The Journal of Nutrition
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
Sildenafil Citrate Treatment Enhances Amino
Acid Availability in the Conceptus and
Fetal Growth in an Ovine Model of
Intrauterine Growth Restriction1–3
M. Carey Satterfield, Fuller W. Bazer, Thomas E. Spencer, and Guoyao Wu*
Department of Animal Science, Texas A&M University, College Station, TX 77843-2471
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
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.J. Nutr. 140: 251–
The programmed link between fetal environment and adult
metabolic functions is well accepted, yet therapeutic means for
increasing nutrient transport from pregnant mothers to the
conceptus to prevent fetal growth retardation have not been
developed (1). Recent evidence indicates that 7–15% of preg-
nancies in women are compromised by fetal intrauterine growth
restriction (IUGR) (2,3). During pregnancy, transport of nutri-
ents from the mother to fetus(es) is predominantly dependent on
utero-placental blood flow, which increases considerably during
the second and third trimesters of gestation (4,5).
Several new vasodilatory drugs have recently been approved
for treatment of erectile dysfunction (6–8). Researchers have
explored other potential therapeutic applications for these drugs
to augment blood flow to tissues, including enhancement of
uteroplacental blood flow. One such drug, sildenafil citrate
(Viagra), induces vasodilation through inhibition of type 5
phosphodiesterase (PDE5) (7). PDE5 is responsible for the
degradation of cGMP to guanosine monophosphate. Therefore,
inhibiting PDE5 delays the breakdown of cGMP and increases
vasodilation (6). A recent report suggested that sildenafil citrate
stimulates vasodilation in myometrial biopsies collected from
IUGR pregnancies at the time of Cesarean section (7). These
findings were preceded by observations that sildenafil citrate
rapidly reduces mean arterial pressure and cardiac output while
simultaneously increasing heart rate andblood flow to the uterus
in an ovine model of surgically induced menopause (8).
Collectively, available data indicate that sildenafil citrate may
be a viable clinical treatment to reduce the incidence and/or
severity of IUGR, but direct evidence is lacking.
Although glucose is an important energy source for the
developing fetus, amino acids play a vital role in development
of the conceptus (embryo/fetus and associated placental mem-
branes) (9). In addition to serving as building blocks for tissue
protein synthesis, amino acids function as antioxidants, regula-
tors of hormone secretion, major fuels for fetal growth, and
cell signaling molecules (9–11). Furthermore, amino acids are
1Supported by the Viagra Research Grants Program-2003, grant no. 594 from
2Author disclosures: M. C. Satterfield, F. W. Bazer, T. E. Spencer, and G. Wu, no
conflicts of interest.
3Supplemental Tables 1–5 are available with the online posting of this paper at
* To whom correspondence should be addressed. E-mail: email@example.com.
0022-3166/08 $8.00 ã 2010 American Society for Nutrition.
Manuscript received August 18, 2009. Initial review completed September 22, 2009. Revision accepted November 11, 2009.
First published online December 16, 2009; doi:10.3945/jn.109.114678.
by guest on October 13, 2011
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