Dexmedetomidine decreases the convulsive potency of bupivacaine and levobupivacaine in rats: involvement of alpha2-adrenoceptor for controlling convulsions.
Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, is used in combination with local anesthetics for sedation and analgesia. We tested the hypothesis that dexmedetomidine used for sedation alters the convulsive potency of racemic bupivacaine and levobupivacaine in awake, spontaneously breathing rats. In the first experiments, male Sprague-Dawley rats were randomly divided into six groups: bupivacaine with no dexmedetomidine (bupivacaine control; BC), bupivacaine with small-dose dexmedetomidine (BS), bupivacaine with large-dose dexmedetomidine (BL), levobupivacaine with no dexmedetomidine (levobupivacaine control; LC), levobupivacaine with small-dose dexmedetomidine (LS), and levobupivacaine with large-dose dexmedetomidine (LL) (n = 10 for each group). Continuous infusion of dexmedetomidine (Groups BC and LC, 0 microg x kg(-1) x h(-1); Groups BS and LS, 3.6 microg x kg(-1) x h(-1); and Groups BL and LL, 10.8 microg x kg(-1) x h(-1)) was started after bolus injection (Groups BC and LC, 0 microg/kg; Groups BS and LS, 0.5 microg/kg; and Groups BL and LL, 1.5 microg/kg). Fifteen minutes after the start of the dexmedetomidine infusion, continuous infusion of bupivacaine (Groups BC, BS, and BL) or levobupivacaine (Groups LC, LS, and LL) at 1 mg x kg(-1) x min(-1) was started and continued until tonic/clonic convulsions occurred. Dexmedetomidine achieved significantly different sedation levels both in Groups BC, BS, and BL and in Groups LC, LS, and LL (P < 0.05). Convulsive doses of bupivacaine and levobupivacaine were significantly larger in Groups BL and LL than in Groups BC and LC, respectively (P < 0.01 for both). Concentrations of bupivacaine and levobupivacaine in plasma and in brain at the onset of convulsions were also larger in Groups BL and LL than in Groups BC and LC (P < 0.01 for both). In the second experiment, yohimbine (1 mg/kg) administered 10 min before and 5 min after the start of dexmedetomidine infusion completely reversed the sedative effect of dexmedetomidine (bolus 1.5 microg/kg, followed by 10.8 microg x kg(-1) x h(-1)). Convulsive doses and plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions in rats receiving yohimbine and dexmedetomidine were significantly smaller than in those receiving only dexmedetomidine (P < 0.05 for all) and were similar to those without dexmedetomidine or yohimbine. We conclude that dexmedetomidine used for sedation decreases the convulsive potency of both bupivacaine and levobupivacaine in rats. Alpha(2)-adrenoceptor agonism may be involved in this anticonvulsant potency.
Tanaka
Katsuaki
K
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Oda
Yutaka
Y
Funao
Tomoharu
T
Takahashi
Ryota
R
Hamaoka
Naoya
N
Asada
Akira
A
D000818:Animals; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D020927:Dexmedetomidine / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D000077554:Levobupivacaine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D015016:Yohimbine / Q000494:pharmacology
D006993:Hypnotics and Sedatives; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D020927:Dexmedetomidine; D000077554:Levobupivacaine; D002045:Bupivacaine
De Kock M, Le Polain B, Henin D, et al. Clonidine pretreatment reduces the systemic toxicity of intravenous bupivacaine in rats. Anesthesiology 1993;79:282–9.
Lee VC, Moscicki JC, DiFazio CA. Propofol sedation produces dose-dependent suppression of lidocaine-induced seizures in rats. Anesth Analg 1998;86:652–7.
Mirski MA, Rossell LA, McPherson RW, Traystman RJ. Dexmedetomidine decreases seizure threshold in a rat model of experimental generalized epilepsy. Anesthesiology 1994;81:1422–8.
Miyazaki Y, Adachi T, Kurata J, et al. Dexmedetomidine reduces seizure threshold during enflurane anaesthesia in cats. Br J Anaesth 1999;82:935–7.
Halonen T, Kotti T, Tuunanen J, et al. Alpha 2-adrenoceptor agonist, dexmedetomidine, protects against kainic acid-induced convulsions and neuronal damage. Brain Res 1995;693:217–24.
Whittington RA, Virag L, Vulliemoz Y, et al. Dexmedetomidine increases the cocaine seizure threshold in rats. Anesthesiology 2002;97:693–700.
Lahdesmaki J, Sallinen J, MacDonald E, et al. Alpha2-adrenergic drug effects on brain monoamines, locomotion, and body temperature are largely abolished in mice lacking the alpha2A-adrenoceptor subtype. Neuropharmacology 2003;44:882–92.
Niederlehner JR, DiFazio CA, Foster J, Westfall TC. Cerebral monoamines and lidocaine toxicity in rats. Anesthesiology 1982;56:184–7.
Altenburg SP, Farah MB. Tizanidine protects mice against convulsions induced by lidocaine: involvement of alpha 2-adrenoceptors. Pharmacol Toxicol 1999;84:29–33.
Santos AC, DeArmas PI. Systemic toxicity of levobupivacaine, bupivacaine, and ropivacaine during continuous intravenous infusion to nonpregnant and pregnant ewes. Anesthesiology 2001;95:1256–64.
Ladd LA, Chang DH, Wilson KA, et al. Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep. Anesthesiology 2002;97:418–28.
Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998;46:245–9.
Mather LE, Edwards SR, Duke CC, Cousins MJ. Enantioselectivity of thiopental distribution into the central neural tissue of rats: an interaction with halothane. Anesth Analg 1999;89:230–5.
Takahashi H, Sato T, Shimoyama Y, et al. Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin Pharmacol Ther 1999;66:569–81.
Funao T, Oda Y, Tanaka K, Asada A. P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats. Can J Anaesth 2003;50:805–11.
Bol C, Danhof M, Stanski DR, Mandema JW. Pharmacokinetic-pharmacodynamic characterization of the cardiovascular, hypnotic, EEG and ventilatory responses to dexmedetomidine in the rat. J Pharmacol Exp Ther 1997;283:1051–8.
Rosenberg PH, Heavner JE. Acute cardiovascular and central nervous system toxicity of bupivacaine and desbutylbupivacaine in the rat. Acta Anaesthesiol Scand 1992;36:138–41.
Kanazawa H, Nishimura R, Sasaki N, et al. Determination of medetomidine, atipamezole and midazolam in pig plasma by liquid chromatography-mass spectrometry. Biomed Chromatogr 1995;9:188–91.
Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382–94.
Dutta S, Lal R, Karol MD, et al. Influence of cardiac output on dexmedetomidine pharmacokinetics. J Pharm Sci 2000;89:519–27.
Englesson S. The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. I. An experimental study in cats. Acta Anaesthesiol Scand 1974;18:79–87.
Heavner JE. Cardiac dysrhythmias induced by infusion of local anesthetics into the lateral cerebral ventricle of cats. Anesth Analg 1986;65:133–8.
Bernards CM, Artru AA. Hexamethonium and midazolam terminate dysrhythmias and hypertension caused by intracerebroventricular bupivacaine in rabbits. Anesthesiology 1991;74:89–96.
MacMillan LB, Hein L, Smith MS, et al. Central hypotensive effects of the alpha2a-adrenergic receptor subtype. Science 1996;273:801–3.
Nelson LE, Lu J, Guo T, et al. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology 2003;98:428–36.
Talke P, Lobo E, Brown R. Systemically administered alpha2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology 2003;99:65–70.
Papanicolaou J, Summers RJ, Vajda FJ, Louis WJ. The relationship between alpha 2-adrenoceptor selectivity and anticonvulsant effect in a series of clonidine-like drugs. Brain Res 1982;241:393–7.
Stevens JE, Fujinaga M, Oshima E, Mori K. The biphasic pattern of the convulsive property of enflurane in cats. Br J Anaesth 1984;56:395–403.
Abed WT. Alterations of lidocaine and pentylenetetrazol-induced convulsions by manipulation of brain monoamines. Pharmacol Toxicol 1994;75:162–5.