Pentoxifylline as a therapeutic option for pre-eclampsia: a study on its placental effects

Abstract

Background and purpose: Recently pentoxifylline, a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre-eclampsia. We therefore investigated the placental transfer, vascular effects and anti-inflammatory actions of pentoxifylline in healthy and pre-eclamptic human placentas.

Experimental approach: The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants.

Key results: Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP- and cGMP-induced vasodilation, as well as causing vasodilation by adenosine A₁ antagonism and via NO synthase and PKG. Pentoxifylline also reduced inflammatory factors secretion. In pre-eclamptic placentas, we observed that its vasodilator capacity was preserved, however not via NO-PKG but likely through adenosine signalling. Pentoxifylline neither potentiated vasodilation through cAMP and cGMP, nor suppressed the release of inflammatory factors from these placentas.

Conclusion and implications: Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre-eclampsia, limiting its application in this disease, although it could be useful for other placenta-related disorders. Future studies might focus on selective A₁ receptor antagonists as a new treatment for pre-eclampsia.

Keywords: inflammation; nitric oxide; pentoxifylline; phosphodiesterase; placenta; pre-eclampsia; vasodilation.

FIGURE 1

Pentoxifylline transfers completely from the maternal to the foetal circulation. Results from three ex vivo placenta perfusion experiments with 10 mg·L⁻¹ pentoxifylline (PTX) in the maternal circulation at the start of the experiment (t = 0). (a) Absolute concentrations of pentoxifylline detected in the maternal and foetal circulations. (b) The foetal to maternal (F/M) pentoxifylline ratio. (c) Absolute concentrations of pentoxifylline metabolite M1 detected in the maternal and foetal circulations. Data are depicted as mean ± SE % relaxation of U46619 pre‐constriction.

FIGURE 2

Pentoxifylline induces vasodilation and potentiates the NO and adenylyl cyclase pathways in healthy human chorionic plate arteries. Concentration–response curves (CRC) from wire myography experiments depicted as percentage relaxation of pre‐constriction by U46619. Experiments with pentoxifylline (PTX) were performed in the absence or presence of (a) NOS inhibitor L‐NAME, adenylyl cyclase inhibitor SQ22536, or both (n = 8–10), (b) A₁ receptor antagonist DPCPX, A_2A receptor antagonist ZM241385, A_2B receptor antagonist MRS1706 (n = 6–7), or (c) PKG inhibitor Rp‐8‐Br‐PET‐cGMPS, PKA inhibitor Rp‐cAMPS, or both (n= 6–13). (d) CRC of M1 (lisofylline) without antagonists (n = 8) or with SQ22536 (n = 8), L‐NAME (n = 8), or Rp‐8‐Br‐PET‐cGMPS (n = 4). Experiments were also performed with (e) SNP in the absence (n = 9) or presence of 10 μmol·L⁻¹ (n = 7) or 100 μmol·L⁻¹ PTX (n= 6), and (f) forskolin in the absence (n = 8) or presence of 10 μmol·L⁻¹ (n = 7) or 100 μmol·L⁻¹ PTX (n = 7). Curves with antagonist were compared with curves without antagonist (control) using GLM‐RM and depicted as mean ± SE % relaxation of U46619 pre‐constriction. *P < 0.05 versus control.

FIGURE 3

In preeclamptic chorionic plate arteries, pentoxifylline induces vasodilation but does not potentiate vasodilation by NO or adenylyl cyclase. Concentration–response curves (CRC) from wire myography experiments depicted as percentage relaxation of pre‐constriction by U46619. (a) CRC of pentoxifylline (PTX), in the absence (n = 11) or presence of L‐NAME (n = 10), SQ22536 (n = 7), or both (n = 9), or (b) in the absence (n = 6) or presence of Rp‐8‐Br‐PET‐cGMPS (n = 6). (c) CRC with SNP in the absence (n = 10) or presence of 10 μmol·L⁻¹ (n = 4) or 100 μmol·L⁻¹ PTX (n = 6). (d) CRC with forskolin in the absence (n = 11) or presence 10 μmol·L⁻¹ (n = 5) or 100 μmol·L⁻¹ PTX (n = 6). Curves with antagonist were compared with curves without antagonist (control) using GLM‐RM and depicted as mean ± SE % relaxation of U46619 pre‐constriction.

FIGURE 4

Comparisons of vasodilation responses between healthy and pre‐eclamptic chorionic plate arteries. Concentration‐response curves (CRC) from wire myography experiments depicted as percentage relaxation of pre‐constriction by U46619. (a) CRC of pentoxifylline (PTX, healthy n = 26, pre‐eclampsia n = 18). (b) CRC of soluble guanylyl cyclase activator BAY 60‐2770 (healthy n = 8, pre‐eclampsia n = 6). (c) CRC of NO donor SNP (healthy n= 19, pre‐eclampsia n= 13). (d) CRC of adenylyl cyclase activator forskolin (healthy n = 8, pre‐eclampsia n = 11). Pre‐eclampsia curves were compared with healthy curves using GLM‐RM and depicted as mean ± SE % relaxation of U46619 pre‐constriction.

FIGURE 5

The effects of pentoxifylline on the release of proteins from placental explants. Placental explants from healthy (a, n = 5–7) and pre‐eclamptic (b, n = 7) women were incubated with or without 100 mg·L⁻¹ (=359 μmol·L⁻¹) pentoxifylline (PTX). The release of cytokines from placental explants with pentoxifylline was normalized to the release of cytokines from its own paired control experiment and displayed as percentage change versus control (mean ± SE). *P < 0.05 versus 100% in one‐sample Student's t test with Benjamini–Hochberg correction.

FIGURE 6

Schematic illustration of the potential effects of pentoxifylline (PTX) in placental blood vessels. Pentoxifylline can improve vasodilation of healthy chorionic plate arteries by enhancement of NOS‐mediated NO synthesis and/or inhibition of PDEs. It can also inhibit vasoconstriction through antagonism of the adenosine type 1 receptor (A₁). A2A/A2B, adenosine type 2A/2B receptor; ATP, adenosine triphosphate; (c)AMP, (cyclic) adenosine monophosphate; (c)GMP, (cyclic) guanosine monophosphate; GTP, guanosine triphosphate; IP₃, inositol triphosphate; PGH₂, prostaglandin H2; PGI₂, prostacyclin; PKG/PKA, protein kinase G/A; PLC, phospholipase C