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.
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The authors declare that they have no conflict of interest.
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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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DOI: https://doi.org/10.1007/s00421-014-2921-y