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European Journal of Applied Physiology

, Volume 114, Issue 9, pp 1995–2006 | Cite as

P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate-induced pulmonary vasoconstriction in vivo in the pig

  • David KylhammarEmail author
  • Laurids T. Bune
  • Göran Rådegran
Original Article

Abstract

Purpose

To investigate the role of P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate (ADP)-induced pulmonary vasoconstriction.

Methods

19 anaesthetized, mechanically ventilated pigs (31.3 ± 0.7 kg) were evaluated in normoxia and hypoxia, without (n = 6) or with P2Y1 receptor antagonist MRS2500 (n = 7) or P2Y12 receptor antagonist cangrelor (n = 6) treatment. 12 pigs (29.3 ± 0.4 kg) were evaluated before and during ADP infusion, without and with MRS2500 (n = 6) or cangrelor (n = 6) pre-treatment.

Results

Hypoxia increased (p < 0.05) mean pulmonary artery pressure (MPAP) by 14.2 ± 1.1 mmHg and pulmonary vascular resistance (PVR) by 2.7 ± 0.4 WU. Without treatment MPAP and PVR remained unaltered (p = ns) for 90 min hypoxia. During hypoxia MRS2500 decreased (p < 0.013) MPAP by 4.3 ± 1.2 mmHg within 15 min. Cangrelor decreased (p < 0.036) MPAP to be 3.3 ± 0.4 and 3.6 ± 0.6 mmHg lower than hypoxia baseline after 10 and 30 min. PVR was, however, unaltered (p = ns) by MRS2500 or cangrelor during hypoxia. ADP increased (p < 0.001) MPAP and PVR to stabilize 11.1 ± 1.3 mmHg and 2.7 ± 0.3 WU higher than baseline. MRS2500 or cangrelor pre-treatment totally abolished the sustained MPAP- and PVR-increases to ADP.

Conclusions

ADP elicits pulmonary vasoconstriction through P2Y1 and P2Y12 receptor activation. ADP is not a mandatory modulator, but may still contribute to pulmonary vascular tone during acute hypoxia. Further investigations into the mechanisms behind ADP-induced pulmonary vasoconstriction and the role of ADP as a modulator of pulmonary vascular tone during hypoxia are warranted.

Keywords

ADP Cangrelor HPV MRS2500 Pulmonary hypertension 

Abbreviations

ANOVA

Analysis of variance

AO

Aorta

ATP

Adenosine triphosphate

ADP

Adenosine diphosphate

CO

Cardiac output

CO2

Oxygen content

FiO2

Inspired oxygen fraction

Hb

Haemoglobin concentration

HPV

Hypoxic pulmonary vasoconstriction

HR

Heart rate

MAP

Mean aortic pressure

MPAP

Mean pulmonary arterial pressure

MRAP

Mean right atrial pressure

PA

Pulmonary artery

PCWP

Pulmonary capillary wedge pressure

pO2

Partial pressure for oxygen

PVR

Pulmonary vascular resistance

SO2

Oxygen saturation

SV

Stroke volume

SVR

Systemic vascular resistance

WU

Wood units

Notes

Acknowledgments

We would like to acknowledge the support of the animal technicians at the Department of Experimental Surgery and Medicine, the Panum Institute, University of Copenhagen, Copenhagen, Denmark, the staff at the Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark, and the staff at the Department of Cardiology, Lund University and the Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden. We moreover acknowledge the financial support of the Copenhagen Muscle Research Centre, Copenhagen, Denmark, the Maggie Stephens-, Crafoord-, Per Westling- and “ALF” Foundations, Lund, Sweden, and the Dr. Hartelii Scholarship Fund, Lund, Sweden. Cangrelor was provided by The Medicines Company, Parsippany, NJ, USA.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

421_2014_2921_MOESM1_ESM.pdf (434 kb)
Supplementary material 1 (PDF 433 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • David Kylhammar
    • 1
    • 2
    • 3
    Email author
  • Laurids T. Bune
    • 3
  • Göran Rådegran
    • 1
    • 2
    • 3
  1. 1.The Öresund Cardiovascular Research Collaboration, The Section for Heart Failure and Valvular Disease, The Clinic for Heart- and Lung DiseaseSkåne University HospitalLundSweden
  2. 2.The Department of Cardiology, Clinical Sciences, Faculty of MedicineLund UniversityLundSweden
  3. 3.The Copenhagen Muscle Research Centre, Rigshospitalet and the Panum InstituteUniversity of CopenhagenCopenhagenDenmark

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