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. 2020 Feb 14;10(2):302.
doi: 10.3390/biom10020302.

Sodium Thiosulfate in the Pregnant Dahl Salt-Sensitive Rat, a Model of Preeclampsia

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Free PMC article

Sodium Thiosulfate in the Pregnant Dahl Salt-Sensitive Rat, a Model of Preeclampsia

Fieke Terstappen et al. Biomolecules. .
Free PMC article

Abstract

Aberrant production of hydrogen sulfide (H2S) has been linked to preeclampsia. We hypothesized that sodium thiosulfate (STS), a H2S donor, reduces hypertension and proteinuria, and diminishes fetal growth restriction in the Dahl salt-sensitive (S) rat, a spontaneous model of superimposed preeclampsia. In addition to a control group (n = 13), two groups received STS via drinking water at a dose of 2 g (n = 9) or 3 g per kg body weight per day (n = 8) from gestational day (GD) 10 to 20. Uterine artery resistance index was measured (GD18), urinary protein excretion rate was determined (GD19), and blood pressure and fetal outcomes were evaluated (GD20). At 2 g, STS had no effect on preeclamptic symptoms or fetal outcome. At 3 g, STS reduced maternal hypertension (121.8 ± 3.0 vs. 136.3 ± 2.9), but increased proteinuria (89 ± 15 vs. 56 ± 5 mg/24h), and relative kidney weight (0.86 ± 0.04 vs. 0.73 ± 0.02%). Fetal/placental weight ratio was reduced (3.83 ± 0.07 vs. 4.31 ± 0.08) without affecting litter size. No differences in uterine artery flow or renal histological damage were noted across treatment groups. While these data suggest a promising antihypertensive effect that could imply prolongation of preeclamptic pregnancies, the unfavorable effects on proteinuria, kidney weight, and fetal/placental weight ratio implies that clinical implementation of STS is contra-indicated until safety for mother and child can be verified.

Keywords: Dahl salt-sensitive rats; blood pressure; cardiovascular; fetal growth restriction; hydrogen sulfide; preeclampsia; sodium thiosulfate; therapeutics.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure A1
Figure A1
Mean urinary thiosulfate excretion per dose. In a pilot study, sodium thiosulfate (STS) was orally administered via the drinking water at incremental doses to four healthy female Sprague Dawley rats. Highest urinary excretions of (A) thiosulfate and (B) free thiol were reached at a dose of 3 g/kg/day STS. BW, body weight. Means ± SEM.
Figure A2
Figure A2
Representative example of glomeruli in PAS staining and labyrinth zone of placentas in HE staining in control and STS treated with 2 g and 3 g in Dahl S rat. CON, control; Dahl S, Dahl Salt-Sensitive rat; STS, Sodium Thiosulfate; 2 g, 2 g per kg body weight per day; 3 g, 3 g per kg body weight per day.
Figure 1
Figure 1
Uterine artery resistance index on GD18. Examples of Doppler waveforms in a (a) control dam; (b) dam treated with 2 g STS per kg body weight per day; and (c) dam treated with 3 g STS per kg body weight per day, white arrows indicate notching; (d) treatment with 2 g STS (n = 9) and 3 g STS (n = 8) showed no significant difference in UARI as compared with the control (n = 13) with persistence of characteristic notching tested with one-way ANOVA Dunnett’s multiple comparisons test, data presented as mean ± S.E.M. CON, control; EDV, end-diastolic flow velocity; GD, gestational day; PSV, peak systolic flow velocity; STS, sodium thiosulfate; UARI, uterine artery resistance index; 2 g, 2 g per kg body weight per day; and 3 g, 3 g per kg body weight per day.
Figure 2
Figure 2
Mean arterial pressure in the Dahl S rat treated with STS versus control. MAP was not different between 2 g STS per kg body weight per day (n = 9) and the control (n = 13) but was significantly reduced by 3 g STS per kg body weight per day (n = 8) as compared with the control dams tested with one-way ANOVA Dunnett’s multiple comparisons test. MAP, mean arterial pressure; CON, control; STS, sodium thiosulfate; 2 g, 2 g per kg body weight per day; and 3 g, 3 g per kg body weight per day. Data presented as mean ± S.E.M. * p < 0.05.
Figure 3
Figure 3
Plasma concentration and daily urinary excretion of thiosulfate and sulfate in the Dahl S rat treated with STS versus a control. Plasma concentrations and urinary excretion between the control dams (n = 13) and treated dams dosed at 2 g STS per kg body weight per day (n = 9) or 3 g STS per kg body weight per day (n = 8) were tested with Brown–Forsythe and Welch ANOVA and Dunnett’s multiple comparison test. CON, control; STS, sodium thiosulfate; 2 g, 2 g per kg body weight per day; and 3 g, 3 g per kg body weight per day. Data presented as mean ± S.E.M. * p < 0.01; ** p < 0.001; *** p < 0.0001.

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