Anesth Analg 2006;102:786-791
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000195441.14929.6d
ANESTHETIC PHARMACOLOGY
Augmented Activity of Adenosine Triphosphate-Sensitive K+ Channels Induced by Droperidol in the Rat Aorta
Hiroyuki Kinoshita, MD, PhD,
Mayuko Dojo, MD, PhD,
Katsutoshi Nakahata, MD, PhD,
Yoshiki Kimoto, MD, PhD,
Tetsuya Kakutani, MD,
Kazuhiro Mizumoto, MD, PhD, and
Yoshio Hatano, MD, PhD
Department of Anesthesiology, Wakayama Medical University, Wakayama, Wakayama, Japan
Address correspondence and reprint requests to Hiroyuki Kinoshita, MD, PhD, Department of Anesthesiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama 641-0012, Japan. Address e-mail to hkinoshi{at}pd5.so-net.ne.jp.
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Abstract
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Droperidol produces the inhibition of K+ channels in cardiac myocytes. However, the effects of droperidol on K+ channels have not been studied in blood vessels. Therefore, we designed the present study to determine whether droperidol modulates the activity of adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells. Rat aortic rings without endothelium were suspended or used for isometric force and membrane potential recordings, respectively. Vasorelaxation and hyperpolarization induced by levcromakalim (10–8 to 10–5 M or 10–5 M, respectively) were completely abolished by the ATP-sensitive K+ channel antagonist glibenclamide (10–5 M). Droperidol (10–7 M) and an 
-adrenergic receptor antagonist phentolamine (3 x 10–9 M) caused a similar vasodilator effect (approximately 20% of vasorelaxation compared with maximal vasorelaxation induced by papaverine [3 x 10–4 M]), whereas glibenclamide did not alter vasorelaxation induced by droperidol. Droperidol (3 x 10–8 M to 10–7 M) augmented vasorelaxation and hyperpolarization produced by levcromakalim, whereas phentolamine (3 x 10–9 M) did not alter this vasorelaxation. Glibenclamide (10–5 M) abolished the vasodilating and hyperpolarizing effects of levcromakalim in the aorta treated with droperidol (10–7 M). These results suggest that droperidol augments vasodilator activity via ATP-sensitive K+ channels. However, it is unlikely that this augmentation is mediated by the inhibition of -adrenergic receptors in vascular smooth muscles.
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Introduction
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Droperidol, a neuroleptic drug used in clinical anesthesia, reportedly produces the inhibition of K+ channels in cardiac myocytes (1). Inhibition of K+ channels in cardiac myocytes is one of the plausible mechanisms to evoke QT-prolongation in the electrocardiogram, which is capable of inducing fatal ventricular arrhythmias in patients (1,2). Indeed, several case reports demonstrated the adverse effects of this IV anesthetic, even using small doses, as an antiemetic (2).
K+ channels play crucial roles in physiological and pathophysiological vasodilation (3–5). However, the effects of droperidol on K+ channels in the vascular smooth muscle have not been studied. Because droperidol has an –adrenergic blocking property on the vascular smooth muscle, resulting in vasodilator effects (6,7), whether an –adrenergic blocking drug mimics the modulator effect of droperidol on K+ channels of the vascular smooth muscle seems to be important.
Therefore, the present study was designed to determine whether clinically relevant concentrations of droperidol modulate the activity of K+ channels of vascular smooth muscle by examining whether droperidol modifies vasodilator and hyperpolarizing effects induced by an adenosine triphosphate (ATP)-sensitive K+ channel opener in the isolated rat aorta and whether an –adrenergic blocking drug, phentolamine, mimics those modulator effects of droperidol.
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Methods
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The institutional animal care and use committee of Wakayama University (Wakayama, Japan) approved this study. Fifteen Male Wistar rats (250 to 350 g) were anesthetized with inhaled 3% halothane using the vaporizer. Under this anesthetic condition, the rats were killed by exsanguination and thoracic aortas were harvested. Thoracic aortic rings of 2.5 mm in length and 1.5 to 2 mm width were studied in modified Krebs-Ringer bicarbonate solution (control solution) of the following composition (mM): NaCl 119, KCl 4.7, CaCl2 2.5, MgSO4 1.17, KH2PO4 1.18, NaHCO3 25, and glucose 11. Endothelial cells were removed mechanically by gently rubbing the lumen with a small forceps to avoid the modification mediated by endothelium-derived vasodilator substances.
Eight rings cut from same artery were studied in parallel. Each ring was connected to an isometric force transducer and suspended in an organ chamber filled with 10 mL control solution (37°C, pH 7.4) bubbled with 95% O2 and 5% CO2. The ring was gradually stretched to the optimal point of its length-tension curve as determined by the contraction to phenylephrine (3 x 10–7 m). In most of the studied arteries, optimal resting tension was achieved at approximately 1.5 g. Preparations were equilibrated for 90 min. During submaximal contraction (75% to 80%) to phenylephrine, the concentration-response curve to levcromakalim (10–8 to 10–5 m), droperidol (10–9 to 10–5 m), or phentolamine (10–10 to 10–6 m) was obtained in a cumulative fashion. Some rings were treated with glibenclamide (10–5 M), droperidol (10–8 to 10–7 M), phentolamine (3 x 10–9 M), or some combination of these compounds given 15 min before addition of phenylephrine (3 x 10–7 m). To examine the possibility that an -adrenergic receptor antagonist may act on ATP-sensitive K+ channels of vascular smooth muscle, the effect of phentolamine (3 x 10–9 M), which causes a similar vasodilator effect to that induced by droperidol (10–7 M), was also evaluated regarding vasodilator responses to levcromakalim. The vasorelaxation was expressed as a percentage of the maximal relaxation in response to papaverine (3 x 10–4 m), which was added at the end of experiments to produce the maximal relaxation (100%) of arteries.
Arterial rings were longitudinally cut and fixed on the bottom of an experimental chamber. The arteries were continuously perfused with control solution (37°C) bubbled with 95% O2-5% CO2 gas mixture. A glass microelectrode (tip resistance 40 to 80 M
) filled with 3 mol/L KCl and held by a micromanipulator (Narishige, Tokyo, Japan), was inserted into a smooth muscle cell from the intimal side of the vessel (8,9). The electrical signal was amplified using a recording amplifier (Electro 705; World Precision Instruments Inc., Sarasota, FL). The membrane potential was continuously monitored and recorded on a chart recorder (SS-250F-1; SENKONIC Inc., Tokyo, Japan). The validity of a successful impalement was assessed by a sudden negative shift followed by a stable negative voltage for more than 2 min (8,9). Changes in membrane potentials produced by levcromakalim (10–5 M) were continuously recorded. Glibenclamide or droperidol was applied 15 min before membrane potential recordings.
The following drugs were used: droperidol, dimethyl sulfoxide, glibenclamide, phentolamine, and phenylephrine (Sigma, St. Louis, MO). Levcromakalim was a generous gift from GlaxoSmithKline (Greenford, UK). Stock solutions of levcromakalim (10–5 M), droperidol (10–5 M), and glibenclamide (10–5 M) were prepared in dimethyl sulfoxide (3 x 10–4 M), and other drugs were dissolved in distilled water. In the preliminary experiments, we have demonstrated that this concentration of dimethyl sulfoxide did not alter vasorelaxation produced by levcromakalim. The concentrations of drugs are expressed as final molar (m) concentration.
The data are expressed as means ± sd; n refers to the number of rats from which the aorta was taken. Statistical analysis was performed using repeated-measures analysis of variance, followed by Student-Newman-Keuls test for multiple comparisons. Differences were considered to be statistically significant at P < 0.05.
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Results
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During submaximal contraction to phenylephrine (3 x 10–7 M), the selective ATP-sensitive K+ channel opener, levcromakalim (10–8 to 10–5 M) induced concentration-dependent relaxation in the rat aorta without endothelium (Fig. 1). A selective ATP-sensitive K+ channel antagonist, glibenclamide (10–5 M) completely abolished this vasorelaxation (Fig. 1), whereas it did not affect the basal tone of aorta. Maximal vasorelaxation induced by papaverine (3 x 10–4 M) in each group of Figure 1 was 100% = 1.46 ± 0.19 g or 1.24 ± 0.74 g for control rings and rings treated with glibenclamide, respectively (statistically insignificant).
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Figure 1. Concentration-response curves to levcromakalim (10–8 to 10–5 M) in the absence or in the presence of glibenclamide (10–5 M), obtained in the rat aorta without endothelium. *Difference between control rings and rings treated with glibenclamide is statistically significant (P < 0.05).
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Droperidol (10–8 to 10–7 M) significantly augmented vasorelaxation in response to levcromakalim in a concentration-dependent fashion (Fig. 2). The effective concentrations to cause 50% of maximal relaxation in response to levcromakalim (EC50) in arteries treated with droperidol were significantly reduced, whereas maximal relaxations induced by papaverine (3 x 10–4 M) did not differ among groups: EC50 (x10–8 M) = 14.43 ± 3.27, 9.85 ± 2.79 (P < 0.05), 6.33 ± 2.41(P < 0.05), or 6.16 ± 0.68 (P < 0.05), and maximal vasorelaxation (100%) = 1.45 ± 0.19 g, 1.44 ± 0.43 g, 1.40 ± 0.21 g, or 1.43 ± 0.19 g for control rings and rings treated with droperidol (10–8 M), droperidol (3 x 10–8 M), or droperidol (10–7 M), respectively.
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Figure 2. Concentration-response curves to levcromakalim in the absence or in the presence of droperidol (10–8, 3 x 10–8, 10–7 M), obtained in the rat aorta without endothelium. *Difference between control rings and rings treated with droperidol is statistically significant (P < 0.05).
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Glibenclamide (10–5 M) abolished vasorelaxation in response to levcromakalim in the rat aorta treated with droperidol (10–7 M) (Fig. 3). Maximal vasorelaxation in each group of Figure 3 was 100% = 1.45 ± 0.21 g or 1.46 ± 0.40 g for control rings and rings treated with glibenclamide plus droperidol, respectively (statistically insignificant).
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Figure 3. Concentration-response curves to levcromakalim in the presence of droperidol (10–7 M) alone or droperidol (10–7 M) in combination with glibenclamide (10–5 M), obtained in the rat aorta without endothelium. *Difference between rings treated with droperidol and rings treated with droperidol in combination with glibenclamide is statistically significant (P < 0.05).
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During contraction to phenylephrine (3 x 10–7 M), droperidol (10–9 to 10–5 M) induced concentration-dependent relaxation in the rat aorta without endothelium, whereas glibenclamide (10–5 M) did not alter this vasorelaxation (Fig. 4). Maximal vasorelaxation in each group of Figure 1 was 100% = 1.48 ± 0.38 g or 1.22 ± 0.22 g for control rings and rings treated with glibenclamide, respectively (statistically insignificant).
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Figure 4. Concentration-response curves to droperidol (10–9 to 10–5 M) in the absence or in the presence of glibenclamide (10–5 M), obtained in the rat aorta without endothelium.
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An –adrenergic receptor antagonist, phentolamine, (10–10 to 10–6 M) induced concentration-dependent relaxation in the rat aorta without endothelium, and phentolamine (3 x 10–9 M) produced a similar vasodilator effect (approximately 20% vasorelaxation) to that obtained by droperidol (10–7 M) (Fig. 5, left). However, phentolamine (3 x 10–9 M) did not affect vasorelaxation in response to levcromakalim (Fig. 5, right). Maximal vasorelaxation in Figure 5 (left) was 100% = 1.28 ± 0.68 g, and that in each group of Figure 5 (right) was 100% = 1.23 ± 0.20 g or 1.27 ± 0.32 g for control rings and rings treated with phentolamine, respectively (statistically insignificant).
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Figure 5. Concentration-response curves to phentolamine (10–10 to 10–6 M) (left) and those to levcromakalim in the absence or in the presence of phentolamine (3 x 10–9 M) (right), obtained in the rat aorta without endothelium.
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Levcromakalim (10–5 M) produced hyperpolarization of smooth muscle cells of rat aorta, which is abolished by glibenclamide (10–5 M), and augmented by droperidol (10–7 M) (Fig. 6, left). In the arteries treated with droperidol (10–7 M) levcromakalim-induced hyperpolarization was abolished by glibenclamide (10–5 M) (Fig. 6, right), whereas droperidol (10–7 M) itself did not induce hyperpolarization of smooth muscle cells (data not shown). Resting membrane potentials did not differ among the groups shown in Figure 6 (control = –43.4 ± 3.1 mV; glibenclamide [10–5 M] = –43.4 ± 1.5 mV; droperidol [10–7 M] = –40.6 ± 1.1 mV, for Fig. 6, left, respectively, and droperidol [10–7 M] = –41.3 ± 2.1 mV; glibenclamide [10–5 M] plus droperidol [10–7 M] = –41.8 ± 0.8 mV, for Fig. 6, right, respectively).
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Figure 6. Changes in membrane potential of smooth muscle cells in the rat aorta induced by levcromakalim (10–5 M). Levcromakalim-induced hyperpolarization is significantly reduced by glibenclamide (10–5 M), whereas it is significantly augmented by droperidol (10–7 M) (left, *P < 0.05). The hyperpolarization in the arteries treated with droperidol (10–7 M) is abolished by the treatment with glibenclamide (10–5 M) (right, *P < 0.05).
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Discussion
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This is the first study evaluating the effect of droperidol on K+ channels of vascular smooth muscle. In the rat aortas without endothelium, droperidol caused augmentation of vasorelaxation and hyperpolarization via ATP-sensitive K+ channels. Our results showing that an ATP-sensitive K+ channel antagonist, glibenclamide, almost abolished vasorelaxation and hyperpolarization in response to levcromakalim in the rat aorta treated with droperidol reinforce the conclusion that ATP-sensitive K+ channels mediate the augmenting effects of droperidol on vasorelaxation and hyperpolarization in the vascular smooth muscle. However, in the current study, the augmenting effects of droperidol on vasorelaxation and hyperpolarization induced by the largest concentration of levcromakalim were not fully antagonized by glibenclamide. Therefore, we cannot completely exclude the possibility that a part of this augmentation may have been mediated by mechanisms other than the activation of ATP-sensitive K+ channels because we used a large concentration of glibenclamide. In contrast to our results, previous studies demonstrated that droperidol inhibits the activity of voltage-dependent K+ channels in cardiac myocytes (above 10–8 M) and neuronal cells (above 10–6 or 10–5 M) (1,10,11). Differences in the types of K+ channels between these studies and ours are the most likely explanation for the differential effects of droperidol on K+ channels in diverse tissues.
The ATP-sensitive K+ channel is a complex of two proteins: the sulfonylurea receptor and Kir6.1 or 6.2, which belongs to the inward rectifier K+ channel family (12). A recent study using the truncated isoforms of ATP-sensitive K+ channel subunits has suggested that the inhibitory effect of another IV anesthetic, ketamine, is mediated by the sulfonylurea receptor subunit expressed on cardiac myocytes, indicating the site of action of IV anesthetics to reduce the activity of these channels (13). Although this study has introduced the likely mechanism in terms of the inhibitory effect of IV anesthetics on these channels, we do not have a clear explanation for the augmenting effects of IV anesthetics on ATP-sensitive K+ channels. However, because the sulfonylurea receptor of ATP-sensitive K+ channel is reportedly a primary target of the openers of this channel, we would ascribe modification of the activity of sulfonylurea receptors in ATP-sensitive K+ channels to the increased activity of these channels induced by droperidol (14).
Our previous studies demonstrated that levcromakalim is a selective ATP-sensitive K+ channel opener in the rat aorta, suggesting that this preparation is a suitable model by which we can evaluate the role of ATP-sensitive K+ channels in vascular smooth muscle (5). Indeed, in the rat aorta, glibenclamide (10–5 M) abolished vasorelaxation as well as hyperpolarization in response to levcromakalim (10–5 M), indicating that both compounds probably act on ATP-sensitive K+ channels (15,16). We used this concentration of glibenclamide because previous studies demonstrated that a larger concentration of glibenclamide (>10–5 M) is needed to completely block ATP-sensitive K+ channels in the vascular smooth muscle cell (17). In our previous study, glibenclamide (10–5 M) did not alter vasorelaxation in response to nitric oxide donors, indicating the relative selectivity of glibenclamide on ATP-sensitive K+ channels in this preparation (18). Indeed, 10–5 M of glibenclamide or levcromakalim has been used as a selective antagonist and an opener of ATP-sensitive K+ channels in electrophysiological studies on vascular smooth muscle cells (19–21).
In the current study, changes in membrane potential induced by levcromakalim (10–5 M) (approximately 4.5 mV) were smaller than we expected, although we have performed these electrophysiological experiments according to our previous studies (8,9). Resting membrane potential of vascular smooth muscle in the current study is consistent with previous studies, demonstrating that it is approximately -40 mV (16). Therefore, the small degree of hyperpolarization induced by levcromakalim in the current study may have been resulted from our experimental condition but not our technical problems. Importantly, previous reports in a similar experimental condition to ours documented that the small change in membrane potential, such as 2.5 mV, can induce almost half of the vasorelaxation in isolated arteries, indicating that the relationship between the degrees of hyperpolarization and vasorelaxation may be diverse, depending on the experimental conditions (22).
During contraction to phenylephrine, droperidol itself induced concentration-dependent relaxation, whereas glibenclamide did not alter this vasorelaxation. In addition, droperidol, in the absence of levcromakalim, did not produce any changes in membrane potential of vascular smooth muscle cells. These results suggest that the vasodilator effects produced by droperidol itself are not attributable to the activation of ATP-sensitive K+ channels. Although we do not have a clear explanation of why there are such negative effects of droperidol itself on these channels, it is clear that droperidol is capable of modifying the function of ATP-sensitive K+ channels in the presence of the channel opener. To further eliminate the possibility that –adrenergic receptor inhibition may be involved in the augmented activity of ATP-sensitive K+ channels in the current study (6,7), we also evaluated the effect of an –adrenergic receptor antagonist phentolamine on vasorelaxation mediated by these channels in other experiments. Phentolamine (3 x 10–9 M), which can produce a similar vasodilator effect (approximately 20% vasorelaxation) to that obtained by droperidol (10–7 M), did not affect vasorelaxation in response to levcromakalim, reinforcing the negative roles of the –adrenergic receptor antagonism induced by droperidol in augmented activity of ATP-sensitive K+ channels in our experimental condition.
A free plasma concentration of droperidol in humans, when this drug is administered as an IV anesthetic, is reported up to 2 x 10–7 M (11,23,24). A small dose of droperidol (0.625 to 1.25 mg) has been used for the management of postoperative nausea and vomiting and, for this use, its estimated free plasma concentration will be 2.5 to 5 x 10–8 M (2,11,23,24). Therefore, our results suggest that droperidol, even when used as an antiemetic, augments the activity of ATP-sensitive K+ channels, resulting in increased vasodilation in the clinical setting.
ATP-sensitive K+ channels expressed on blood vessels play an important role in the maintenance of organ blood flow during ischemia (4,25–27). In addition, mitochondrial ATP-sensitive K+ channels contribute to the enhancement of tissue tolerance toward ischemia, although their molecular structures have not been cloned (28,29). Therefore, our results suggest the possibility that droperidol, even when used as an antiemetic, may produce protective effects on diverse organs against ischemia during anesthesia in the presence of ATP-sensitive K+ channel openers. Droperidol may also increase the vasodilator potential of several available ATP-sensitive K+ channel openers that can be administered to treat cardiovascular disorders, including hypertension and ischemic heart disease (30–32). However, whether this augmentation of vasodilation is beneficial or not will be an issue that remains to be clarified in future studies.
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Footnotes
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Supported, in part, by Grant-in-Aid, 16390458 (H. K.), 16659426 (H. K.), 15790829 (M. D.), 14770786 (Y. K.), 16591558 (K. M.) and 13470327 (Y. H.) for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, Tokyo Japan, and 11-7(H. K.) for Medical Research from Wakayama prefecture, Wakayama, Japan.
Accepted for publication October 4, 2005.
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Las Vegas, Nevada, October 23–27, 2004.
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Abstract
Introduction
