Journal of Anesthesia

, Volume 30, Issue 1, pp 123–131 | Cite as

Reduction in amino-acid-induced anti-hypothermic effects during general anesthesia in ovariectomized rats with progesterone replacement

  • Masahiro Kanazawa
  • Mariko Watanabe
  • Toshiyasu Suzuki
Original Article



The aim of the present study was to determine whether the ovarian hormones, estrogen and progesterone, had different influences on amino-acid-induced anti-hypothermic effects during general anesthesia.


Ovariectomized Sprague–Dawley female rats were divided into four groups: those administered 17β-estradiol plus saline or an amino acid mixture (E2-Sal and E2-AA, respectively) and progesterone plus saline or an amino acid mixture (P-Sal and P-AA, respectively). Five weeks after ovariectomy, rats were given either E2 or P and then administered either Sal or AA solution for 180 min during anesthesia with sevoflurane. Rectal temperatures were measured.


Rectal temperatures were significantly higher in the E2-AA group than in the E2-Sal group 165 and 180 min after initiating the infusion of the test solutions. However, no significant differences were observed between the P-treated groups. The phosphorylation of 4E-BP1 and S6K1 was significantly greater in the E2-AA group than in the E2-Sal group (P < 0.05, P < 0.001, respectively). In contrast, the phosphorylation of 4E-BP1 was significantly lower in the P-AA group than in the P-Sal group (P < 0.001).


These results suggest that progesterone reduces amino-acid-induced anti-hypothermic effects during general anesthesia.


General anesthesia Hypothermia Amino acids Female sex hormones 



We thank the Support Center for Medical Research and Education, Tokai University for use of facilities. We are also grateful to Katsuko Naito and Sachie Tanaka for assistance during the experiments; and Hideo Tsukamoto for performing the immunoblotting procedure.


  1. 1.
    Sessler DI. Perioperative heat balance. Anesthesiology. 2000;92:578–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Sessler DI. Temperature monitoring. In: Miller RD, editor. Miller’s anesthesia. Philadelphia: Elsevier, Churchill Livingstone; 2005. p. 1571–97.Google Scholar
  3. 3.
    Selldén E, Brundin T, Wahren J. Augmented thermic effect of amino acids under general anaesthesia: a mechanism useful for prevention of anaesthesia-induced hypothermia. Clin Sci. 1994;86:611–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Yamaoka I, Doi M, Nakayama M, Ozeki A, Mochizuki S, Sugahara K, Yoshizawa F. Intravenous administration of amino acids during anesthesia stimulates muscle protein synthesis and heat accumulation in the body. Am J Physiol Endocrinol Metab. 2006;290:E882–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Uchida Y, Tokizawa K, Nakamura M, Mori H, Nagashima K. Estrogen in the medial preoptic nucleus of the hypothalamus modulates cold responses in female rats. Brain Res. 2010;2010(1339):49–59.CrossRefGoogle Scholar
  6. 6.
    Uchida Y, Kano M, Yasuhara S, Kobayashi A, Tokizawa K, Nagashima K. Estrogen modulates central and peripheral responses to cold in female rats. J Physiol Sci. 2010;60:151–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Muller KR, Cox RF, Carey NH. Effects of progesterone on protein metabolism in chicken oviduct tissue pretreated with oestrogen. Biochem J. 1970;120:337–44.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Ando S, Kanazawa M, Tsuda M, Suzuki T. Effects of intravenous amino acids on anesthesia-induced hypothermia in ovariectomized rats. J Nutr Sci Vitaminol (Tokyo). 2012;58:143–8.CrossRefGoogle Scholar
  9. 9.
    Yoshizawa F, Kimball SR, Vary TC, Jefferson LS. Effect of dietary protein on translation initiation in rat skeletal muscle and liver. Am J Physiol. 1998;275:E814–20.PubMedGoogle Scholar
  10. 10.
    Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273:14484–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR. Leucine stimulates translation initiation in skeletal muscle of post-absorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000;130:2413–9.PubMedGoogle Scholar
  12. 12.
    Proud CG. Regulation of mammalian translation factors by nutrients. Eur J Biochem. 2002;269:5338–49.CrossRefPubMedGoogle Scholar
  13. 13.
    Proud CG. Control of the translational machinery by amino acids. Am J Clin Nutr. 2014;99:231S–6S.CrossRefPubMedGoogle Scholar
  14. 14.
    Shah OJ, Anthony JC, Kimball SR, Jefferson LS. 4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle. Am J Physiol Endocrinol Metab. 2000;279:E715–29.PubMedGoogle Scholar
  15. 15.
    Yoshizawa F. Regulation of protein synthesis by branched-chain amino acids in vivo. Biochem Biophys Res Commun. 2004;313:417–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60:3504–13.PubMedGoogle Scholar
  17. 17.
    Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt (PKB) signaling pathway. Genes Dev. 1998;12:502–13.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Proud CG. Signaling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J. 2007;403:217–34.CrossRefPubMedGoogle Scholar
  19. 19.
    Obayashi M, Shimomura Y, Nakai N, Jeoung NH, Nagasaki M, Murakami T, Sato Y, Harris RA. Estrogen controls branched-chain amino acid catabolism in female rats. J Nutr. 2004;134:2628–33.PubMedGoogle Scholar
  20. 20.
    Lin TA, Kong X, Saltiel AR, Blackshear PJ, Lawrence JC Jr. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem. 1995;270:18531–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Kimball SR, Jefferson LS, Fadden P, Haystead TA, Lawrence JC Jr. Insulin and diabetes cause reciprocal changes in the association of eIF-4E and PHAS-I in rat skeletal muscle. Am J Physiol Cell Physiol. 1996;270:C705–9.Google Scholar
  22. 22.
    Shen W, Boyle DW, Liechty EA. Changes in 4E-BP1 and p70S6 K phosphorylation in skeletal muscle of the ovine fetus after prolonged maternal fasting: effects of insulin and IGF-I. Pediatr Res. 2005;58:833–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Franke TF, Kaplan DR, Cantley LC. PI3 K: downstream AKTion blocks apoptosis. Cell. 1997;88:435–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001;114:2903–10.PubMedGoogle Scholar
  25. 25.
    Dennis MD, Baum JI, Kimball SR, Jefferson LS. Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. J Biol Chem. 2011;286:8287–96.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Anthony JC, Reiter AK, Anthony TG, Crozier SJ, Lang CH, MacLean DA, Kimball SR, Jefferson LS. Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. Diabetes. 2002;51:928–36.CrossRefPubMedGoogle Scholar
  27. 27.
    Shen W, Mallon D, Boyle DW, Liechty EA. IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus. Am J Physiol Endocrinol Metab. 2002;283:E593–603.CrossRefPubMedGoogle Scholar
  28. 28.
    Yoshizawa F, Sekizawa H, Hirayama S, Yamazaki Y, Nagasawa T, Sugahara K. Tissue-specific regulation of 4E-BP1 and S6K1 phosphorylation by alpha-ketoisocaproate. J Nutr Sci Vitaminol (Tokyo). 2004;50:56–60.CrossRefGoogle Scholar
  29. 29.
    Kanazawa M, Ando S, Tsuda M, Suzuki T. The effect of amino acid infusion on anesthesia-induced hypothermia in muscle atrophy model rats. J Nutr Sci Vitaminol (Tokyo). 2010;56:117–22.CrossRefGoogle Scholar
  30. 30.
    Stachenfeld NS, Silva C, Keefe DL. Estrogen modifies the temperature effects of progesterone. J Appl Physiol. 2000;88:1643–9.PubMedGoogle Scholar
  31. 31.
    Lehtovirta P. Peripheral haemodynamic effects of combined oestrogen/progestogen oral contraceptives. J Obstet Gynecol Neonatal Nurs. 1974;81:526–34.Google Scholar
  32. 32.
    Hayashi T, Yamada K, Esaki T, Kuzuya M, Satake S, Ishikawa T, Hidaka H, Iguchi A. Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun. 1995;214:847–55.CrossRefPubMedGoogle Scholar
  33. 33.
    Yamakage M, Kameda Y, Honma Y, Tsujiguchi N, Nakmiki A. Predictive variables of hypothermia in the early phase of general anesthesia. Anesth Analg. 2000;90:456–9.PubMedGoogle Scholar
  34. 34.
    Orr CS, Eberhart RC. Overview of bioheat transfer. In: Welsh AJ, van Gemert MJ, editors. Optical-thermal response of laser-irradiated tissue. New York: Plenum; 1995. p. 367–84.CrossRefGoogle Scholar
  35. 35.
    Yamaoka I, Doi M, Kawano Y, Nakayama M, Watanabe Y, Oba K, Sugahara K, Yoshizawa F. Insulin mediates the linkage acceleration of muscle protein synthesis, thermogenesis, and heat storage by amino acids. Biochem Biophys Res Commun. 2009;386:252–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Costrini NV, Kalkhoff RK. Relative effects of pregnancy, estradiol, and progesterone on plasma insulin and pancreatic islet insulin secretion. J Clin Invest. 1971;50:992–9.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Kalkhoff RK. Metabolic effects of progesterone. Am J Obstet Gynecol. 1982;142:735–8.PubMedGoogle Scholar
  38. 38.
    Kumagai S, Holmäng A, Björntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand. 1993;149:91–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Toth MJ, Poehlman ET, Matthews DE, Tchernof A, MacCoss MJ. Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats. Am J Physiol Endocrinol Metab. 2001;280:E496–501.PubMedGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2015

Authors and Affiliations

  • Masahiro Kanazawa
    • 1
  • Mariko Watanabe
    • 1
  • Toshiyasu Suzuki
    • 2
  1. 1.Division of AnesthesiaTokai University Oiso HospitalNaka-gunJapan
  2. 2.Department of AnesthesiologyTokai University School of MedicineIseharaJapan

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