditions, was established according to the methods described by Eger et al. (16) using a long hemostat (8-inch Rochester Pean Hemostatic Forceps, Biomedical Research Instruments, Inc., Rockville, MD) clamped to the first ratchet lock on the tail for 1 min. The tail was always stimulated proximal to a previous test site. Gross movement of the head, extremities, or body was taken as a positive test, whereas grimacing, swallowing, chewing, or tail flick were considered negative. The isoflurane concentration was reduced in decrements of 0.10% until the negative response became positive, allowing 12 to 15 min equilibration after changes in concentration. The MAC was considered to be the concentration midway between the largest concentration that permitted movement in response to the stimulus and the smallest concentration that prevented movement.
Because of its limited aqueous solubility, ODQ was administered by intraperitoneal injection after the drug was sonicated with peanut oil (3 mL). After initial baseline MAC determination, ODQ was administered at a dose of 20, 50, 100, 250, or 500 mg/kg. The order of administration of the various doses of soluble guanylyl cyclase inhibitor was performed in an unblinded, random manner. Six rats were studied at each of the inhibitor concentrations, except for the 500-mg/kg dose at which 4 rats were studied. An isoflurane concentration was chosen at which movement did not occur in the last negative response before the positive test. At this isoflurane concentration, 30 min after the administration of the ODQ, MAC was again determined with the concentration of isoflurane reduced, and response to tail clamp was checked every 12–15 min thereafter until a positive response was achieved.
The stability of the MAC determinations over time, in the presence of ODQ, was assessed in the following manner. Six rats had their control MAC determined as described above. The MAC was again determined 60 and 120 min after administering ODQ (250 mg/kg) in 3 mL of peanut oil. The stability of the MAC determinations over time, in the presence of only the vehicle (peanut oil), was assessed in the following manner. Four rats had their control MAC determined as previously described. After the administration of 3 mL of peanut oil, the MAC was again determined after an additional 60 and 120 min.
Four adult male Sprague-Dawley rats were anesthetized with ketamine: xylazine (70:7 mg/kg intraperitoneally [ip]) and placed in a stereotaxic apparatus (Stereotaxic System SAS-4100, ASI Instruments Inc., Warren, MI). The skin was retracted, and the remaining tissue was scraped from the skull until the coronal and sagittal sutures of the skull were identified. A small hole was made using a hand-held drill, and the underlying meninges were incised using a 27-gauge needle. A probe (CMA 10, Carnegie Medicine, Sweden) attached to a micromanipulator on the stereotaxic device was then lowered through the hole to a position just above the brain surface. Using this position as a zero reference (vertical), the microdialysis probe was lowered into the right locus coeruleus using the micromanipulator (coordinates taken from the bregma with the skull flat: A: 9.7 mm, L: 1.1 mm, and V: 8.0 mm from the atlas of Paxinos and Watson). The position of the probe was fastened with 3 screws onto the skull of the rat and fixed with dental cement. The rat was allowed to recover for 48 h.
On the second day after the placement of the microdialysis probe, the rat was anesthetized with isoflurane (1.2%), as described above, in the section relating to the MAC determinations. The probe was dialyzed (5 µL/min) with artificial cerebrospinal fluid (130 mM of NaCl, 2.66 mM of KCl, 24.6 mM of NaHCO3, 1.2 mM of CaCl2.2H2O, and 10 µM of glycine) for 1 h before sample collection. Three 20-min fractions were collected to determine baseline cGMP concentrations before administering ODQ (250 mg/kg ip), followed by the collection of an additional 9 samples. The location of the probe was subsequently verified by histological examination. The cGMP content was analyzed by radioimmunoassay (NEN Life Science, Boston, MA).
Indwelling intrathecal catheters were inserted in 3 male Sprague-Dawley rats using methods described previously (17). In brief, the rats were anesthetized with ketamine: xylazine (70:7 mg/kg ip). The neck of each animal was shaved and then cleaned with an iodine solution. A midline incision was made on the skull, extending from a line between the ears to a point 2 cm caudal, and the fascia and muscle were retracted from the skull and first vertebra. The atlanto-occipital membrane was visualized, and an indwelling intrathecal catheter was placed by passing a PE-10 catheter (Becton Dickson, Sparks, MD) through an incision in the atlanto-occipital membrane to a position 9 cm caudal to the cisterna at the level of the lumbar enlargement. The catheter was externalized on the top of the skull, and the wound was closed with 3-0 silk sutures. The rat was allowed to recover from the anesthetic and surgery. Rats showing postoperative neurological deficits or evidence of infection or inflammation were killed with an anesthetic overdose. Measurement of the MAC was performed 4–9 days after the intrathecal implantation of the catheter. The MAC determinations were done as described above, except that the ODQ (0.5 – 1.0 mM) was solubilized in DMSO in normal saline (1:1; 10 µL) and then flushed with an additional 10 µL of normal saline.
All data are reported as mean ± SEM. Statistical analysis was performed using analysis of variance with multiple-range testing (Newman-Keuls test) where required. P < 0.05 was accepted as significant.
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Results
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The control value for isoflurane MAC in the rat was 1.07 ± 0.01 vol%, which agrees with previous determinations. As seen in Figure 1, ODQ (20, 50, 100, 250, or 500 mg/kg) produced a statistically significant dose-dependent decrease from isoflurane control MAC of 0% ± 0%, 10.9% ± 4.1%, 12.3% ± 4.0%, 27.7% ± 2.1%, and 52.4% ± 2.7%, respectively. Each concentration was significantly decreased (P < 0.05) from the isoflurane control MAC except the smallest (20 mg/kg) dose. No ceiling effect was observed over the dose range investigated. This reduction in isoflurane MAC was not accompanied by changes in arterial blood pressure, as seen in Figure 2A. Similarly, the heart rate was unchanged by ODQ administration, as shown in Figure 2B. At the largest dose, 2 of the 4 rats died of apparent cardiovascular collapse approximately 30 min after ODQ administration, suggesting that although based on a limited sample, 500 mg/kg may be the 50% lethal dose for this compound. Arterial blood gas analysis after ODQ administration revealed no effect on pH vale or PCO2; however, PO2 was noted to decrease significantly (384 ± 22 mm Hg versus 252 ± 29 mm Hg for the control and the ODQ-treated blood samples, respectively).
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Figure 1. Isoflurane minimum alveolar anesthetic concentration (MAC) reduction by increasing concentrations of 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), measured 60 min after intraperitoneal administration. Data are presented as the mean ± SEM; n = 6 rats for each data point, except n = 4 for the 500-mg/kg ODQ dose. *P < 0.05 versus control. **P < 0.05 versus the 250-mg/kg dose.
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The lack of effect of the vehicle (peanut oil) used to administer ODQ on the MAC of isoflurane was previously reported (13). The stability of the MAC determinations, in the presence of ODQ (250 mg/kg), was assessed 60 and 120 min after administering the soluble guanylyl cyclase inhibitor. The control MAC for these additional rats was 1.05 ± 0.04 vol%. The MAC decreased by 26.7% ± 3.8% and by 54.7% ± 4.2% after 60 and 120 min, respectively. Our previously published data involving another insoluble inhibitor of the NO-guanylyl cyclase signaling pathway, the neuronally-selective NOS inhibitor 7-nitro indazole, was obtained 60 min after administration of the test compound (13). To allow for a more direct comparison to these previously published data, we choose the 60 min time point for the experimental MAC determinations in the current study.
Systemic administration of ODQ (by intraperitoneal injection) resulted in a statistically-significant reduction in cGMP efflux (maximal reduction of 35% ± 2.8%) from the locus coeruleus compared with the baseline levels, as seen in Figure 3. Intrathecal administration of ODQ resulted in a statistically significant, although modest (13.1% ± 4.9%), reduction in the MAC of isoflurane anesthesia, which was not associated with any hemodynamic changes.
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Figure 3. The effect of the soluble guanylyl cyclase inhibitor of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) on the efflux of cyclic guanosine monophosphate (cGMP) contained in the microdialysate from the locus coeruleus. Data are presented as mean ± SEM; n = 4 rats for each data point. *P < 0.05 versus baseline.
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Discussion
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ODQ produced a statistically significant, dose-dependent reduction in the MAC for isoflurane anesthesia, further suggesting a role for the NOS-guanylyl cyclase signaling pathway in the anesthetic state. This finding is consistent with the results of Masaki and Kondo (14) showing that the intracerebroventricular administration of the nonspecific soluble guanylyl cyclase inhibitor, methylene blue, decreased the MAC for sevoflurane anesthesia. Additionally, our previously reported findings that both specific and nonspecific inhibitors of NOS reduce the MAC for isoflurane anesthesia provide further support of the hypothesis that the NOS-guanylyl cyclase signaling pathway is involved in the anesthetic state (13).
The microdialysis data provide evidence that the systemic administration of ODQ can reduce the efflux of cGMP from the CNS, specifically the locus coeruleus. This apparent decrease in cGMP production demonstrates the ability of this compound to interfere with the NOS-guanylyl cyclase signaling pathway within the CNS after systemic administration.
Intrathecal administration of ODQ resulted in a modest reduction in the MAC for isoflurane anesthesia, although the limited solubility of this compound precluded a full exploration of its MAC-reducing potential. Clearly, the increased effect of the intraperitoneally administered 250-mg/kg dose of ODQ at 120 versus 60 minutes suggests that equilibration had not been achieved. The predicted time course for the effects of ODQ on soluble guanylyl cyclase is limited by the rate of absorption after the intraperitoneal administration. Using purified bovine lung soluble guanylyl cyclase, Schrammel et al. (15) reported that the inhibitory effect of ODQ was time-dependent (half-time approximately three minutes) and virtually complete after about 10 minutes. Given our observation that a larger MAC reduction was seen at 120 minutes versus 60 minutes, one could assume that absorption from the peritoneal cavity was continuing to take place.
The site(s) of action for MAC reduction by various compounds that were administered systemically and assayed using the MAC model described by Eger et al. (16) include the spinal cord and brain, as well as the peripheral nervous system. That a compound that is administered systemically and intrathecally would result in MAC reduction as well as decrease cGMP in the brain supports the hypothesis that at least the spinal cord and brain are potential sites of action for ODQ. The bulk of evidence supporting the possible involvement of the NOS-guanylyl cyclase signaling pathway in mediating central nociceptive pathways along with its possible involvement in mechanisms of consciousness and anesthesia arises from pharmacologic studies (12,13,18,19). One shortcoming of this method has been the lack of specific inhibitors for soluble guanylyl cyclase. Our present study addressed this issue by using the specific inhibitor ODQ, implicating soluble guanylyl cyclase as the site of inhibition.
The observation that pharmacologic inhibition of the NOS-guanylyl cyclase signaling pathway decreased anesthetic requirements was extended by Ichinose et al. (20), who reported on the generation of a neuronal NOS knockout mouse model. The neuronal knockout mice exhibited a normal MAC for isoflurane and demonstrated no obvious change in baseline consciousness. These mice, which showed no evidence of neuronal NOS gene expression, demonstrated no alteration in the righting reflex or isoflurane MAC after the administration of the nonspecific NOS inhibitor L-nitro arginine methyl ester (L-NAME), in contrast to that seen with the wild-type mice. Thus, the reduction of MAC and inhibition of the righting reflex by the NOS inhibitor were clearly and specifically linked to the inhibition of neuronal NOS. Consistent with the presumed importance of consciousness and pain responses, these responses in the knockout mice would imply the existence of compensatory mechanisms, given the importance of these vital functions.
Whereas a key feature of the general anesthetic state is the prevention of movement, the sites and mechanisms by which volatile anesthetics achieve a state of unresponsiveness remain unknown. The spinal cord was investigated in this regard with data suggesting that motor responses may be inhibited by anesthetics at the spinal cord level (21). Using a model of a preferentially anesthetized brain, with minimal anesthetic delivery to the rest of the body, markedly increased cerebral anesthetic requirements were observed, suggesting that the spinal cord is an important site of anesthetic inhibition (22). Although this evidence would support the spinal cord being the important site linking lack of movement with the anesthetic state, ablation of discrete brainstem neurons or electric stimulation of the periaqueductal gray matter also alters MAC (23,24).
The mechanism of inhibition of the NO-guanylyl cyclase signaling pathway by inhaled anesthetics remains unresolved. Whereas there is significant evidence for an interaction of inhaled anesthetics with the neuronal NO-guanylyl cyclase signaling pathway, discrepancies between the in vivo and in vitro situations have not been fully reconciled. There is general agreement supporting the hypothesis that inhaled anesthetics inhibit NOS activity and decrease cGMP levels in vivo in the cerebellum and other areas of the brain (8,9). The in vivo situation, however, remains controversial in that some studies fail to demonstrate an inhibition of in vivo NOS activity. Terasako et al. (25) reported that whereas both halothane and isoflurane suppressed NMDA-stimulated formation of cGMP in rat cerebellum, the mechanisms by which this was achieved differed between the two inhaled anesthetics. It was suggested that halothane inactivated NOS or related cofactors, without a marked interaction with the NMDA receptor, and isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels.
Investigating the possibility that NMDA stimulation of the neuronal NO-guanylyl cyclase signaling pathway may be inhibited by inhaled anesthetics, Zuo et al. (26) combined in vitro quantitative autoradiography and immunohistochemical analysis to simultaneously localize and quantitate cGMP immunoreactive binding in the adult rat cerebellum. In addition, they reported that NMDA-induced increases in cGMP levels were dose-dependently inhibited by the inhaled anesthetics halothane and isoflurane. The involvement of NOS in the cerebellar NO-guanylyl cyclase signaling pathway was demonstrated by showing that NMDA-induced increases in cGMP were inhibited by L-NAME. L-arginine administration reversed the L-NAME-induced inhibition. In a further investigation of the effects of volatile anesthetics on the NO-guanylyl cyclase signaling pathway, Zuo et al. (27) reported that the inhaled anesthetics halothane, enflurane, and isoflurane do not alter the basal or agonist-stimulated activity of partially isolated soluble and particulate guanylyl cyclases from rat brain. These findings would suggest that the activation of guanylyl cyclase by agonists and guanylyl cyclase itself are not the sites of the inhibition of the NO-guanylyl cyclase signaling pathway by inhaled anesthetics, supporting the hypothesis that inhaled anesthetics seem to inhibit the NO-guanylyl cyclase signaling pathway proximal to activation of guanylyl cyclase.
Inhibition of the NOS-guanylyl cyclase signaling pathway, using both nonselective and selective guanylyl cyclase inhibitors, decreases the MAC for isoflurane. Although uncertainty remains regarding the sites and mechanisms by which anesthetics reduce the somatic responses to noxious stimuli, the reduction in the MAC for isoflurane anesthesia by two structurally distinct guanylyl cyclase inhibitors suggests the specificity of the effect on soluble guanylyl cyclase. These findings further support a role for the NOS-guanylyl cyclase signaling pathway in mechanisms of anesthesia and analgesia.
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Acknowledgments
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Supported, in part, by a FAER/Zeneca Anesthesiology Young Investigator Award (to Dr. Pajewski).
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Footnotes
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Presented, in part, at the Association of University Anesthesiologists Meeting, San Francisco, CA, May 5–7, 1998, and the American Society of Anesthesiologist’s Annual Meeting, Orlando, FL, October 17–21, 1998.
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Accepted for publication March 9, 2004.
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Abstract
Introduction
); ODQ mean arterial blood pressure (•). (B) The effect of the soluble guanylyl cyclase inhibitor of ODQ measured 60 min after intraperitoneal administration on heart rate under isoflurane anesthesia. Data are presented as the mean ± SEM; n = 6 rats for each data point, except n = 4 for the 500-mg/kg ODQ dose. Control heart rate (
