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

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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.

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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

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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.

Author information

Authors and Affiliations

  1. The Öresund Cardiovascular Research Collaboration, The Section for Heart Failure and Valvular Disease, The Clinic for Heart- and Lung Disease, Skåne University Hospital, 221 85, Lund, Sweden

    David Kylhammar & Göran Rådegran

  2. The Department of Cardiology, Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden

    David Kylhammar & Göran Rådegran

  3. The Copenhagen Muscle Research Centre, Rigshospitalet and the Panum Institute, University of Copenhagen, Copenhagen, Denmark

    David Kylhammar, Laurids T. Bune & Göran Rådegran

Authors
  1. David Kylhammar
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  2. Laurids T. Bune
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  3. Göran Rådegran
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Correspondence to David Kylhammar.

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Communicated by Carsten Lundby.

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Kylhammar, D., Bune, L.T. & Rådegran, G. P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate-induced pulmonary vasoconstriction in vivo in the pig. Eur J Appl Physiol 114, 1995–2006 (2014). https://doi.org/10.1007/s00421-014-2921-y

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