DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

JAPANESE
font size
font size_s
font size_m
font size_l
color
Research Units

Hypertension & Autonomic Nervous Function Research Unit


To Japanese version on this page

menu Research Outline Main Research Themes and Relevant Publications Principle Investigator of the group Staff and Research Focus

Main Research Themes and Relevant Publications


  1. Basic research on blood pressure regulation and sympathetic nerve control by circulating biologically active substances: to elucidate the intracerebral target molecular mechanisms for the activation of sympathetic nervous activity in hypertension and heart failure by gene transfer into the cardiovascular center
  2. To develop clinical research related to the effects of circulating biologically active substances on peripheral and coronary abnormalities and elucidate its pathophysiological significance

1. Basic Research on blood pressure regulation and sympathetic nerve control by circulating biologically active substances: to elucidate the intracerebral target molecular mechanisms for the activation of sympathetic nervous activity in hypertension and heart failure by gene transfer into the cardiovascular center






First we demonstrated that atrial natriuretic peptide (ANP) modifies the baroreflex. Next we elucidated the mechanisms by which ANP, which has emerged as a therapeutic drug for heart failure in the clinical setting, prevents reflex tachycardia. With this knowledge, it was inevitable to research on the role of neural dysregulation on the cardiovascular center that regulates blood pressure and sympathetic nerve activity. Therefore we conducted basic research related to the control of sympathetic nerve activity by the cardiovascular center. We found that the sympathetic nerve activities regulated by the cardiovascular center are modified by angiotensin II (Ang II) and NO, which are known to play important roles in peripheral blood vessels. These findings were confirmed by other investigators, and the resulting expansion of studies on the roles of Ang II and NO in the brain has led to the recognition of their importance.

Furthermore, to conduct novel research on the control of circulation, a series of studies to analyze functions from gene and molecular level to in vivo level are necessary. For this purpose, we succeeded for the first time in the world to develop the techniques of transferring specific genes into target brain region to increase the local production of specific substances or proteins through gene expression, and also using radio-telemetry to monitor blood pressure, heart rate, sympathetic nerve activity and cardiac function under an unanesthetized conscious state (Sakai K, Hirooka Y, et al. Hypertension 2000、Kishi T, Hirooka Y, et al. Hypertension 2001).

Using the above techniques, we researched on the roles of NO, reactive oxygen species and Rho/Rho-kinase system that are present in the brain. We discovered that abnormalities of these factors or systems are profoundly involved in over-activity of sympathetic nerves and abnormal blood pressure regulation in hypertension and heart failure (Sakai K, Hirooka Y, et al. Am J Physiol 2005. Kishi T, Hirooka Y, et al. Circulation 2004; Hypertension 2002, 2003; J Hypertens 2003; Clin Exp Hypertens 2007. Ito K, Hirooka Y, et al. Circ Res 2003; Hypertension 2004, 2005, 2006. Kimura Y, Hirooka Y, et al. Circ res 2005. Sagara Y, Hirooka Y, et al. J Hypertens 2007). These research achievements drew spotlight from researchers worldwide. Our publications triggered a rapid expansion of studies in the field of circulation control, targeting diseases such as hypertension and heart failure, and pioneered the development of new Research Units. As a result, the citation index of related articles published after 2000 exceeds several hundreds, despite the fact that they are relatively recent papers.

Moreover, many national and international awards were received in recognition of these achievements. Kishi of our research unit received several awards in Japan including the Young Investigator Award (YIA) from the Japanese Circulation Society, YIA from the Nitric Oxide Society of Japan, Okamoto Research Award from the Adult Cardiovascular Disease Research Foundation, Osaki Award from the Society for Hypertension Related Disease Model Research; as well as international awards such as the YIA from the Neural Circulation Control Meeting of the International Society of Autonomic Neuroscience, YIA from the Central Nerve and Central Circulation Control Part 2 of American Physiological Society, and Travel Award from the International Society of Hypertension. Ito received YIA from the Japanese Society of Hypertension, Travel Award from the Nitric Oxide Society of Japan, YIA from the Japan Society of Circulation Control in Medicine, and Travel Award from the International Society of Hypertension. Kimura received YIA from the Japanese Society of Hypertension. Sagara received the Osaki Award from the Society for Hypertension Related Disease Model Research. Nozoe received Travel Award from the Nitric Oxide Society of Japan. Furthermore, our group held a symposium at the 2006 meeting of the International Society of Hypertension held in Fukuoka.

 

Relevant publications
  1. Nozoe M, Hirooka Y, Koga Y, Sagara Y, Kishi T, John FE, Sunagawa K. Inhibition of Rac-1-derived reactive oxygen species in NTS decreases blood pressure and heart rate in stroke-prone SHR. Hypertension. 50:62-68, 2007.
  2. Sagara Y, Hirooka Y, Nozoe M, Ito K, Kimura Y, Sunagawa K. Pressor response induced by central angiotensin II is mediated by activation of Rho/Rho-kinase pathway via AT1 receptors. J Hypertens. 25: 399-406, 2007.
  3. Ito K, Hirooka Y, Kimura Y, Sagara Y, Sunagawa K. Ovariectomy augments hypertension through Rho-kinase activation in the brain stem in female spontaneously hypertensive rats. Hypertension. 48: 651-657, 2006.
  4. Hirooka Y, Shigematsu H, Kishi T, Ito K, Shimokawa H, Takeshita A, Sunagawa K. Overexpression of eNOS in the brainstem reduces enhanced sympathetic drive in mice with myocardial infarction. Am J Physiol. 289: H2159-H2166, 2005.
  5. Ito K, Hirooka Y. Localized gene transfer and its application for the study of central cardiovascular control. Auton Neurosci. 126-127: 120-129, 2006.
  6. Sakai K, Hirooka Y, Hori N, Kimura Y, Sagara Y, Shimokawa H, Takeshita A, Sunagawa K. Inhibition of Rho-kinase in the nucleus tractus solitarius enhances glutamate sensitivity in rats. Hypertension. 46: 360-365, 2005.
  7. Kimura Y, Hirooka Y, Sagara Y, Ito K, Kishi T, Shimokawa H, Takeshita A, Sunagawa K. Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. Circ Res. 96: 252-260, 2005.
  8. Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation. 109: 2357-2362, 2004.
  9. Ito K, Hirooka Y, Sagara Y, Kimura Y, Kaibuchi K, Shimokawa H, Takeshita A, Sunagawa K. Inhibition of Rho-kinase in the brainstem augments baroreflex control of heart rate in rats. Hypertension. 44: 478-483, 2004.
  10. Ito K, Hirooka Y, Kishi T, Kimura Y, Kaibuchi K, Shimokawa H, Takeshita A. Rho/Rho-kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition. Hypertension. 43: 156-162, 2004.
  11. Hirooka Y. Adenovirus-mediated gene transfer into the brain stem to examine cardiovascular function: Role of nitric oxide and Rho-kinase. Prog Biophys Mol Biol. 84: 233-249, 2004.
  12. Kishi T, Hirooka Y, Mukai Y, Shimokawa H, Takeshita A. Atorvastatin causes depressor and sympatho-inhibitory effects with upregulation of nitric oxide synthases in stroke-prone spontaneously hypertensive rats. J Hypertens. 21: 379-386, 2003.
  13. Kishi T, Hirooka Y, Kimura Y, Sakai K, Ito K, Shimokawa H, Takeshita A. Overexpression of eNOS in RVLM improves the impaired baroreflex control of heart rate in SHRSP. Hypertension. 41: 255-260, 2003.
  14. Ito K, Hirooka Y, Sakai K, Kishi T, Kaibuchi K, Shimokawa H, Takeshita A. Rho/Rho-kinase pathway in brain stem contributes to blood pressure regulation via sympathetic nervous system: possible involvement in neural mechanisms of hypertension. Circ Res. 92: 1337-1343, 2003.
  15. Kishi T, Hirooka Y, Ito K, Sakai K, Shimokawa H, Takeshita A. Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats. Hypertension. 39: 264-268, 2002.
  16. Kishi T, Hirooka Y, Sakai K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release. Hypertension. 38: 896-901, 2001.
  17. Sakai K, Hirooka Y, Matsuo I, Eshima K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in NTS causes hypotension and bradycardia in vivo. Hypertension. 36: 1023-1028, 2000.
  18. Kishi T, Hirooka Y, Konno S, Ogawa K, Sunagawa K. Angiotensin II type 1 receptor-activated caspase-3 through ras/mitogen-activated protein kinase/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats. Hypertension 55:291-7, 2010.
  19. Kishi T, Hirooka Y, Konno S, Sunagawa K. Sympathoinhibition induced by centrally administered atorvastatin is associated with alteration of NAD(P)H and Mn superoxide dismutase activity in rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol 55:184-90, 2010.
  20. Someya N, Endo MY, Fukuba Y, Hirooka Y, Hayashi N. Effects of a mental task on splanchnic blood flow in fasting and postprandial conditions. Eur J Appl Physiol. 108:1107-13, 2010.
  21. Kishi T, Hirooka Y, Konno S, Sunagawa K. Atorvastatin improves the impaired baroreflex sensitivity via anti-oxidant effect in the rostral ventrolateral medulla of SHRSP. Kishi T, Hirooka Y, Konno S, Sunagawa K. Clin Exp Hypertens 31:698-704, 2009.
  22. Araki S, Hirooka Y, Kishi T, Yasukawa K, Utsumi H, Sunagawa K. Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method. Hypertens Res 32:1091-6, 2009.
  23. Hayashi N, Someya N, Maruyama T, Hirooka Y, Endo MY, Fukuba Y. Vascular responses to fear-induced stress in humans. Physiol Behav 98:441-6, 2009.
  24. Kishi T, Yamada A, Okamatsu S, Sunagawa K. Atorvastatin might improve ventricular electrostability and decelerate the deterioration of renal function in patients with heart failure and diabetes mellitus. J Cardiol. 53:341-348, 2009.
  25. Kimura Y, Hirooka Y, Kishi T, Ito K, Sagara Y, Sunagawa K. Role of inducible nitric oxide synthase in rostral ventrolateral medulla in blood pressure regulation in spontaneously hypertensive rats. Clin Exp Hypertens 31:281-6, 2009.
  26. Kishi T, Hirooka Y, Konno S, Sunagawa K. Cilnidipine inhibits the sympathetic nerve activity and improves baroreflex sensitivity in patients with hypertension. Clin Exp Hypertens 31:241-9, 2009.
  27. Ito K, Hirooka Y, Sunagawa K. Acquisition of brain Na sensitivity contributes to salt-induced sympathoexcitation and cardiac dysfunction in mice with pressure overload.. Circ Res 104:1004-11, 2009.
  28. Koga Y, Hirooka Y, Araki S, Nozoe M, Kishi T, Sunagawa K. High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertens Res 31:2075-83, 2009.
  29. Konno S, Hirooka Y, Araki S, Koga Y, Kishi T, Sunagawa K. Azelnidipine decreases sympathetic nerve activity via antioxidant effect in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol 52:555-60, 2009.
  30. Nozoe M, Hirooka Y, Koga Y, Araki S, Konno S, Kishi T, Ide T, Sunagawa K. Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla. J Hypertens 26: 2176-84, 2009.
  31. Hayashi N, Someya N, Hirooka Y, Koga S. Ambient temperature affects glabrous skin vasculature and sweating responses to mental task in humans. J Physiol Anthropol 27:227-31, 2008.
  32. Ito K, Kimura Y, Hirooka Y, Sagara Y, Sunagawa K. Activation of Rho-kinase in the brainstem enhances sympathetic drive in mice with heart failure. Auton Neurosci 142:77-81, 2008.
  33. Hirooka Y. Role of reactive oxygen species in brainstem in neural mechanisms of hypertension. Auton Neurosci 142:20-4, 2008.
  34. Kishi T, Yamada A, Okamatsu S, Sunagawa K. Percutaneous coronary arterial thrombectomy for
    acute myocardial infarction reduces no-reflow phenomenon and protects against left ventricular
    remodeling related to the proximal left anterior descending and right coronary artery. Inter Heart J.
    48:287-303, 2007.
  35. Hirooka Y, Kimura Y, Sagara Y, Ito K, Sunagawa K. Effects of valsartan or amlodipine on endothelial function and oxidative stress after one year follow-up in patients with essential hypertension. Clin Exp Hypertens 30:267-76, 2008.
  36. Kishi T, Hirooka Y, Shimokawa H, Takeshita A, Sunagawa K. Atorvastatin reduces oxidative stress in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens 30:3-11, 2008.
  37. Tsutsumi T, Ide T, Yamato M, Kudou W, Andou M, Hirooka Y, Utsumi H, Tsutsui H, Sunagawa K. Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction. Cardiovasc Res 77:713-21, 2007.

  1. Basic research on blood pressure regulation and sympathetic nerve control by circulating biologically active substances: to elucidate the intracerebral target molecular mechanisms for the activation of sympathetic nervous activity in hypertension and heart failure by gene transfer into the cardiovascular center
  2. To develop clinical research related to the effects of circulating biologically active substances on peripheral and coronary abnormalities and elucidate its pathophysiological significance

▲Page Top