Intracellular regulation and anesthetic modification regarding the augmentation of vascular contraction in diabetic condition

• Project/Area Number: 17591650
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Anesthesiology/Resuscitation studies
• Research Institution: Wakayama Medical University
• Principal Investigator: KAKUTANI Tetsuya Wakayama Medical University, School of Medicine, Assistant Professor (00264896)
• Co-Investigator(Kenkyū-buntansha): OGAWA Koji Wakayama Medical University, School of Medicine, Associate Professor (30204077) ; HATANO Yoshio Wakayama Medical University, School of Medicine, Professor (70115913)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥2,940,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥240,000); Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: Angiotensin II / Vascular smooth muscle / Volatile anesthetics / Diabetes Mellitus / Intracellular Ca^<2+> concentration / Protein kinases / 血管収縮性 / カルシウム

Research Abstract

This study was to investigate both the mechanism of enhanced vascular contractility in diabetes mellitus and the effects of volatile anesthetics including sevoflurane and isoflurane on the expression of various protein kinase or the intracellular signal pathway.
1) The contraction of isolated rat aorta without endothelium induced by angiotensin II was enhanced in diabetic group compared with non-diabetic group. Sevoflurane inhibited the mnsrle tension in concentration-dependent manner, but isoflurane did not.
2) Sevoflurane attenuated angiotensin II-induced phosphorylation of protein kinase C, which was examined by Western blotting, but not intracellular calcium concentration. This result suggests that sevoflurane would inhibit calcium sensitization of vascular contraction pathway.
3) Angiotensin H and phenylephrine transiently stimulated the phosphorylation of MLC, CPI-17, MYPT1/Thr853, and /Thr696.
4) Volatile anesthetics, both sevoflurane and isoflurane, inhibited the phosphorylation of MLC stimulated by angiotensin II and phenylephrine in concentration-dependent manner.
5) Sevoflurane attenuated vascular smooth muscle tension induced by vasopressin, which was associated with Rho kinase phosphorylation.
6) Reactive oxygen radicals affected the NO-soluble guanylate cyclase (sGC) -cGMP pathway by the desensitization of sGC activity, which was exaggerated by sevoflurane exposure, particularly in hyperoxic condition.
These results suggested that that the ability of volatile anesthetics including sevoflurane and isoflurane to alter the vascular smooth muscle tension through different combination of mechanisms, including the vasclular contraction pathway such as protein kinase phospholyration and calcium sensitization, or the relaxation pathway such as NO-soluble guanylate cyclase (sGC) -cGMP pathway, which was also affected by diabetic condition.

Research Products

• [Journal Article] Effects of isoflurane and sevoflurane anesthesia on arteriovenous shunt flow in the lower limb of diabetic patients without neuropathy (2007)
  • Author(s): Negoro T, Mizumoto K, Ogawa K, Hironaka Y, Kakutani T, Hatano Y
  • Journal Title: Anesthesiology 107 Pages: 45-52
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The mechanism behind the inhibitory effect of isoflurane on angiotensin II-induced contraction is different from that of sevoflurane (2007)
  • Author(s): Ishikawa A, Ogawa K, Tokinaga Y, Uematsu N, Mizumoto K, Hatano Y
  • Journal Title: Anesth Analg 105 Pages: 97-102
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mechanism of the ropivacaine-induced increase in intracellular Ca^<2+> concentration in rat aortic smooth muscle (2007)
  • Author(s): Tokinaga Y, Ogawa K, Yu J, Kuriyama T, Minonishi T, Hatano Y
  • Journal Title: Acta Anaesthesiol Scand 51 Pages: 1155-1160
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of isoflurane and sevoflurane anesthesia onarteriovenous shunt flow in the lower limb of diabetic patients without neuropathy (2007)
  • Author(s): Negoro T, Mizumoto K, Ogawa K, Hironaka Y, Kakutani T, Hatano, Y
  • Journal Title: Anesthesiology 107 Pages: 45-52
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The mechanism behind the inhibitory effect of iso flurane on Angiotensin II-induced contraction is different from that of sevoflurane (2007)
  • Author(s): Ishikawa A, Ogawa K, Tokinaga Y, Uematsu N, Mizumoto K, Hatano, Y
  • Journal Title: Anesth Analg 105 Pages: 97-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of isoflurane and sevoflurane anesthesia on arteriovenous shunt flow in the lower limb of diabetic patients without neuropathy. (2007)
  • Author(s): Negoro T, Mizumoto K, Ogawa K, Hironaka Y, Kakutani T, Hatano Y
  • Journal Title: Anesthesiology 107 Pages: 45-52
  • Peer Reviewed
• [Journal Article] The mechanism behind the inhibitory effect of isoflurane on angiotensin II-induced contraction is different from that of sevoflurane. (2007)
  • Author(s): Ishikawa A, Ogawa K, Tokinaga Y, Uematsu N, Mizumoto K, Hatano Y
  • Journal Title: Anesth Analg 105 Pages: 97-102
  • Peer Reviewed
• [Journal Article] Mechanism of the ropivacaine-induced increase in intracellUlar Ca2+concentration in rat aortic smooth muscle. (2007)
  • Author(s): Tokinaga Y, Ogawa K, Yu J, Kuriyama T, Minonishi T, Hatano Y
  • Journal Title: Acta Anaesthesiol Scand 51 Pages: 1155-1160
  • Peer Reviewed
• [Journal Article] the mechanism behind inhibitory effect of isoflurane on Angiotensin II-induced contraction is different from that of sevoflurane. (2007)
  • Author(s): Ishikawa A, Ogawa K, Tokinaga Y, Uematsu N, Mizumoto K, Hatano Y
  • Journal Title: anesth Analg (In press)
• [Journal Article] Propofol inhibits phorbol 12, 13-dibutyrate-induced, protein kinase C-mediated contraction of rat aortic smooth muscle. (2006)
  • Author(s): Yu J, Tetsuya, Kakutani, Kazuhiro, Mizumoto, Ai, Hasegawa, Yoshio, Hatano
  • Journal Title: Acta Anaesthesiol Scand 50(9) Pages: 1131-1138
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Propofol inhibits phorbol 12, 13-dibutyrate-induced protein kinase C-mediated contraction of rat aortic smooty muscle. (2006)
  • Author(s): Yu J, Kakutai T, Mizumoto K, Hasegawa A, Hatano Y
  • Journal Title: Acta Anesthesiol Scand 50 Pages: 1131-8
• [Journal Article] Vasodilation mediated by inward rectifier K^+ channels in cerebral microvessels of hypertensive and normotensive rats. (2006)
  • Author(s): Nakahata K, Kinoshita H, Mizumoto K, Ogawa K, Hatano Y
  • Journal Title: anesth Analg 102 Pages: 571-6
• [Journal Article] Augmented activity of adenosine triphospate-sensitive K+-channels induced by droperidol in the rat aorta. (2006)
  • Author(s): Kinoshita H, Dojo M, Nakahata K, Kimoto Y, Kakutani T, Hatano Y
  • Journal Title: Anesth Analg 102 Pages: 786-791
• [Journal Article] Trasient phlebitis induced by a bolus injection of propofol. (2006)
  • Author(s): Kinoshita H, Kakutani T, Minonishi T, Mizumoto K, Hatano Y
  • Journal Title: J Anesth 20 Pages: 74-75
• [Journal Article] Sevoflurane enhances nitroglycerin tolerance in rat aorta : Implications for the desensitization of soluble guanylate cyclase possibly through the additive generation of superoxide anions and/or hydroxyl radicals within vascular smooth muscle (2005)
  • Author(s): Kakutani T, Ogawa K, Mizumoto K, Iwahashi S, Hatano, Y
  • Journal Title: Anesth Analg 101(4) Pages: 1015-1022
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] he inhibit ory effects of sevoflurane on angiotensin II-induced, p44/42 mitogen-activated protein kinase-mediated contraction of rat aortic smooth muscle. (2005)
  • Author(s): Yu J, Mizumoto K, Tokinaga Y, Ogawa K, Hatano, Y
  • Journal Title: Anesth Analg 101(2) Pages: 315-321
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of the effects of isoflurane and sevoflurane on protein tyrosine phosphorylation-mediated vascular contraction (2005)
  • Author(s): Yu J, Mizumoto K, Kakutani T, Hasegawa A, Ogawa K, Hatano, Y
  • Journal Title: Acta Anaesthesiol Scand 49(6) Pages: 852-858
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sevoflurane enhances nitroglycerin tolerance in rat aorta. (2005)
  • Author(s): Kakutani T, Ogawa K, Hatano Y, Mizumoto K, Iwahashi S
  • Journal Title: Anesth Analg 101 Pages: 1015-1022
• [Journal Article] Effectiveness of bolus landiolol on paroxysmal atrial tachycardia. (2005)
  • Author(s): Kinoshita H, Kakutani T, Mizumoto K, Hatano Y
  • Journal Title: Can J Anaesth 52 Pages: 999-1000
• [Journal Article] Comparison of the effects of isoflurane and sevoflurane on protein tyrosine phosphorylation-mediated vascular contraction. (2005)
  • Author(s): Yu J, Mizumoto K, Kakutani T, Hasegawa A, Ogawa K, Hatano Y
  • Journal Title: Acta Anaestesiol Scand 49 Pages: 852-858
• [Presentation] Donopezil dilates cerebral parenchymal arterioles via activation of neuronal nitric oxide synthase (2007)
  • Author(s): Nakahata K, Kinoshita H, Seto Y, Kakutani T, Hatano Y
  • Organizer: Annual meeting of American society of the anesth esiologists
  • Place of Presentation: San Francisco,CA,USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Sevoflurane Inhibits Ang-II Induced Rho-Kinase-Mediated Contraction of Rat Aorta in Hypertension (2007)
  • Author(s): Nobuhiko, Uematsu, M. D. Mayuko, Dojo, M. D. Yoshiki, Kimoto, M.D. Kazuhiro, Mizumoto, M.D. Yoshio, Hatano, M.D
  • Organizer: 2007 Annual Meeting of American Society of Anesthesiologists
  • Place of Presentation: San Francisco, CA, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Donopezil diates cerebral parenchymal arterioles via activation of neuronal nitric oxide synthase. (2007)
  • Author(s): Nakahata K, Kinoshita H, Seto Y, Kakutani T, Hatano Y
  • Organizer: Annual meeting of American society of the anesth esiologists
  • Place of Presentation: San Francisco,CA,USA
• [Presentation] The Effects of Sevoflurane and Isoflurane on Angiotensin II-Induced Vaso constriction in Hypertension (2006)
  • Author(s): Nobuhiko, Uematsu, M. D. Tetsuya, Kakutani, M. D. Takaaki, Negoro M.D. Koji Ogawa, M.D. Yoshio Hatano, M.D.
  • Organizer: 2006 Annual Meeting of American Society of Anesthesiologists
  • Place of Presentation: Chicago, IL, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Sevoflurane Inhibits Angiotensin II-Induced, MAPK-Mediated Contraction of Rat Aortic Smooth Muscle (2005)
  • Author(s): Koji, Ogawa, Jingui, Yu, Yasuyuki, Tokinaga, Tetsuya, Kakutani, Yoshio, Hatano
  • Organizer: 2005 Annual Meeting of American Society of Anesthesiologists
  • Place of Presentation: Atlanta, GA, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Effects of Sevoflurane on the Activation of cAMP-and cGMP-Dependent Protein Kinases Induced by cAMP in Rat Aorta (2005)
  • Author(s): Nobuhiko, Uematsu, Koji, Ogawa, Tetsuya, Kakutani, Keiko, Hama, Yoshio, Hatano
  • Organizer: 2005 Annual Meeting of American Society of Anesthesiologists
  • Place of Presentation: Atlanta, GA, USA
  • Description: 「研究成果報告書概要(欧文)」より