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Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia

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Abstract

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

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Authors and Affiliations

  1. Women’s Health & Perinatal Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway

    Amarnath Bhide PhD & Ganesh Acharya PhD

  2. Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland

    Leena Alanne MD

  3. Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland

    Juha Rasanen PhD

  4. Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland

    Juha Rasanen PhD, Heikki Huhta PhD & Juulia Junno MD

  5. Department of Anesthesiology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland

    Merja Kokki PhD

  6. Department of Anesthesiology, Oulu University Hospital, Oulu, Finland

    Tiina Erkinaro PhD

  7. Department of Statistics, Oulu University Hospital, Oulu, Finland

    Pasi Ohtonen MSc

  8. Department of Obstetrics and Gynecology, Lapland Central Hospital, Rovaniemi, Finland

    Mervi Haapsamo PhD

  9. Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden

    Ganesh Acharya PhD

  10. Molecular and Clinical Sciences Research Institute, St George’s, University of London & St George’s University Hospital Foundation Trust, London, SW17 0RE, United Kingdom

    Amarnath Bhide PhD

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  1. Amarnath Bhide PhD
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  2. Leena Alanne MD
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  3. Juha Rasanen PhD
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Correspondence to Amarnath Bhide PhD.

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Authors’ Contribution

AB contributed to acquisition, analysis or interpretation of data for the work, and drafting the manuscript; LA contributed to acquisition, analysis or interpretation of data for the work, and revising it critically for important intellectual content; JR and GA contributed to conception and design of the work, acquisition, analysis and interpretation of data for the work, and revising it critically for important intellectual content; HH, JJ, MK, TE, PO, and MH revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Bhide, A., Alanne, L., Rasanen, J. et al. Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia. Reprod. Sci. 26, 337–347 (2019). https://doi.org/10.1177/1933719118773412

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