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α2-Adrenoreceptor mediated sympathoinhibition of heart rate during acute hypoxia is diminished in conscious prostacyclin synthase deficient mice

  • James T. Pearson
  • Mikiyasu Shirai
  • Chieko Yokoyama
  • Hirotsugu Tsuchimochi
  • Daryl O. Schwenke
  • Akito Shimouchi
  • Kenji Kangawa
  • Tadashi Tanabe
Cardiovascular System

Abstract

Acute hypoxia increases ventilatory drive in conscious animals, resulting in tachycardia. Sustained hypoxia changes the initial chemoreflex ventilatory increase to secondary ventilatory depression, which then evokes a gradual secondary heart rate (HR) reduction. Prostacyclin (PGI2) release is known to potentiate α2-adrenoreceptor (α2-AR) mediated inhibition of sympathoactivation during ischaemia and hypoxia. We examined whether α2-AR mediated sympathoinhibition was responsible for limiting hypoxic heart rate increases during initial sympathoactivation, and subsequent secondary HR depression, and if PGI2 is required for sympathoinhibition of HR. The responses of unrestrained PGI2 synthase deficient (PGID) and wild type (WT) mice to acute hypoxia (10% O2 for 30 min) were investigated by simultaneous telemetry, whole body plethysmography and open-flow respirometry. PGID mice exhibited potentiated \({\mathop V\limits^ \cdot }_{E} \) (p < 0.007) after intraperitoneal vehicle injection (n = 8), but not so HR responses compared to WT mice during sustained hypoxia. Idazoxan (α2-AR antagonist, i.p. bolus 3 mg/kg) pretreatment did not change hypoxic ventilatory response in either group, but significantly elevated hypoxic HR in WT mice only (p < 0.013). Sodium meclofenamate (cyclooxygenase inhibition, i.p. bolus 25 mg/kg) pretreatment eliminated the potentiated \({\mathop V\limits^ \cdot }_{E} \) of PGID and caused significant basal hypotension that led to a transient hypertensive response to hypoxia. From these results, we suggest that α2-AR activation is required for coupling HR to central inspiratory drive during acute hypoxia, and that PGI2 is required to enhance the inhibition of sympathoactivation.

Keywords

Acute hypoxia α2-Adrenergic receptor Sympathetic nervous system Prostaglandins Transgenic mouse Respiratory control 

Notes

Acknowledgments

This work was supported in part by the Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PDMA) of Japan to K. Kangawa and a Ministerial Grant-in-Aid for Scientific Research to M. Shirai (13670053). We are grateful to T. Ono (Primetech, Osaka) for his technical support.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • James T. Pearson
    • 1
    • 5
  • Mikiyasu Shirai
    • 1
    • 6
  • Chieko Yokoyama
    • 2
    • 7
  • Hirotsugu Tsuchimochi
    • 1
    • 8
  • Daryl O. Schwenke
    • 1
  • Akito Shimouchi
    • 3
  • Kenji Kangawa
    • 4
  • Tadashi Tanabe
    • 2
  1. 1.Department of Cardiac PhysiologyNational Cardiovascular Center Research InstituteOsakaJapan
  2. 2.Department of PharmacologyNational Cardiovascular Center Research InstituteOsakaJapan
  3. 3.Department of Cardiovascular DynamicsNational Cardiovascular Center Research InstituteOsakaJapan
  4. 4.Department of BiochemistryNational Cardiovascular Center Research InstituteOsakaJapan
  5. 5.Department of PhysiologyMonash UniversityVictoriaAustralia
  6. 6.Department of Clinical RadiologyHiroshima International UniversityHiroshimaJapan
  7. 7.Department of Cellular Physiological ChemistryTokyo Medical and Dental UniversityTokyoJapan
  8. 8.Graduate School of Health SciencesHiroshima UniversityHiroshima CityJapan

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