Anesth Analg 2006;103:443-447
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000236785.17606.58
OBSTETRIC ANESTHESIA
The Effects of Volatile Anesthetics on Spontaneous Contractility of Isolated Human Pregnant Uterine Muscle: A Comparison Among Sevoflurane, Desflurane, Isoflurane, and Halothane
Kyung Y. Yoo, MD, PhD*,
Jun C. Lee, MD*,
Myung H. Yoon, MD, PhD*,
Min-HO Shin, MD
,
Seok J. Kim, MD*,
Yoon H. Kim, MD, PhD
,
Tae B. Song, MD, PhD, and
JongUn Lee, MD, PhD
From the Departments of *Anesthesiology, Gynecology and Obstetrics, and Physiology, Chonnam National University Medical School, Gwangju, South Korea; Department of Preventive Medicine, Seonam University College of Medicine, Namwon, South Korea.
Address correspondence and reprint requests to Kyung Yeon Yoo, MD, Department of Anesthesiology, Chonnam National University Medical School, 5 Hak-dong, Gwangju 501-746, Korea. Address e-mail to kyyoo{at}jnu.ac.kr.
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Abstract
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We examined the effects of equianesthetic concentrations of sevoflurane, desflurane, isoflurane, and halothane on the spontaneous contractility of isolated human pregnant uterine muscles. We also determined if their action was related to potassium channels. Uterine specimens were obtained from normal full-term pregnant women undergoing elective lower-segment cesarean delivery. Longitudinal muscle strips were mounted vertically in tissue chambers. Their isometric tension was recorded while they were exposed to 0.5–3 minimum alveolar concentration (MAC) of volatile anesthetics in the absence and presence of the high conductance calcium-activated potassium channel blocker, tetraethylammonium, or the adenosine triphosphate-sensitive potassium channel (KATP)-blocker, glibenclamide. The anesthetics examined produced a dose-dependent depression of contractility. The inhibitory potency of sevoflurane and desflurane was comparable to, whereas that of isoflurane was smaller than, that of halothane: concentrations causing 50% inhibition of the contractile amplitude (ED50) were 1.72, 1.44, 2.35, and 1.66 MAC (P < 0.05), respectively. Tetraethylammonium and glibenclamide did not affect the uterine response to the anesthetics, except for glibenclamide, which attenuated the response to isoflurane. These results indicate that the volatile anesthetics have inhibitory effects on the contractility of the human uterus. The inhibitory effect of isoflurane may in part be mediated through activation of KATP channels.
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Introduction
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Uterine relaxation may prolong labor and, more importantly, may result in increased blood loss after delivery. Therefore, large concentrations of volatile anesthetics that may cause profound uterine relaxation are best avoided during cesarean delivery (1,2). However, they may be paradoxically used to achieve uterine relaxation to facilitate complicated deliveries in some instances (3,4).
Sevoflurane and desflurane have gained widespread acceptance in obstetric anesthesia. Their inhibitory effects on myometrial contractility have been documented in rat (5,6) and human preparations (7,8). However, the inhibitory potency and mode of action may differ among various volatile anesthetics, including isoflurane and halothane.
There is ample evidence indicating that K+ channels, including calcium-activated (BKCa), adenosine triphosphate-sensitive (KATP), and voltage-dependent (KV) channels, play a critical role in regulating spontaneous myometrial contractility (9–11). These channels may in turn be affected by volatile anesthetics. For example, sevoflurane inhibits the contractility through activation of BKCa channels in the isolated rat myometrium (12). On the contrary, halothane and isoflurane inhibit BKCa channels in canine cerebral arteries (13) and bovine aortic endothelial cells (14). Taken together, the effects of volatile anesthetics on K+ channels may differ according to tissue and animal species. However, the effects of volatile anesthetics on K+ channels have not been determined in the human myometrium.
The aim of the present study was to examine and compare the effects of sevoflurane, desflurane, isoflurane, and halothane on the spontaneous contractility of isolated human pregnant uterine muscles over a wide range of concentrations. It was also determined whether their actions were related to altered activity of K+ channels. Segments of human uterus were taken from patients undergoing elective lower-segment cesarean delivery, and their isometric tension was recorded.
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METHODS
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The protocol of the study was approved by the IRB. One-hundred-six ASA physical status I–II full-term pregnant women undergoing elective lower-segment cesarean delivery before the onset of labor enrolled the study. Written informed consent was obtained from each patient. All patients received epidural anesthesia with 17–22 mL of 0.5% bupivacaine and fentanyl 100 µg. A small segment of myometrium was excised from the upper incisional surface of the lower uterine segment after delivery of the infant and placenta. The specimen was placed in cold physiological salt solution (PSS) and immediately transferred to the laboratory. PSS had the following composition (in mM): NaCl, 112; KCl, 5; NaHCO3, 25; KH2PO4, 1; MgSO4, 1.2; CaCl2, 2.5; glucose, 11.5.
Four longitudinal muscle strips (12 x 2 x 2 mm) from each specimen were made and mounted vertically in 10-mL tissue chambers. They were connected to isometric force transducers (Grass FT03, Grass; Quincy, MA) to record the active tension on a polygraph (Grass 7D). A resting tension of 0.5 g was placed. PSS in the chamber was maintained at 37°C and aerated with a gas mixture of 95% oxygen and 5% CO2 (pH = 7.4).
Approximately 90 min elapsed before the muscle strip developed spontaneous contractility in the chamber. When contractions became uniform in the active tension and contraction interval, 2 of the 4 muscle preparations in which the contractions were similar in contractile amplitude (1.5 g or more) and interval were selected for the study. Increasing concentrations (0.5, 1.0, 1.5, 2.0, 2.5, and 3 minimum alveolar concentration [MAC]) of anesthetics (sevoflurane, desflurane, isoflurane, or halothane) were applied for 30 min at each concentration, and resultant contractile activities during the last 15 min were averaged to yield a value at each concentration. When spontaneous contractile activity disappeared, oxytocin (100 to 200 µU/mL) was given to redeem the contractility.
We also examined whether the anesthetic-induced uterine depression was mediated through action on K+ channels. Muscle strips were treated with either tetraethylammonium (TEA, 10–3 M) to inhibit high conductance BKCa channels, or glibenclamide (10–5 M) to inhibit KATP channels. They were applied at least 30 min before applying the anesthetics. At the end of each experiment, spontaneous contractility was allowed to return to confirm muscle viability.
The anesthetics were delivered through a vaporizer to O2/CO2 mixture aerating PSS in the tissue chamber, which was sealed with a thin paraffin sheet. The anesthetic concentration in the gas mixture was monitored by infrared analyzer (Model 254; Datex, Helsinki, Finland). In a preliminary study, the concentrations in PSS were confirmed by gas chromatography (GC-14B; Shimatzu, Duisburg, Germany). The anesthetics reached steady-state concentrations in the tissue chamber in 10–15 min, and mM concentration and partial pressure of anesthetics in the chamber reflected its concentration in the gas mixture bubbled into the buffer solution (anesthetic concentrations in the perfusate were 0.28 ± 0.05 mM and 0.65 ± 0.08 mM for sevoflurane, 0.50 ± 0.03 mM and 1.16 ± 0.17 mM for desflurane, 0.25 ± 0.05 mM and 0.61 ± 0.09 mM for isoflurane, and 0.21 ± 0.06 mM and 0.35 ± 0.08 mM for halothane). Calculated vapor concentrations were 1.9 vol% and 4.3 vol% for sevoflurane and 5.7 vol% and 13.1 vol% for desflurane, 1.2 vol% and 2.9 vol% for isoflurane, and 0.8 vol% and 1.4 vol% for halothane, which corresponded approximately to 1 MAC and 2 MAC in vivo (n = 7 each). One MAC of volatile anesthetics in the gas phase was calculated as 2.0 vol% for sevoflurane, 6.0 vol% for desflurane, 1.3 vol% for isoflurane, and 0.75 vol% for halothane. Sevoflurane and isoflurane were purchased from Abbott Laboratories (North Chicago, IL), desflurane from Baxter Healthcare Corporation (Deerfield, IL), and halothane from Ilsung Pharmaceutical Company (Seoul, Korea). Glibenclamide and TEA were purchased from Sigma Chemical Company (St. Louis, MO). TEA was dissolved in PSS, and glibenclamide was dissolved in a small volume of N, N-dimethylformamide.
Power analysis revealed that a sample size of 10 for each group provided 80% power at 
= 0.05. Data were expressed as mean ± sd. Differences in the amplitude and the frequency of contractions were tested by analysis of variance with repeated-measures factor, followed by Dunnett's t-test. Concentrations causing 50% inhibition of the contractile amplitude (ED50) were calculated using linear regression. Probability values <0.05 were considered statistically significant. Statistical analyses were performed on a computer using StatView 4.5 software (SAS Institute Inc, Cary, NC).
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RESULTS
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The spontaneous contractility lasted, without fading, for up to 7–10 h, which was progressively attenuated by increasing concentrations of volatile anesthetics (Figs. 1–4). All volatile anesthetics studied induced concentration-dependent decreases in amplitude and frequency (Figs. 2–4). The inhibitory potency of sevoflurane, desflurane, and halothane was comparable with and significantly more than that of isoflurane (P < 0.05, Fig. 2): ED50 for sevoflurane, desflurane, isoflurane, and halothane was 1.72 ± 0.49, 1.44 ± 0.23, 2.35 ± 0.87, and 1.66 ± 0.19 MAC, respectively. Oxytocin restored uterine contractility abolished by small concentrations of anesthetics (<1.0 MAC), whereas it was without effect on uterine activity abolished by larger concentrations.
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Figure 1. A representative trace showing spontaneous contractility of isolated pregnant human uterine muscle. The contractile activity lasted without fading during the experimental period (A). Effects of increasing concentrations of isoflurane on spontaneous uterine contraction in the absence (B) and presence of glibenclamide (C). Their concentrations are indicated above or below the arrow in MAC. Glib = glibenclamide.
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Figure 2. Effects of volatile anesthetics on spontaneous uterine contractility. Each point represents mean ± sd (n = number of subjects). *P < 0.05 versus baseline; P < 0.05 versus halothane.
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Figure 3. Effects of volatile anesthetics on the frequency of uterine contractions. Each point represents mean ± sd (n = number of subjects). *P < 0.05 versus baseline. Each anesthetic significantly affected the frequency of uterine contraction (P < 0.05), with no differences among the anesthetics.
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Figure 4. Effects of volatile anesthetics on spontaneous uterine contractility in the absence (control) and presence of tetraethylammonium (TEA) or glibenclamide (Glib). Each point represents mean ± sd (n = number of subjects). TEA (10–3 M) and Glib (10–5 M) did not affect the response to either anesthetic, except that Glib attenuated the response to isoflurane. *P < 0.05 versus the control group.
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TEA (10–4–10–2 M) and glibenclamide (10–6–10–4 M) increased spontaneous uterine contractility (13% ± 8% and 10% ± 9% of basal at 3 x 10–3 and 3 x 10–5, respectively; n = 12 each, P < 0.05). The inhibitory effect of isoflurane was not affected by TEA (10–3 M) but was attenuated by glibenclamide (10–5 M). Neither TEA nor glibenclamide affected the uterine response to sevoflurane, desflurane, or halothane (Fig. 4). Washing with PSS after one series of experiment fully restored basal contractility.
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DISCUSSION
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The present study demonstrated that sevoflurane and desflurane inhibited the spontaneous contractility of pregnant human uterine muscles. This is in agreement with previous investigations (7,8). Furthermore, our study showed that the inhibitory potency of sevoflurane and desflurane was comparable to that of halothane. However, isoflurane was found to have less prominent depressant effects than halothane. This finding is contradictory to previous data that demonstrated equally depressant effects of halothane, isoflurane, and enflurane at equivalent MAC in isolated human uterine muscle (15). The discrepancy between the studies may in part be accounted for by different methodology.
A critical role of K+ channels in regulating spontaneous myometrial contractility has been reported. Kafali et al. (12) showed that TEA and glibenclamide increased spontaneous myometrial contractions in a concentration-dependent manner in isolated pregnant rat uterine muscle. Our study also demonstrated that TEA and glibenclamide significantly increased spontaneous uterine contractility, implying a role of BKCa and KATP channels in regulating the basal myometrial excitability in human uterus. Furthermore, glibenclamide caused a rightward shift of dose-response curves in the present study, suggesting that the inhibitory effect of isoflurane was attenuated by KATP channel blockade. Taken together, it is likely that isoflurane affects uterine contractility in part through modulating KATP channels. However, the inhibitory effect of sevoflurane, desflurane, and halothane was not affected by TEA or glibenclamide, suggesting that the inhibitory effect of these anesthetics may involve pathways other than these K+ channels.
It is not clear why only isoflurane had an effect on KATP channels. The modern anesthetics, in fact, are all very similar in structure and would be expected to have similar effects on all types of enzymes and receptors. In addition, the discrepancy may not lie with a difference in lipid solubility among the anesthetics. It was found that the volatile anesthetics desflurane, sevoflurane, isoflurane, and halothane caused coronary vasodilation through opening the KATP channels in in vivo canine studies in which isoflurane was the greatest in the vasodilator potency (16,17). Although these findings suggest that isoflurane has high efficacy in modulating KATP channel activity, it is uncertain if this is also true in the human myometrium.
An increase in intracellular free Ca2+ triggers myometrial contractions (18), and drugs that reduce the Ca2+ availability depress the contractile activity of isolated uterine muscles in rats (19) and in pregnant humans (20). Volatile anesthetics halothane, isoflurane, and sevoflurane, at clinically relevant concentrations (1%–3%), decrease the intracellular free Ca2+ through inhibition of L-type Ca2+ channel current in rat uterine muscles (21). The inhibitory effect of volatile anesthetics on the human uterus may also be related to their effects on transmembrane Ca2+ flux. Although isoflurane decreased the spontaneous myometrial contractility through activating KATP channels in the present study, it cannot be concluded that the volatile anesthetics have a direct effect on these K+ channels without definitive electrophysiological evidence. The relation between K+ channels and the inward Ca2+ current in inhibiting spontaneous uterine contractility requires further investigation.
Kafali et al. (12) demonstrated that sevoflurane-induced uterine relaxation was attenuated by inhibiting BKCa channels by TEA in isolated pregnant rat uterine muscle. Previous studies have demonstrated regional differences of uterine response to various drugs. Prostaglandin E2 was found to cause strips of myometrium from the fundus to contract with no significant effects on those from the lower uterine segment in the pregnant baboon uterus (22). The relaxant effect of vasoactive intestinal peptide is more effective in the outer layer of human non-pregnant uterus than in the inner layer (23). Kafali et al. (12) used full-thickness cross-sectional rat myometrial strips excised from the fundus. In contrast, our study used muscle preparations excised from the middle layer of the lower human uterine segment. Therefore, discrepancies between the studies may in part be related to regional differences of uterine specimens and difference in species.
The circulating levels of oxytocin may vary in different stages of labor that, in turn, may alter uterine responses to anesthetics. In this context, one may not extrapolate effective concentrations of the volatile anesthetics to inhibit uterine contractions in parturients from the data obtained in vitro. It has also been suggested that a down-regulation of K+ channels occurs during late pregnancy. A down-regulation of - and ß-subunits of BKCa channels in parturient human myometrium may underlie the loss of calcium and voltage-sensitivity of BKCa channel (24). Moreover, the properties of large-conductance K+ channels of myocytes may significantly differ between the laboring and nonlaboring uterus (25). The uterine responses to anesthetics may differ at different stages of gestation.
In the present study, both sevoflurane and desflurane inhibited pregnant human uterine contractility to a similar magnitude to that of the earlier anesthetics. However, they are relatively rapid in onset and offset of action as a result of their low blood gas partition coefficients (26). Both anesthetics at 1.0–1.5 MAC or more may be appropriate when rapid uterine relaxation is required in difficult obstetric deliveries. The rapid wash-in may allow the obstetric anesthesiologist to provide rapid uterine relaxation, which could be advantageous in the emergency setting. In addition, the rapid washout makes it possible to rapidly increase uterine tone when uterine relaxation is no longer required. This is especially true when the ex utero intrapartum treatment procedure is performed under general anesthesia (3). Furthermore, oxytocin alone may not be effective to reverse the uterine depression associated with large concentrations of volatile anesthetics as demonstrated in the present study.
In summary, the volatile anesthetics sevoflurane, desflurane, isoflurane, and halothane inhibited the spontaneous contractility of isolated pregnant human uterine muscle in a dose-related manner. The degree of inhibition induced by sevoflurane and desflurane was comparable to that of halothane, whereas that induced by isoflurane was less. The inhibitory effects of isoflurane may be related, at least in part, to its ability to modulate KATP channels.
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Footnotes
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Supported, in part, by a research grant from Research Institute of Clinical Medicine Chonnam University Hospital (CUHRI-U-200329).
Accepted for publication March 28, 2006.
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Abstract
Introduction
