Abstract
Aim:
To investigate the presynaptic effects of propofol, a short-acting intravenous anesthetic, in the frog neuromuscular junction.
Methods:
Frog cutaneous pectoris nerve muscle preparations were prepared. A fluorescent tool (FM1-43) was used to visualize the effect of propofol on synaptic vesicle exocytosos in the frog neuromuscular junction.
Results:
Low concentrations of propofol, ranging from 10 to 25 μmol/L, enhanced spontaneous vesicle exocytosis monitored by FM1-43 in a Ca2+-dependent and Na+-independent fashion. Higher concentrations of propofol (50, 100, and 200 μmol/L) had no effect on spontaneous exocytosis. By contrast, higher concentrations of propofol inhibited the Na+-dependent exocytosis evoked by 4-aminopyridine but did not affect the Na+-independent exocytosis evoked by KCl. This action was similar and non-additive with that observed by tetrodotoxin, a Na+ channel blocker.
Conclusion:
Our data suggest that propofol has a dose-dependent presynaptic effect at the neuromuscular transmission which may help to understand some of the clinical effects of this agent on neuromuscular function.
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References
Franks NP, Lieb WR . Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.
Yamakura T, Bertaccini E, Trudell JR, Harris RA . Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol 2001; 41: 23–51.
Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL . Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005; 26: 503–10.
Franks NP . Molecular targets underlying general anaesthesia. Br J Pharmacol 2006; 147: S72–81.
Inoue Y, Shibuya I, Kabashima N, Noguchi J, Harayama N, Ueta Y, et al. The mechanism of inhibitory actions of propofol on rat supraoptic neurons. Anesthesiology. 1999; 91: 167–78.
Shirasaka T, Yoshimura Y, Qiu DL, Takasaki M . The effects of propofol on hypothalamic paraventricular nucleus neurons in the rat. Anesth Analg 2004; 98: 1017–23.
Martella G, De Persis C, Bonsi P, Natoli S, Cuomo D, Bernardi G, et al. Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: implications for its antiepileptic activity. Epilepsia 2005; 46: 624–35.
Ratnakumari L, Hemmings HC Jr . Effects of propofol on sodium channel-dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes. Anesthesiology 1997; 86: 428–39.
Lingamaneni R, Birch ML Hemmings HC Jr . Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol. Anesthesiology 2001; 95: 1460–6.
Frenkel C, Urban BW . Human brain sodium channels as one of the molecular target sites for the new intravenous anaesthetic propofol (2,6-diisopropylphenol). Eur J Pharmacol 1991; 208: 75–9.
Frenkel C, Duch DS, Urban BW . Effects of iv anaesthetics on human brain sodium channels. Br J Anaesth 1993; 71: 15–24.
Lingamaneni R, Hemmings HC Jr . Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABA(A) receptors. Br J Anaesth 2003; 90: 199–211.
Martella G, De Persis C, Bonsi P, Natoli S, Cuomo D, Bernardi G, et al. Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: implications for its antiepileptic activity. Epilepsia 2005; 46: 624–35.
Wali FA . Effects of some intravenous anaesthetics on the contractile responses produced in the chick biventer cervicis skeletal muscle. Pharmacol Res Commun 1985; 17: 361–76.
Lebeda MD, Wegrzynowicz ES, Wachtel RE . Propofol potentiates both pre- and postsynaptic effects of vecuronium in the rat hemidiaphragm. Br J Anaesth 1992; 68: 282–5.
Abdel-Zaher AO, Askar FG . The myoneural effects of propofol emulsion (Diprivan) on the nerve-muscle preparations of rats. Pharmacol Res 1997; 36: 323–32.
Robertson EN, Fragen RJ, Booij LH, van Egmond J, Crul JF . Some effects of diisopropylphenol (ICI35868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man. Br J Anaesth 1983; 55: 723–8.
Fujii Y, Hoshi T, Takahashi S, Toyooka H . Propofol decreases diaphragmatic contractility in dogs. Anesth Analg 1999; 89: 1557–60.
Fujii Y, Hoshi T, Takahashi S, Toyooka H . The effect of sedative drugs on diaphragmatic contractility in dogs: propofol versus midazolam. Anesth Analg 2000; 91: 1035–7.
Fujii Y, Uemura A, Toyooka H . The dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Anesth Analg 2001; 93: 1194–8.
Fujii Y, Toyooka H . Midazolam versus propofol for reducing contractility of fatigued canine diaphragm. Br J Anaesth 2001; 86: 879–81.
Bouhemad B, Langeron O, Orliaguet G, Coriat P, Riou B . Effects of halothane and isoflurane on the contraction, relaxation and energetics of rat diaphragmatic muscle. Br J Anaesth 2002; 89: 479–85.
Nishina K, Mikawa K, Kodama S-I, Kagawa T, Uesugi T, Obara H . The effects of enflurane, isoflurane, and intravenous anesthetics on rat diaphragmatic function and fatigability. Anesth Analg 2003; 96: 1674–8.
Betz WJ, Bewick GS . Optical analysis of synaptic vesicle recycling at the frog neuromuscular junction. Science 1992; 255: 200–3.
Betz WJ, Mao F, Bewick GS . Activity-dependent fluorescent staining and destaining of living vertebrate motor nerve terminals. J Neurosci 1992; 12: 363–75.
Gaffield MA, Betz WJ . Imaging synaptic vesicle exocytosis and endocytosis with FM dyes. Nat Protoc 2006; 1: 2916–21.
Guatimosim C, Romano-Silva MA, Gomez MV, Prado MAM . Use of fluorescent probes to follow membrane traffic in nerve terminals. Braz J Med Biol Res 1998; 31: 1491–500.
Rizzoli SO, Richards DA, Betz WJ . Monitoring synaptic vesicle recycling in frog motor nerve terminals with FM dyes. J Neurocytol 2003; 32: 539–49.
Nicholls DG . The glutamatergic nerve terminal. Eur J Biochem 1993; 212: 613–31.
Hemmings HC Jr, Yan W, Westphalen RI, Ryan TA . The general anesthetic isoflurane depresses synaptic vesicle exocytosis. Mol Pharmacol 2005; 67: 1591–9.
Kochi T, Ide T, Isono S, Mizuguchi T, Nishino T . Different effects of halothane and enflurane on diaphragmatic contractility in vivo. Anesth Analg 1990; 70: 362–8.
Ide T, Kochi T, Isono S, Mizuguchi T . Diaphragmatic activity during isoflurane anaesthesia in dogs. Acta Anaesthesiol Scand 1993; 37: 253–7.
Kagawa T, Maekawa N, Mikawa K, Nishina K, Yaku H, Obara H . The effect of halothane and sevoflurane on fatigue-induced changes in hamster diaphragmatic contractility. Anesth Analg 1998; 86: 392–7.
Südhof TC . The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 1995; 375: 645–53.
Ratnakumari L, Hemmings HC Jr . Effects of propofol on sodium channel-dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes. Anesthesiology 1997; 86: 428–39.
Lingamaneni R, Birch ML, Hemmings HC Jr . Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol. Anesthesiology 2001; 95: 1460–6.
Pashkov VN, Hemmings HC Jr . The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals. Anesth Analg 2002; 95: 1274–81.
Wakasugi M, Hirota K, Roth SH, Ito Y . The effects of general anesthetics on excitatory and inhibitory synaptic transmission in area CA1 of the rat hippocampus in vitro. Anesth Analg 1999; 88: 676–80.
Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith R, et al. The interaction of fentanyl on the CP50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81: 820–8.
Kazama T, Ikeda K, Morita K . The pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses to skin incision, peritoneum incision, and abdominal wall retraction. Anesthesiology 1998; 89: 894–06.
Haeseler G, Störmer M, Bufler J, Dengler R, Hecker H, Piepenbrock S, et al. Propofol blocks human skeletal muscle sodium channels in a voltage-dependent manner. Anesth Analg 2001; 92: 1192–8.
Servin F, Desmonts JM, Haberer JP, Cockshott ID, Plummer GF, Farinotti R . Pharmacokinetics and protein binding of propofol in patients with cirrhosis. Anesthesiology 1988; 69: 887–91.
Rehberg B, Duch DS . Suppression of central nervous system sodium channels by propofol. Anesthesiology 1999; 91: 512–20.
Shyr MH, Tsai TH, Tan PP, Chen CF, Chan SH . Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat. Neurosci Lett 1995; 184: 212–5.
Tonner PH, Poppers DM, Miller KW . The general anesthetic potency of propofol and its dependence on hydrostatic pressure. Anesthesiology 1992; 77: 926–31.
Eckenhoff RG, Johansson JS . On the relevance of “clinically relevant concentrations” of inhaled anesthetics in in vitro experiments. Anesthesiology 1999; 91: 856–60.
Acknowledgements
This work was supported by grants from CNPq, FAPEMIG and CAPES. We thank Dr Hugh C HEMMINGS Jr for valuable comments on this manuscript.
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Leite, L., Gomez, R., Fonseca, M. et al. Effect of intravenous anesthetic propofol on synaptic vesicle exocytosis at the frog neuromuscular junction. Acta Pharmacol Sin 32, 31–37 (2011). https://doi.org/10.1038/aps.2010.175
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DOI: https://doi.org/10.1038/aps.2010.175
