Free
Pain Medicine  |   October 2002
Ketamine Stereoselectively Affects Vasorelaxation Mediated by ATP-sensitive K+Channels in the Rat Aorta
Author Affiliations & Notes
  • Mayuko Dojo, M.D.
    *
  • Hiroyuki Kinoshita, M.D.
  • Hiroshi Iranami, M.D.
  • Katsutoshi Nakahata, M.D.
    §
  • Yoshiki Kimoto, M.D.
    §
  • Yoshio Hatano, M.D.
  • *Staff Anesthesiologist, §Instructor, ∥Professor and Chair, Department of Anesthesiology, Wakayama Medical College, and †Staff Anesthesiologist, ‡Chief Anesthesiologist, Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center.
  • Received from the Department of Anesthesiology, Wakayama Medical College, and from the Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan.
Article Information
Pain Medicine
Pain Medicine   |   October 2002
Ketamine Stereoselectively Affects Vasorelaxation Mediated by ATP-sensitive K+Channels in the Rat Aorta
Anesthesiology 10 2002, Vol.97, 882-886. doi:
Anesthesiology 10 2002, Vol.97, 882-886. doi:
IT is well known that the commercially available ketamine is a racemic mixture of two isomers, S(+) and R(−) ketamine. The S(+) isomer reportedly has a more potent anesthetic effect and fewer psychotomimetic side effects compared with the R(−) isomer or the racemate. 1,2 These appear to be reasons for the expectation that in the near future S(+) ketamine, rather than ketamine racemate, should be available for clinical use as an intravenous anesthetic or a N  -methyl-d-aspartate receptor antagonist.
A recent study in cardiac myocytes has demonstrated that ketamine racemate inhibits the activity of sarcolemmal adenosine triphosphate (ATP)-sensitive K+channels. 3 In addition, more recent studies in the isolated rat heart and the in vivo  model of rabbit have demonstrated that ketamine racemate and R(−) ketamine, but not S(+) ketamine, are capable of attenuating the ischemic preconditioning of heart, indicating that R(−) ketamine inhibits the activity of mitochondrial ATP-sensitive K+channels in these preparations. 4,5 These results suggest that ketamine may stereoselectively reduce the activity of these channels in cardiac myocytes.
Cumulative findings from recent studies have indicated that ATP-sensitive K+channels play a crucial role in physiologic and pathophysiologic vasodilation. 6–8 In contrast to above findings in cardiac myocytes, the effect of ketamine on vasorelaxation mediated by ATP-sensitive K+channels has not been studied. In addition, the subtype of ATP-sensitive K+channels in vascular smooth muscle cells is distinct from other subtypes, including those expressed in cardiac sarcolemma. 9 Therefore, the present study was designed to investigate whether clinically relevant concentrations of ketamine alter vasorelaxation induced by an ATP-sensitive K+channel opener in the isolated rat aorta, and whether this effect of ketamine is stereoselective.
Materials and Methods
The institutional animal care and use committee approved this study. Male Wistar rats (250–350 g) were anesthetized with inhalation of 3% halothane. During this anesthetic condition, the rats were killed by exsanguination, and their thoracic aortas were harvested. Thoracic aortic rings of 2.5-mm length were studied in modified Krebs-Ringer's bicarbonate solution (control solution) of the following composition: NaCl 119, mm; KCl 4.7, mm; CaCl2, 2.5 mm; MgSO4, 1.17 mm; KH2PO4, 1.18 mm; NaHCO3, 25 mm; and glucose, 11 mm. In some rings, the endothelium was removed mechanically. Endothelial removal or intact endothelial function was confirmed by the absence and the presence of the relaxation in response to acetylcholine (10−5m), respectively. Several 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 of control solution (37°C, pH 7.4) bubbled with 95% O2and 5% CO2. The artery was gradually stretched to the optimal point of its length–tension curve as determined by the contraction to phenylephrine (3 × 10−7m). In most of studied arteries, optimal tension was achieved approximately at 1.5 g. Preparations were equilibrated for 90 min. During submaximal contraction to phenylephrine, the concentration–response curve to levcromakalim (10−8to 10−5m) or sodium nitroprusside (10−10-to 10−5m) was obtained. Some rings were pretreated with glibenclamide (10−5m), S(+) ketamine (10−4m), or ketamine racemate (10−5to 10−4m), which was given 15 min before addition of phenylephrine (3 × 10−7m). The vasorelaxation was expressed as a percentage of the maximal relaxation in response to papaverine (3 × 10−4m), which was added at the end of experiments to produce the maximal relaxation (100%) of arteries.
Drugs
The following pharmacologic agents were used: dimethyl sulfoxide (DMSO), glibenclamide, S(+) ketamine, ketamine racemate, phenylephrine, and sodium nitroprusside (Sigma, St. Louis, MO). Levcromakalim was a generous gift from GlaxoSmithKline plc (Greenford, UK). Drugs were dissolved in distilled water such that volumes of less than 60 μl are added to the organ chambers. Stock solutions of levcromakalim (10−5m) and glibenclamide (10−5m) were prepared in DMSO (3 × 10−4m). The vehicle (DMSO) of glibenclamide itself did not affect the vasorelaxation in response to levcromakalim (data not shown). The concentrations of drugs are expressed as final molar (m) concentration.
Statistical Analysis
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 (ANOVA), followed by Scheffé F test for multiple comparisons. Differences were considered to be statistically significant when P  was less than 0.05.
Results
During submaximal contraction to phenylephrine (3 × 10−7m), a selective ATP-sensitive K+channel opener levcromakalim (10−8to 10−5m) produced vasorelaxation of the rat aorta with or without endothelium in a concentration-dependent fashion (fig. 1). This relaxation induced by levcromakalim was completely abolished by a selective ATP-sensitive K+channel antagonist glibenclamide (10−5m;fig. 1). Ketamine racemate (3 × 10−5to 10−4m) significantly inhibited vasorelaxation in response to levcromakalim in a concentration-dependent fashion (fig. 2), whereas S(+) ketamine (10−4m) did not affect the relaxation (fig. 3). In contrast, ketamine racemate (10−4m) and S(+) ketamine (10−4m) did not alter vasorelaxation in response to a nitric oxide donor sodium nitroprusside (10−10to 10−5m) in the aorta without endothelium (fig. 4). Ketamine racemate (10−5to 10−4m) and S(+) ketamine (10−5to 10−4m) produced only slight vasorelaxation in the endothelium-denuded aorta contracted by phenylephrine (3 × 10−7m), and the relaxations produced by these compounds were not different (fig. 5). In addition, neither ketamine racemate nor S(+) ketamine affected contraction in response to phenylephrine (3 × 10−7m) (data not shown) and maximal relaxation induced by papaverine (3 × 10−4m) (see figure legends).
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P  < 0.05).
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P 
	< 0.05).
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P  < 0.05).
×
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P  < 0.05).
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P 
	< 0.05).
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P  < 0.05).
×
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
×
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
×
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
×
Discussion
This is the first study demonstrating that in the isolated rat aorta, ketamine racemate inhibits vasorelaxation induced by an ATP-sensitive K+channel opener, whereas S(+) ketamine did not produce any inhibitory effect on this relaxation. These results suggest that ketamine enantiomers may differentially alter vasodilation via  ATP-sensitive K+channels.
Our previous studies demonstrated that levcromakalim is a selective ATP-sensitive K+channel opener in the rat aorta, suggesting that this preparation is one of the established models by which we can evaluate the role of ATP-sensitive K+channels in a conduit artery. 8,10 Indeed, in the present study and in our previous studies, a selective ATP-sensitive K+channel antagonist glibenclamide abolished vasorelaxation in response to levcromakalim, also indicating the selectivity of levcromakalim on ATP-sensitive K+channels in blood vessels. 8,10–12 In addition, our previous finding that glibenclamide does not alter vasorelaxation in response to nitric oxide donors in the rat aorta reinforces the selectivity of glibenclamide on ATP-sensitive K+channels in this preparation. 13 
In the rat aorta, ketamine racemate inhibited vasorelaxation induced by levcromakalim in a concentration-dependent fashion, and this inhibitory effect was unchanged even in the presence of endothelium. These results support the conclusion that ketamine racemate may modulate ATP-sensitive K+channels on vascular smooth muscle, although a previous study demonstrated that rat aorta endothelial cells express ATP-sensitive K+channels. 14 Our finding is also in agreement with a recent study documenting that the same concentrations of ketamine racemate as used in the present study inhibit the activity of sarcolemmal ATP-sensitive K+channels in cardiac myocytes. 3 Therefore, ketamine racemate appears to similarly reduce the activity of two different subtypes of ATP-sensitive K+channels expressed in vascular smooth muscle cells and cardiac myocytes. 9 Additionally, in the rat aorta, ketamine racemate did not alter vasorelaxation induced by sodium nitroprusside. Our results suggest that this intravenous anesthetic agent may selectively affect ATP-sensitive K+channels and that a nitric oxide donor may be capable of offsetting the inhibitory effect of ketamine racemate on vasodilation mediated by these channels.
In the blood vessels, the effects of ketamine on K+channels, other than those of ATP-sensitive, have not been well studied. A recent study on canine pulmonary artery has demonstrated that ketamine racemate inhibits vasorelaxation induced by endothelium-derived hyperpolarizing factor, which can produce relaxation mediated by Ca2+-dependent K+channels. 15 However, in this study, Murray et al.  15 documented that ketamine decreases Ca2+levels in the cultured endothelial cells, suggesting that ketamine racemate may impair vasorelaxation mediated by the hyperpolarizing factor via  the inhibition of increase in endothelial Ca2+, which can induce production of this factor. Therefore, even considering these previous studies, it is unclear whether ketamine racemate can produce the inhibition of Ca2+-dependent K+channels in vascular smooth muscle cells.
In contrast to the results with ketamine racemate, S  (+) ketamine did not produce any inhibitory effect on vasorelaxation mediated by ATP-sensitive K+channels. Because ketamine racemate is the mixture of S  (+) and R  (−) ketamine stereoisomers, our results suggest that R  (−) ketamine can solely produce the impairment of vasodilation mediated by ATP-sensitive K+channels. The ATP-sensitive K+channel is a complex of two proteins: the sulfonylurea receptor, which is a member of the ATP-binding cassette transporter family, and Kir6.1 or 6.2, which belongs to the inward rectifier K+channel family. 9 As recent biochemical studies have revealed that the sulfonylurea receptor of ATP-sensitive K+channel is a primary target of the openers of this channel, R  (−) ketamine appears to alter vasorelaxation in response to an ATP-sensitive K+channel opener via  the effect on the sulfonylurea receptor of these channels. 16 In the isolated rat heart and in the in vivo  model of rabbit, ketamine racemate and R  (−) ketamine, but not S  (+) ketamine, were capable of attenuating the ischemic preconditioning of heart, indicating that R  (−) ketamine may inhibit the activity of mitochondrial ATP-sensitive K+channels in cardiac myocytes. 4,5 In contrast to the subtype of smooth muscle ATP-sensitive K+channels, that of mitochondrial ATP-sensitive K+channels has not been cloned, and, therefore, it is still unclear whether R  (−) ketamine can similarly affect the channel compartments like the sulfonylurea receptor expressed in cardiac myocytes and vascular smooth muscle cells, resulting in the inhibition of these ATP-sensitive K+channels. 17 However, these studies, including ours, strongly support the conclusion that ketamine stereoselectively reduces the activity of ATP-sensitive K+channels in these preparations.
Less than 10−4m of ketamine racemate and S  (+) ketamine itself similarly produced only slight vasorelaxation in the aorta contracted by phenylephrine. As already reported in the rat aorta, ketamine enantiomers, including S  (+) ketamine and ketamine racemate, seem to be capable of inducing only slight vasodilator effect in these concentration ranges. 18 Previous studies in pulmonary and mesenteric arteries also demonstrated that ketamine racemate, within the concentration ranges similar to the present study, can produce only slight vasorelaxation in arteries contracted with an α-agonist norepinephrine. 19,20 In addition, in the present study, neither ketamine racemate nor S  (+) ketamine affected contraction in response to phenylephrine. Therefore, it is unlikely that the effect of ketamine racemate on vasorelaxation mediated by ATP-sensitive K+channels are modified by its vasoconstrictor and vasodilator effect on the aorta.
It was reported that 5 min after induction of anesthesia with 2 mg/kg of ketamine racemate, the plasma concentration reaches 6 × 10−5m. 21 As about 20% of ketamine are bound to plasma proteins, concentrations of ketamine used in the present study are clinically relevant. 22 Therefore, our results suggest that in clinical situations, ketamine racemate impairs vasodilation mediated by ATP-sensitive K+channels, whereas the same concentrations of S(+) ketamine do not alter the vasodilation.
During hypoxia, acidosis, and ischemia, ATP-sensitive K+channels are activated, resulting in arterial dilation or increased tolerance of tissues to ischemia. 7,23,24 In addition, several available ATP-sensitive K+channel openers are expected to manage cardiovascular disorders, including hypertension and ischemic heart disease. 25–27 Therefore, during pathophysiologic situations, ketamine racemate and R  (−) ketamine, but not S  (+) ketamine, may impair vasodilator effects induced by activation of ATP-sensitive K+channels, which play an important role in regulation of circulation. A recent in vivo  study on the rat demonstrated that high doses of S  (+) ketamine, but not R  (−) ketamine, significantly reduce neuronal cell damage in the cerebral cortex after global forebrain ischemia. 28 These results, in addition to our own, may indicate the possibility that ketamine stereoselectively modulates ATP-sensitive K+channels or N  -methyl-d-aspartate receptors, resulting in changes of outcome after cerebral ischemia. Because the same subtype of ATP-sensitive K+channels appears to be expressed in conduit and resistance arteries, our results obtained from a conduit artery may have relevance to vasodilation in resistance blood vessels, such as cerebral arterioles.
References
White PF, Ham J, Way WL, Trevor AJ: Pharmacology of ketamine isomers in surgical patients. A nesthesiology 1980; 52: 231–9White, PF Ham, J Way, WL Trevor, AJ
White PF, Schuttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ: Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth 1985; 57: 197–203White, PF Schuttler, J Shafer, A Stanski, DR Horai, Y Trevor, AJ
Ko S-H, Lee S-K, Han Y-J, Choe H, Kwak Y-G, Chae S-W, Cho K-P, Song H-S: Blockade of myocardial ATP-sensitive potassium channels by ketamine. A nesthesiology 1997; 87: 68–74Ko, S-H Lee, S-K Han, Y-J Choe, H Kwak, Y-G Chae, S-W Cho, K-P Song, H-S
Molojavyi A, Preckel B, Comfère T, Müllenheim J, Thämer V, Schlack W: Effects of ketamine and its isomers on ischemic preconditioning in the isolated rat heart. A nesthesiology 2001; 94: 623–9Molojavyi, A Preckel, B Comfère, T Müllenheim, J Thämer, V Schlack, W
Müllenheim J, Fräβdorf J, Preckel B, Thämer V, Schlack W: Ketamine, but not S(+)-ketamine, blocks ischemic preconditioning in rabbit hearts in vivo. A nesthesiology 2001; 94: 630–6Müllenheim, J Fräβdorf, J Preckel, B Thämer, V Schlack, W
Quayle JM, Nelson MT, Standen NB: ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 1997; 77: 1165–232Quayle, JM Nelson, MT Standen, NB
Kinoshita H, Katusic ZS: Role of potassium channels in relaxations of isolated canine basilar arteries to acidosis. Stroke 1997; 28: 433–8Kinoshita, H Katusic, ZS
Kinoshita H, Iranami H, Kimoto Y, Dojo M, Hatano Y: Mild alkalinization and acidification differentially modify the effects of lidocaine or mexiletine on vasorelaxation mediated by ATP-sensitive K+channels. A nesthesiology 2001; 95: 200–6Kinoshita, H Iranami, H Kimoto, Y Dojo, M Hatano, Y
Fujita A, Kurachi Y: Molecular aspects of ATP-sensitive K+channels in the cardiovascular system and K+channel openers. Pharmacol Ther 2000; 85: 39–53Fujita, A Kurachi, Y
Kinoshita H, Iwahashi S, Kakutani T, Mizumoto K, Iranami H, Hatano Y: The role of endothelium-derived nitric oxide in relaxations to levcromakalim in the rat aorta. Jpn J Pharmacol 1999; 81: 362–6Kinoshita, H Iwahashi, S Kakutani, T Mizumoto, K Iranami, H Hatano, Y
Meisheri KD, Khan SA, Martin JL: Vascular pharmacology of ATP-sensitive K+channels: Interactions between glyburide and K+channel openers. J Vasc Res 1993; 30: 2–12Meisheri, KD Khan, SA Martin, JL
Nelson MT, Quayle JM: Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 268: C799–822Nelson, MT Quayle, JM
Kinoshita H, Ishikawa T, Hatano Y: Role of K+channels in augmented relaxations to sodium nitroprusside induced by mexiletine in rat aortas. A nesthesiology 2000; 92: 813–20Kinoshita, H Ishikawa, T Hatano, Y
Janigro D, West GA, Gordon EL, Winn HR: ATP-sensitive K+channels in rat aorta and brain microvascular endothelial cells. Am J Physiol 1993; 265: C812–21Janigro, D West, GA Gordon, EL Winn, HR
Ogawa K, Tanaka S, Murray PA: Inhibitory effects of etomidate and ketamine on endothelium-dependent relaxation in canine pulmonary artery. A nesthesiology 2001; 94: 668–77Ogawa, K Tanaka, S Murray, PA
D'Hahan N, Jacquet H, Moreau C, Catty P, Vivaudou M: A transmembrane domain of the sulfonylurea receptor mediates activation of ATP-sensitive K+channels by K+channel openers. Mol Pharmacol 1999; 56: 308–15D'Hahan, N Jacquet, H Moreau, C Catty, P Vivaudou, M
O'Rourke B: Myocardial KATP channels in preconditioning. Circ Res 2000; 87: 845–55O'Rourke, B
Kanellopoulos A, Lenz G, Mühlbauer B: Stereoselective differences in the vasorelaxing effects of S(+) and R(−) ketamine on rat isolated aorta. A nesthesiology 1998; 88: 718–24Kanellopoulos, A Lenz, G Mühlbauer, B
Lee T-S, Hou X: Vasoactive effects of ketamine on isolated rabbit pulmonary arteries. Chest 1995; 107: 1152–5Lee, T-S Hou, X
Akata T, Izumi K, Nakashima M: Mechanisms of direst inhibitory action of ketamine on vascular smooth muscle in mesenteric resistance arteries. A nesthesiology 2001; 95: 452–62Akata, T Izumi, K Nakashima, M
Idvall J, Ahlgren I, Aronsen KF, Stenberg P: Ketamine infusions: Pharmacokinetics and clinical effects. Br J Anaesth 1979; 51: 1167–73Idvall, J Ahlgren, I Aronsen, KF Stenberg, P
Gelissen HPM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, Hertog AD: Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. A nesthesiology 1996; 84: 397–403Gelissen, HPM Epema, AH Henning, RH Krijnen, HJ Hennis, PJ Hertog, AD
Taguchi H, Heistad DD, Kitazono T, Faraci FM: ATP-sensitive K+channels mediate dilatation of cerebral arterioles during hypoxia. Circ Res 1994; 74: 1005–8Taguchi, H Heistad, DD Kitazono, T Faraci, FM
Heurteaux C, Lauritzen I, Widmann C, Lazdunski M: Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A 1995; 92: 4666–70Heurteaux, C Lauritzen, I Widmann, C Lazdunski, M
Cook NS: The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci 1988; 9: 21–8Cook, NS
Liu M-H, Floten S, Furnary AP, Yim APC, He G-W: Effects of potassium channel opener aprikalim on the receptor-mediated vasoconstriction in the human internal mammary artery. Ann Thorac Surg 2001; 71: 636–41Liu, M-H Floten, S Furnary, AP Yim, APC He, G-W
Müller-Ehmsen J, Brixius K, Hoischen S, Schwinger HG: Inotropic and coronary vasodilatory actions of the K-adenosine triphosphate channel modulator nicorandil in human tissue. J Pharmacol Exp Ther 1996; 279: 1220–8Müller-Ehmsen, J Brixius, K Hoischen, S Schwinger, HG
Proescholdt M, Heimann A, Kempski O: Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res 2001; 904: 245–51Proescholdt, M Heimann, A Kempski, O
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P  < 0.05).
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P 
	< 0.05).
Fig. 1. Concentration-response curves to levcromakalim (10−8to 10−5m) in the absence and in the presence of glibenclamide (10−5m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,060 ± 134 mg [n = 5] and 1,020 ± 305 mg [n = 5] for control rings with endothelium or rings treated with glibenclamide, 100%= 1,045 ± 91 mg [n = 4] and 1,030 ± 289 mg [n = 4] for control rings without endothelium or rings treated with glibenclamide, respectively). * Difference between control rings and rings treated with glibenclamide is statistically significant (P  < 0.05).
×
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P  < 0.05).
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P 
	< 0.05).
Fig. 2. Concentration-response curves to levcromakalim in the absence or in the presence of ketamine racemate (10−5, 3 × 10−5, 10− 4m), obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,160 ± 221 mg [n = 5], 1,032 ± 267 mg [n = 5], 976 ± 54 mg [n = 5], and 1,008 ± 270 mg [n = 5], for control rings with endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], 100%= 1,060 ± 86 mg [n = 5], 936 ± 43 mg [n = 5], 956 ± 120 mg [n = 5], and 944 ± 100 mg [n = 5], for control rings without endothelium and rings treated with ketamine racemate [ 10−5, 3 × 10− 5, or 10−4m], respectively). *Difference between control rings and rings treated with ketamine racemate (3 × 10−5, 10−4m) is statistically significant (P  < 0.05).
×
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
Fig. 3. Concentration-response curves to levcromakalim in the absence or in the presence of S(+) ketamine (10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,216 ± 278 mg [n = 5] and 1,072 ± 195 mg [n = 5], for control rings with endothelium and rings treated with S(+) ketamine [10−4m], 100%= 1,180 ± 155 mg [n = 6] and 1,083 ± 154 mg [n = 6], for control rings without endothelium and rings treated with S(+) ketamine [10−4m], respectively).
×
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
Fig. 4. Concentration-response curves to sodium nitroprusside (10−10to 10−5m) in the absence or in the presence of ketamine racemate or S(+) ketamine (10−4m), obtained in the rat thoracic aorta without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 784 ± 215 mg [n = 5] and 788 ± 228 mg [n = 5] for control rings or rings treated with ketamine racemate [10−4m], 903 ± 158 mg [n = 6] and 900 ± 204 mg [n = 6] for control rings or rings treated with S(+) ketamine [10−4m], respectively).
×
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
Fig. 5. Concentration-response curves to ketamine racemate or S(+) ketamine (10−5to 10−4m) obtained in the rat thoracic aorta with or without endothelium. Data are shown as means ± SD and expressed as percent of maximal relaxation induced by papaverine (3 × 10−4m; 100%= 1,044 ± 67 mg [n = 5] and 1,024 ± 243 mg [n = 5] for rings with endothelium treated with ketamine racemate or S(+) ketamine, 100%= 1,224 ± 100 mg [n = 5] and 1,204 ± 179 mg [n = 5] for rings without endothelium treated with ketamine racemate or S(+) ketamine, respectively).
×