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Soluble guanylyl cyclase (sGC) stimulators and activators decrease blood pressure and proteinuria in a rat model of preeclampsia
Author(s) -
Robinson Ta'Shariah,
Gillis Ellen E,
Garrett Michael R,
George Eric,
Granger Joey P,
Sasser Jennifer M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1212.5
Subject(s) - soluble guanylyl cyclase , medicine , preeclampsia , nitric oxide , endocrinology , cyclic guanosine monophosphate , blood pressure , proteinuria , urine , pregnancy , kidney , guanylate cyclase , biology , genetics
Preeclampsia is a pregnancy disorder that adversely affects both the mother and the fetus and is characterized by the onset of hypertension and proteinuria after the twentieth week of gestation. While there are currently no effective treatments, agents that improve nitric oxide (NO) ‐ cyclic guanosine monophosphate (cGMP) signaling and endothelial function may be therapeutic targets to treat patients with preeclampsia. Recent studies suggest that soluble guanylyl cyclase (sGC) stimulators and sGC activators can enhance reduced sensitivity to NO and increase the enzymatic activity of sGC, respectively. The purpose of this study was to determine the efficacy of a sGC stimulator and a sGC activator on the maternal syndrome and fetal outcomes in the pregnant Dahl S rat. Baseline blood pressure (BP) was recorded (DSI telemetry), and rats were placed in metabolic cages for 24 hr urine collection before mating. On day 14 of pregnancy, rats were randomly placed on either the control diet (n=5), the BR5918 sGC stimulating diet (80mg/kg/day, n=7), or the BR5919 sGC activating diet (16mg/kg/day, n=4). Uterine artery resistance index (UARI) was measured by Doppler ultrasound (Vevo 770) on day 18, urine was collected again on day 19, and blood and tissues were harvested on day 20. Plasma and urinary cGMP concentrations were measured using a commercially available ELISA (Cayman Chemical). Only the sGC activator enhanced the sGC activity as evidenced by increased cGMP in the urine (p=0.06) and plasma (see Table, *P<0.05 vs Control); however, both treatments improved the maternal syndrome as measured by a decrease in blood pressure (from baseline to day 19) and proteinuria. These treatments did not affect UARI, litter size, or pup weight. These preliminary findings demonstrate reductions in blood pressure and proteinuria following treatment with either a sGC activator or stimulator with no adverse effects on fetal growth. Therefore, our findings support further investigation into the therapeutic effects of sGC stimulators and activators for the treatment of preeclampsia.Urine cGMP (nmol/day) Plasma cGMP (pmol/ml) ΔBP (mmllg) UPE (mg/d) UARI Pup weight Litter sizeControl 66.3±0.03 7.5±1.8 +7.9±1.1 264±49 0.67±0.05 2.3±0.1 10.0±0.6 BR5918 (stimulator) 63.8±5.9 5.6±0.9 −12.6±1.7* 128±39* 0.66±0.07 2.3±0.1 10.4±0.4 BR5919 (activator) 81.7±10.3 11.5±1.3* −14.7±7.4* 106±17* 0.69±0.07 2.3±0.1 12.3±1.1