Association of circulating endothelin and noradrenaline with increased calcium-channel binding sites in the placental bed in pre-eclampsia

Authors

  • José A. Ferreira-de-Almeida,

    Consultant (Obstetrics and Gynaecology) , Corresponding author
    1. Department of Obstetrics-Gynaecology, Fuculty of Medicine of Oporto, Portugal
      Correspondence: Professor J. A. Ferreira-de-Almeida, Unidade de Farmacologia Clinica da Faculdade de Medicina, Hospital de S. JoBo, 4200 Porto, Portugal.
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  • Francesco Amenta,

    Associate Professor (Pharmacology)
    1. Institute of Phurmacology, Camerino University, Italy
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  • Filomena Cardoso,

    Senior Staff (Obstetrics and Gynaecology)
    1. Department of Obstetrics-Gynaecology, Fuculty of Medicine of Oporto, Portugal
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  • Jorge J. Polónia

    Consultant and Aggregated Professor (Internal Medicine)
    1. Clinical Pharmacology Unit, Pharmacology and Therapeutics Institute, Fuculty of Medicine of Oporto, Portugal
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Correspondence: Professor J. A. Ferreira-de-Almeida, Unidade de Farmacologia Clinica da Faculdade de Medicina, Hospital de S. JoBo, 4200 Porto, Portugal.

Abstract

Objective To evaluate factors contributing to both placental hypoperfusion and maternal vasoconstriction in pre-eclampsia.

Design Single centre, comparative study of calcium-channel density and affinity in the placental bed of pregnant women with normotension and pre-eclampsia.

Setting Teaching hospital.

Participants Twenty-two primigravidae in the third trimester of pregnancy: 10 with pre-eclampsia and 12 normotensive.

Methods Plasma levels of endothelin-1 (by RIA) and noradrenaline (by HPLC-ED) were measured. Both pharmacological characterisation and anatomical localisation of dihydropyridine-sensitive binding sites (using radioligand-binding studies and autorradiographic techniques) were determined with 3H-isradipine in placental bed tissues to determine both the density (Bmax) and the affinity (Kd) of receptor sites.

Results Higher plasma levels of endothelin-1 and noradrenalin were found in women with pre-eclampsia compared with normotensive women. Placental bed tissues bound 3H-isradipine in a saturable, reversible time and temperature-dependent manner with very low Kd values. Study of the 3H-isradipine specificity binding included the use of several dihydropyridine displacers. In the group with pre-eclampsia the Scatchard analysis of the results showed a significant increase (P < 0.001) both in the affinity [Kd = 0.23 nmol (0.04) vs 0.45 nmol (0.03), pre-eclampsia vs norrnotensive] and in the density of calcium-channel binding sites [Brnax = 77.70 frnol/rng (1.30) vs 64.30 fmourng (1.80) tissue, pre-eclampsia vs normotensive]. Autoradiography confirmed that in the placental bed tissue of those with pre-eclampsia there was a much higher silver grain density in the arteries walls, compared with norrnotensive women.

Conclusions In pre-eclampsia there is an increase in the maternal circulation of two strong vasoconstrictor factors (endothelin-1 and noradrenalin) and a sharp increase both in the density and the affinity of calcium-channel binding sites in placental bed central area. The latter may strongly contribute to the perpetuation of the uteroplacental hypoperfusion either by itself or by amplifying the local actions of circulating factors, such as endothelin-1 and noradrenalin.

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