Basic Research in Cardiology

, 109:432 | Cite as

Pulmonary vascular tone is dependent on the central modulation of sympathetic nerve activity following chronic intermittent hypoxia

  • Mikiyasu Shirai
  • Hirotsugu Tsuchimochi
  • Hisashi Nagai
  • Emily Gray
  • James T. Pearson
  • Takashi Sonobe
  • Misa Yoshimoto
  • Tadakatsu Inagaki
  • Yutaka Fujii
  • Keiji Umetani
  • Ichiro Kuwahira
  • Daryl O. SchwenkeEmail author
Original Contribution


Chronic intermittent hypoxia (IH) provokes a centrally mediated increase in sympathetic nerve activity (SNA). Although this sympathetic hyperexcitation has been linked to systemic hypertension, its effect on the pulmonary vasculature is unclear. This study aimed to assess IH-mediated sympathetic excitation in modulating pulmonary vasculature tone, particularly acute hypoxia vasoconstrictor response (HPV), and the central β-adrenergic signaling pathway for facilitating the increase in SNA. Sprague–Dawley rats were exposed to IH (cycle of 4 % O2 for 90 s/air for 90 s) for 8 h/day for 6 weeks. Subsequently, rats were anesthetized and either pulmonary SNA was recorded (electrophysiology), or the pulmonary vasculature was visualized using microangiography. Pulmonary sympathetic and vascular responses to acute hypoxia were assessed before and after central β1-adrenergic receptor blockade (Metoprolol, 200 nmol i.c.v.). Chronic IH increased baseline SNA (110 % increase), and exacerbated the sympathetic response to acute hypoxia. Moreover, the magnitude of HPV in IH rats was blunted compared to control rats (e.g., 10 and 20 % vasoconstriction, respectively). In only the IH rats, β1-receptor blockade with metoprolol attenuated the hypoxia-induced increase in pSNA and exacerbated the magnitude of acute HPV, so that both sympathetic and HPV responses were similar to that of control rats. Interestingly, the expression of β1-receptors within the brainstem was similar between both control and IH rats. These results suggest that the centrally mediated increase in SNA following IH acts to blunt the local vasoconstrictor effect of acute hypoxia, which reflects an inherent difference between vasodilator and vasoconstrictor actions of SNA in pulmonary and systemic circulations.


Pulmonary sympathetic nerve activity Intermittent hypoxia Beta-adrenergic Synchrotron radiation microangiography Rat 



The synchrotron radiation experiments were performed at the BL28B2 in the SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (Proposal No. 2011A1305). This study was supported by the Department of Physiology, Otago University, New Zealand, and by Intramural Research Fund (22-2-3, 25-3-1) for Cardiovascular Diseases of National Cerebral and Cardiovascular Center, and a Grant-in Aid for Scientific Research (16659210, 20590242, 23650213, 23249038) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan.

Conflict of interest

Concerning the material presented in this manuscript, there are no conflicts of interest.


  1. 1.
    Ablad B, Bjuro T, Bjorkman JA, Brax O, Ewaldsson L, Forshult E, Lidfors L, Lundberg JM (2010) Metoprolol, but not atenolol, reduces stress induced neuropeptide Y release in pigs. Scand Cardiovasc J 44:273–278. doi: 10.3109/14017431.2010.498923 PubMedCrossRefGoogle Scholar
  2. 2.
    Bosc LV, Resta T, Walker B, Kanagy NL (2010) Mechanisms of intermittent hypoxia induced hypertension. J Cell Mol Med 14:3–17. doi: 10.1111/j.1582-4934.2009.00929.x PubMedCrossRefGoogle Scholar
  3. 3.
    Burns J, Sivananthan MU, Ball SG, Mackintosh AF, Mary DA, Greenwood JP (2007) Relationship between central sympathetic drive and magnetic resonance imaging–determined left ventricular mass in essential hypertension. Circulation 115:1999–2005. doi: 10.1161/CIRCULATIONAHA.106.668863 PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Costa-Silva JH, Zoccal DB, Machado BH (2012) Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats. Am J Physiol Regul Integr Comp Physiol 302:R785–R793. doi: 10.1152/ajpregu.00363.2011 PubMedCrossRefGoogle Scholar
  5. 5.
    da Silva AQ, Fontes MA, Kanagy NL (2011) Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea. Brain Res 1368:231–238. doi: 10.1016/j.brainres.2010.10.087 PubMedCrossRefGoogle Scholar
  6. 6.
    Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP (2010) Pathophysiology of sleep apnea. Physiol Rev 90:47–112. doi: 10.1152/physrev.00043.2008 PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Fletcher EC (2000) Effect of episodic hypoxia on sympathetic activity and blood pressure. Respir Physiol 119:189–197PubMedCrossRefGoogle Scholar
  8. 8.
    Fletcher EC (2001) Invited review: physiological consequences of intermittent hypoxia: systemic blood pressure. J Appl Physiol 90:1600–1605PubMedCrossRefGoogle Scholar
  9. 9.
    Fletcher EC (2003) Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea. Sleep 26:15–19PubMedGoogle Scholar
  10. 10.
    Fletcher EC, Bao G (1996) Effect of episodic eucapnic and hypocapnic hypoxia on systemic blood pressure in hypertension-prone rats. J Appl Physiol (1985) 81:2088–2094Google Scholar
  11. 11.
    Gabor A, Leenen FH (2013) Central mineralocorticoid receptors and the role of angiotensin II and glutamate in the paraventricular nucleus of rats with angiotensin II-induced hypertension. Hypertension 61:1083–1090. doi: 10.1161/HYPERTENSIONAHA.111.00797 PubMedCrossRefGoogle Scholar
  12. 12.
    Gourine A, Bondar SI, Spyer KM, Gourine AV (2008) Beneficial effect of the central nervous system beta-adrenoceptor blockade on the failing heart. Circ Res 102:633–636. doi: 10.1161/CIRCRESAHA.107.165183 PubMedCrossRefGoogle Scholar
  13. 13.
    Greenberg HE, Sica A, Batson D, Scharf SM (1999) Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 86:298–305PubMedGoogle Scholar
  14. 14.
    Huang BS, Ahmadi S, Ahmad M, White RA, Leenen FH (2010) Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-"ouabain” pathway. Am J Physiol Heart Circ Physiol 299:H422–H430. doi: 10.1152/ajpheart.00256.2010 PubMedCrossRefGoogle Scholar
  15. 15.
    Huang J, Lusina S, Xie T, Ji E, Xiang S, Liu Y, Weiss JW (2009) Sympathetic response to chemostimulation in conscious rats exposed to chronic intermittent hypoxia. Respir Physiol Neurobiol 166:102–106. doi: 10.1016/j.resp.2009.02.010 PubMedCrossRefGoogle Scholar
  16. 16.
    Huang J, Xie T, Wu Y, Li X, Lusina S, Ji ES, Xiang S, Liu Y, Gautam S, Weiss JW (2010) Cyclic intermittent hypoxia enhances renal sympathetic response to ICV ET-1 in conscious rats. Respir Physiol Neurobiol 171:83–89. doi: 10.1016/j.resp.2010.03.008 PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Kline DD, Ramirez-Navarro A, Kunze DL (2007) Adaptive depression in synaptic transmission in the nucleus of the solitary tract after in vivo chronic intermittent hypoxia: evidence for homeostatic plasticity. J Neurosci 27:4663–4673. doi: 10.1523/JNEUROSCI.4946-06.2007 PubMedCrossRefGoogle Scholar
  18. 18.
    Malpas SC (2010) Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90:513–557. doi: 10.1152/physrev.00007.2009 PubMedCrossRefGoogle Scholar
  19. 19.
    Marina N, Tang F, Figueiredo M, Mastitskaya S, Kasimov V, Mohamed-Ali V, Roloff E, Teschemacher AG, Gourine AV, Kasparov S (2013) Purinergic signalling in the rostral ventro-lateral medulla controls sympathetic drive and contributes to the progression of heart failure following myocardial infarction in rats. Basic Res Cardiol 108:317. doi: 10.1007/s00395-012-0317-x PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Merkus D, de Beer VJ, Houweling B, Duncker DJ (2008) Control of pulmonary vascular tone during exercise in health and pulmonary hypertension. Pharmacol Ther 119:242–263. doi: 10.1016/j.pharmthera.2008.04.003 PubMedCrossRefGoogle Scholar
  21. 21.
    Moraes DJ, Zoccal DB, Machado BH (2012) Medullary respiratory network drives sympathetic overactivity and hypertension in rats submitted to chronic intermittent hypoxia. Hypertension 60:1374–1380. doi: 10.1161/HYPERTENSIONAHA.111.189332 PubMedCrossRefGoogle Scholar
  22. 22.
    Morrison SF (2001) Differential control of sympathetic outflow. Am J Physiol Regul Integr Comp Physiol 281:R683–R698PubMedGoogle Scholar
  23. 23.
    Mueller PJ, Mischel NA, Scislo TJ (2011) Differential activation of adrenal, renal, and lumbar sympathetic nerves following stimulation of the rostral ventrolateral medulla of the rat. Am J Physiol Regul Integr Comp Physiol 300:R1230–R1240. doi: 10.1152/ajpregu.00713.2010 PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Neubauer JA (2001) Invited review: physiological and pathophysiological responses to intermittent hypoxia. J Appl Physiol 90:1593–1599PubMedGoogle Scholar
  25. 25.
    Norton CE, Jernigan NL, Kanagy NL, Walker BR, Resta TC (2011) Intermittent hypoxia augments pulmonary vascular smooth muscle reactivity to NO: regulation by reactive oxygen species. J Appl Physiol (1985) 111:980–988. doi: 10.1152/japplphysiol.01286.2010 CrossRefGoogle Scholar
  26. 26.
    Paschalis A, Churchill L, Marina N, Kasymov V, Gourine A, Ackland G (2009) beta1-adrenoceptor distribution in the rat brain: an immunohistochemical study. Neurosci Lett 458:84–88. doi: 10.1016/j.neulet.2009.04.023 PubMedCrossRefGoogle Scholar
  27. 27.
    Patel KP, Li YF, Hirooka Y (2001) Role of nitric oxide in central sympathetic outflow. Exp Biol Med 226:814–824Google Scholar
  28. 28.
    Saphier D, Feldman S (1991) Catecholaminergic projections to tuberoinfundibular neurons of the paraventricular nucleus: III. effects of adrenoceptor agonists and antagonists. Brain Res Bull 26:863–870PubMedCrossRefGoogle Scholar
  29. 29.
    Schwenke DO, Gray EA, Pearson JT, Sonobe T, Ishibashi-Ueda H, Campillo I, Kangawa K, Umetani K, Shirai M (2011) Exogenous ghrelin improves blood flow distribution in pulmonary hypertension-assessed using synchrotron radiation microangiography. Pflügers Archiv: Euro J Physiol 462:397–406. doi: 10.1007/s00424-011-0992-8 CrossRefGoogle Scholar
  30. 30.
    Schwenke DO, Pearson JT, Kangawa K, Umetani K, Shirai M (2008) Changes in macrovessel pulmonary blood flow distribution following chronic hypoxia: assessed using synchrotron radiation microangiography. J Appl Physiol 104:88–96. doi: 10.1152/japplphysiol.00610.2007 PubMedCrossRefGoogle Scholar
  31. 31.
    Schwenke DO, Pearson JT, Kangawa K, Umetani K, Shirai M (2007) Imaging of the pulmonary circulation in the closed-chest rat using synchrotron radiation microangiography. J Appl Physiol 102:787–793. doi: 10.1152/japplphysiol.00596.2006 PubMedCrossRefGoogle Scholar
  32. 32.
    Schwenke DO, Tokudome T, Kishimoto I, Horio T, Cragg PA, Shirai M, Kangawa K (2012) One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction. Endocrinology 153:2436–2443. doi: 10.1210/en.2011-2057 PubMedCrossRefGoogle Scholar
  33. 33.
    Schwenke DO, Tokudome T, Shirai M, Hosoda H, Horio T, Kishimoto I, Cragg PA, Kangawa K (2008) Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Endocrinology 149:5172–5176. doi: 10.1210/en.2008-0472 PubMedCrossRefGoogle Scholar
  34. 34.
    Shirai M, Beard M, Pearson JT, Sonobe T, Tsuchimochi H, Fujii Y, Gray E, Umetani K, Schwenke DO (2013) Impaired pulmonary blood flow distribution in congestive heart failure assessed using synchrotron radiation microangiography. J Synchrotron Radiat 20:441–448. doi: 10.1107/S0909049513007413 PubMedCrossRefGoogle Scholar
  35. 35.
    Shirai M, Matsukawa K, Nishiura N, Kawaguchi AT, Ninomiya I (1995) Changes in efferent pulmonary sympathetic nerve activity during systemic hypoxia in anesthetized cats. Am J Physiol Regul Integr Comp Physiol 269:R1404–R1409Google Scholar
  36. 36.
    Shirai M, Schwenke DO, Tsuchimochi H, Umetani K, Yagi N, Pearson JT (2013) Synchrotron radiation imaging for advancing our understanding of cardiovascular function. Circ Res 112:209–221. doi: 10.1161/CIRCRESAHA.111.300096 PubMedCrossRefGoogle Scholar
  37. 37.
    Silva AQ, Schreihofer AM (2011) Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia. J Physiol 589:1463–1476. doi: 10.1113/jphysiol.2010.200691 PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA (2004) Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens 17:217–222. doi: 10.1016/j.amjhyper.2003.10.010 PubMedCrossRefGoogle Scholar
  39. 39.
    Sylvester JT, Shimoda LA, Aaronson PI, Ward JP (2012) Hypoxic pulmonary vasoconstriction. Physiol Rev 92:367–520. doi: 10.1152/physrev.00041.2010 PubMedCrossRefGoogle Scholar
  40. 40.
    Wang D, Feng H, Li YS, Qiu DL, Jin H, Jin QH (2013) Beta-adrenoceptors in the hypothalamic paraventricular nucleus modulate the baroreflex in conscious rats. Neurosci Lett 551:43–46. doi: 10.1016/j.neulet.2013.07.005 PubMedCrossRefGoogle Scholar
  41. 41.
    Xu B, Zheng H, Patel KP (2013) Relative contributions of the thalamus and the paraventricular nucleus of the hypothalamus to the cardiac sympathetic afferent reflex. Am J Physiol Regul Integr Comp Physiol 305:R50–R59. doi: 10.1152/ajpregu.00004.2013 PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Zoccal DB, Huidobro-Toro JP, Machado BH (2011) Chronic intermittent hypoxia augments sympatho-excitatory response to ATP but not to l-glutamate in the RVLM of rats. Auton Neurosci 165:156–162. doi: 10.1016/j.autneu.2011.06.001 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Mikiyasu Shirai
    • 1
  • Hirotsugu Tsuchimochi
    • 1
  • Hisashi Nagai
    • 2
  • Emily Gray
    • 3
  • James T. Pearson
    • 4
  • Takashi Sonobe
    • 1
  • Misa Yoshimoto
    • 1
  • Tadakatsu Inagaki
    • 1
  • Yutaka Fujii
    • 1
  • Keiji Umetani
    • 5
  • Ichiro Kuwahira
    • 6
  • Daryl O. Schwenke
    • 3
    Email author
  1. 1.Department of Cardiac PhysiologyNational Cerebral and Cardiovascular Center Research InstituteSuitaJapan
  2. 2.Department of Forensic MedicineUniversity of TokyoTokyoJapan
  3. 3.Department of Physiology-Heart OtagoUniversity of OtagoDunedinNew Zealand
  4. 4.Monash Biomedical Imaging Facility, Department of PhysiologyMonash UniversityMelbourneAustralia
  5. 5.Japan Synchrotron Radiation Research InstituteHyogoJapan
  6. 6.Department of Respiratory MedicineTokai University School of MedicineTokyoJapan

Personalised recommendations