Sildenafil Citrate Treatment Enhances Amino Acid Availability in the Conceptus and Fetal Growth in an Ovine Model of Intrauterine Growth Restriction

Department of Animal Science, Texas A&M University, College Station, TX 77843-2471, USA.
Journal of Nutrition (Impact Factor: 3.88). 12/2009; 140(2):251-8. DOI: 10.3945/jn.109.114678
Source: PubMed


Adequate placental blood flow is essential for the optimal delivery of nutrients from mother to fetus for conceptus growth. Restricted fetal development results from pathophysiological and environmental factors that alter utero-placental blood flow, placental function, and, therefore, nutrient availability in the fetus. To test this hypothesis, 0, 75, or 150 mg/d sildenafil citrate (Viagra) was administered subcutaneously from d 28 to 115 of gestation to either nutrient-restricted [50% of NRC requirements) or adequately-fed ewes (100% of NRC requirements). On d 115, maternal, fetal, and placental tissues and fluids were collected. Concentrations of total amino acids and polyamines in uterine venous and arterial sera, amniotic and allantoic fluids, and fetal umbilical venous serum were lower (P < 0.05) in nutrient-restricted ewes than in adequately fed ewes, as were the ratios of total amino acids in fetal umbilical venous serum to uterine arterial serum. Sildenafil citrate dose-dependently increased (P < 0.05) total amino acids and polyamines in amniotic fluid, allantoic fluid, and fetal serum without affecting values in maternal serum. Fetal weight was lower (P < 0.05) in nutrient-restricted ewes on d 115. Sildenafil citrate treatment dose-dependently increased (P < 0.05) fetal weight in both nutrient-restricted and adequately fed ewes. This study supports the hypothesis that long-term sildenafil citrate treatment enhances fetal growth, at least in part, by increasing the availability of amino acids in the conceptus. These findings may lead to the clinical use of sildenafil citrate in human pregnancies suspected to be at risk for intrauterine fetal growth retardation.

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    • "We hypothesize that impaired placental growth (including vascular growth) or function results from reduced placental synthesis of NO and polyamines, thereby contributing to IUGR in both underfed and overfed dams (Wu et al. 2004). This hypothesis has gained support from experiments involving sheep (Satterfield et al. 2010, 2012, 2013; Lassala et al. 2010, 2011), pigs (Li et al. 2014; Mateo et al. 2007), and rats (Zeng et al. 2008, 2013). "
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    ABSTRACT: Interferon tau (IFNT) was discovered as the pregnancy recognition signal in ruminants, but is now known to have a plethora of physiological functions in the mammalian uterus. The mammalian uterus includes, from the outer surface to the lumen, the serosa, myometrium and endometrium. The endometrium consists of the luminal, superficial glandular, and glandular epithelia, each with a unique phenotype, stromal cells, vascular elements, nerves and immune cells. The uterine epithelia secrete or selectively transport molecules into the uterine lumen that are collectively known as histotroph. Histotroph is required for growth and development of the conceptus (embryo and its associated extra-embryonic membranes) and includes nutrients such as amino acids and glucose, enzymes, growth factors, cytokines, lymphokines, transport proteins for vitamins and minerals and extracellular matrix molecules. Interferon tau and progesterone stimulate transport of amino acids in histotroph, particularly arginine. Arginine stimulates the mechanistic target of rapamycin pathway to induce proliferation, migration and protein synthesis by cells of the conceptus, and arginine is the substrate for synthesis of nitric oxide and polyamines required for growth and development of the conceptus. In ruminants, IFNT also acts in concert with progesterone from the corpus luteum to increase expression of genes for transport of nutrients into the uterine lumen, as well as proteases, protease inhibitors, growth factors for hematopoiesis and angiogenesis and other molecules critical for implantation and placentation. Collectively, the pleiotropic effects of IFNT contribute to survival, growth and development of the ruminant conceptus.
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    • "Also, most amino acids exhibit a positive relationship between fetal and maternal concentrations in normal pregnancies (Cetin et al. 1996), suggesting that an increase in concentrations of amino acids in maternal plasma can lead to an elevation of their availabilities in the fetus. Even though concentrations of amino acids in maternal plasma are not changed, an increase in uteroplacental blood flows can augment their transport to the fetal plasma (Satterfield et al. 2010). Two classes of amino acid transport systems have been identified in both the apical (maternal) and basal (fetal) facing membranes of trophoblast in the placenta: Na ? "
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    ABSTRACT: Intrauterine growth restriction (IUGR) is one of the most common concerns in human obstetrics and domestic animal production. It is usually caused by placental insufficiency, which decreases fetal uptake of nutrients (especially amino acids) from the placenta. Amino acids are not only building blocks for protein but also key regulators of metabolic pathways in fetoplacental development. The enhanced demands of amino acids by the developing conceptus must be met via active transport systems across the placenta as normal pregnancy advances. Growing evidence indicates that IUGR is associated with a reduction in placental amino acid transport capacity and metabolic pathways within the embryonic/fetal development. The positive relationships between amino acid concentrations in circulating maternal blood and placental amino acid transport into fetus encourage designing new therapies to prevent or treat IUGR by enhancing amino acid availability in maternal diets or maternal circulation. Despite the positive effects of available dietary interventions, nutritional therapy for IUGR is still in its infancy. Based on understanding of the underlying mechanisms whereby amino acids promote fetal growth and of their dietary requirements by IUGR, supplementation with functional amino acids (e.g., arginine and glutamine) hold great promise for preventing fetal growth restriction and improving health and growth of IUGR offspring.
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    • "The dose of Sildenafil citrate used during the treatment of erection problems in adult men varied between 25 to a maximum 100 mg per individual. In an experiment performed by Satterfield et al. (2010), the dose for adult pregnant sheep was calculated between 75 and 150 mg. In our experiment, having no information which doses would be safe but also effective, we decided to use a double maximum dose used for men. "
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