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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1831
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2550-2555
Copyright © 2005 by The Endocrine Society

Sildenafil Citrate (Viagra) Enhances Vasodilatation in Fetal Growth Restriction

Mark Wareing, Jenny E. Myers, Maureen O’Hara and Philip N. Baker

Maternal and Fetal Health Research Centre, The University of Manchester, St. Mary’s Hospital, Manchester M13 0JH, United Kingdom

Address all correspondence and requests for reprints to: Mark Wareing, Maternal and Fetal Health Research Centre, The University of Manchester, St. Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom. E-mail: mark.wareing{at}man.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR and to assess whether sildenafil citrate could improve vasodilatation in FGR pregnancies.

Methods: Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) before and after incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate.

Results: We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries.

Conclusions: We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FETAL GROWTH RESTRICTION (FGR), when the fetus fails to attain its growth potential, affects approximately 8% of all pregnancies contributing to infant prematurity (1). FGR is responsible for considerable perinatal mortality and morbidity; infants are at increased risk of perinatal complications such as fetal distress, asphyxia, neonatal encephalopathy, hypothermia, hypoglycemia, and poor feeding as well as risks of long-term neurological and developmental disorders (2, 3). These direct effects of FGR have massive implications for the delivery of health care (4). Infants of FGR pregnancies may show modification of metabolic/hematological pathways and altered immune function (5). In the long term, deficient growth in utero is related to an increased incidence of hypertension, diabetes mellitus, and coronary heart disease in adulthood (6, 7, 8).

The underlying pathology of FGR is multifactorial and poorly understood. For example, growth restriction has been shown to have a genetic component such as trisomies and cases of placental mosaicism (9) or be a result of physiological factors such as maternal undernutrition (10, 11) or smoking during pregnancy (12). However, the reduced growth of the FGR fetus is typically associated with placental insufficiency, i.e. abnormalities in placental growth, development, and function.

In normal pregnancy (NP), uterine blood flow increases dramatically from approximately 50 ml/min (8.3 x 10–4 liter/sec) at 10 wk gestation to over 1200 ml/min (0.02l liter/sec) at term (13); this massive increase in flow is facilitated by a radical trophoblast-driven modification of the uterine spiral arteries (14). Using the noninvasive technique of Doppler ultrasound velocimetry, a number of studies have documented abnormal uterine artery waveforms in FGR (15). These data suggest reduced flow/increased resistance in the uterine arteries, indicative of a poorly modified uteroplacental vasculature downstream to the measurement site. Magnetic resonance imaging studies of the placental bed in FGR pregnancies have suggested that uteroplacental flow is indeed reduced, leading to a hypoperfused placenta (16, 17).

A poorly modified uteroplacental vasculature is also a hallmark of the current pathogenic model of preeclampsia (18, 19) where aberrant spiral artery modification leads to a hypoperfused uteroplacental unit later in pregnancy (20, 21). This results in the release of a factor(s) from the placenta that activates the maternal vascular endothelium. These data suggest that the pathophysiology of FGR and preeclampsia may be related. A recent report that markers of endothelial dysfunction are increased in FGR (22), a commonly reported phenomenon of preeclampsia, supports such a hypothesis (23, 24).

Endothelium-dependent responses in a variety of blood vessels from women with preeclampsia are markedly different, compared with those isolated from NP women (25, 26, 27). We have demonstrated, using small-vessel myography, reduced endothelium-dependent responses to bradykinin in myometrial resistance arteries isolated from women with preeclampsia (26, 27) and have shown that the small residual response to bradykinin is entirely mediated via nitric oxide (28).

The first aim of the current study was to investigate our hypothesis that uterine resistance artery function is aberrant in FGR, by performing the first comparison of myometrial small-artery vasoconstriction and endothelium-dependent relaxation in pregnancies complicated by FGR with that seen in NP.

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil citrate, may improve uterine blood flow via cGMP-mediated endothelial relaxation of uterine vessels (29). Our second aim was thus to assess the effects of PDE5 inhibition in small arteries from women whose pregnancies were complicated by FGR.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
General

The ethics committee at St. Mary’s Hospital, Manchester, gave approval for this work, and consent was obtained for all tissue samples used in the study. The investigation conforms to the principles outlined in the Declaration of Helsinki (30).

Myometrial biopsies were obtained at delivery by cesarean section from the upper lip of the lower segment incision from healthy women (NP; n = 27) with uncomplicated pregnancies. Women with hypertension, diabetes, or other significant medical disorders were excluded. Biopsies were also obtained from women with intrauterine growth restriction (FGR; n = 12). All women in this group were identified on the basis of serial antenatal ultrasound scans demonstrating deficient fetal growth and delivered by cesarean section for maternal or fetal reasons; the diagnosis of FGR was confirmed by an individualized birthweight ratio (IBR) found to be less than the fifth centile. IBR is a correction of birthweight for known confounding variables and relates to a predicted birthweight calculated using independent coefficients for gestation at delivery, fetal sex, parity, ethnic origin, maternal height, and booking weight. The IBR enables a more accurate prediction of pregnancies with a poor outcome than birthweight for gestational age alone (31).

General chemicals were obtained from Sigma-Aldrich (Poole, UK) or BDH (Poole, UK). Arginine vasopressin (AVP) and bradykinin (BK) were obtained from Sigma-Aldrich. The thromboxane mimetic U46619 was obtained from Calbiochem (Nottingham, UK). The PDE5 inhibitors sildenafil citrate (Viagra) and UK-343664 were obtained from Pfizer (Sandwich, UK).

Samples

Biopsies were placed directly into ice-cold physiological salt solution, a modified Krebs solution (see below for chemical composition). Myometrial small arteries were identified and dissected under a stereomicroscope. Myometrial artery diameters were 379 ± 4 µm for NP biopsies (n = 49 arteries from 27 patients) and 310 ± 2 µm for FGR biopsies (n = 62 arteries from 12 patients).

Wire myography

Myometrial small arteries were carefully cut into small (approximately 2 mm) lengths and mounted onto 40-µm steel wire in a Danish Myo Technology (Aarhus, Denmark) M610 wire myograph as described elsewhere (32). Myometrial arteries were normalized to 0.9 of L13.3kPa using the classical normalization procedure (33) as we have described in detail elsewhere (32, 34). Initially, the bath contained 7 ml of physiological salt solution (in mmol/liter: 127.76 NaCl, 25 NaHCO3, 4.69 KCl, 2.4 MgSO4, 1.6 CaCl2, 1.18 KH2PO4, 6.05 glucose, 0.034 EDTA; pH 7.4), warmed to 37 C and gassed with air/5%CO2.

Contraction/relaxation responses of myometrial small arteries

Dose-response constriction curves to AVP (0.1–10 nmol/liter; 2-min intervals) or the thromboxane-mimetic U46619 (0.1–1000 nmol/liter; 2-min intervals) were constructed followed by relaxation to BK (0.1–1000 nmol/liter; 2-min intervals). Vessels were washed to baseline tension and then incubated for 1 h in the presence of 0, 10, or 100 nmol/liter of the PDE5 inhibitor sildenafil citrate or UK-343664. The protocol of constriction to AVP or U46619/relaxation to BK was repeated as outlined above in the maintained presence of the PDE5 inhibitor.

Statistics

Data were first tested whether they fitted to a Gaussian (normal) distribution using the Kolmogorov-Smirnov test. Data that passed the normality test were compared using parametric statistical tests (unpaired/paired t test; repeated-measures ANOVA) and are represented as mean ± SEM. All other data were compared using nonparametric statistical tests (Mann-Whitney U test) and are presented as median-range. The effect of PDE5 incubation on agonist-induced constriction of myometrial small arteries was compared by paired t test. BK-induced relaxation of myometrial small arteries was compared using repeated-measures ANOVA. Data for the number of patients are indicated by (N). A P < 0.05 was indicative of significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
General clinical data

Demographic clinical details are collated in Table 1Go. Women whose pregnancies were complicated by FGR delivered significantly earlier in gestation than the NP group (P < 0.05). Women in the FGR group also delivered smaller babies as assessed by birthweight (P < 0.001) and IBR (P < 0.001, Mann-Whitney U test).


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  		TABLE 1. Demographic and clinical details

 
Wire myography: contraction responses of small arteries from myometrium

The effect of AVP and the thromboxane-mimetic U46619 on myometrial small artery contractility is shown in Fig. 1Go. Small arteries from women whose pregnancies were complicated by FGR showed significantly increased vasoconstriction compared with that seen in small arteries taken from NP women (P < 0.05, repeated-measures ANOVA). Addition of U46619 evoked maximal constriction (active effective pressure) of 18.2 ± 1.8 kPa (n = 34 arteries from 10 patients) in vessels from women with pregnancies complicated by intrauterine growth restriction (FGR) compared with 12.2 ± 1.4 kPa (n = 27 arteries from seven patients) in NP women (P < 0.05, t test). However, the sensitivity of myometrial small arteries from women whose pregnancies were complicated by FGR to U46619-induced vasoconstriction was not significantly altered compared with vessels from NP women (EC50, 64 ± 23 nmol/liter FGR vs. 73 ± 32 nmol/liter NP; P > 0.05, t test). Addition of AVP to myometrial small arteries from women with FGR evoked maximal constriction of 21.5 ± 0.4 kPa (n = 24 arteries from seven patients) compared with 16.7 ± 0.4 kPa (n = 22 arteries from seven patients) in NP women (P = 0.06, t test). However, the sensitivity of myometrial small arteries from women whose pregnancies were complicated by FGR to AVP-induced vasoconstriction was not significantly altered compared with vessels from NP women (EC50, 0.47 ± 0.15 nmol/liter in FGR vs. 0.58 ± 0.11 nmol/liter in NP; P > 0.05, t test). These data suggest modified vasoconstriction of myometrial small arteries from women whose pregnancies are complicated by FGR.



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  		FIG. 1. Effect of U46619 and AVP on myometrial small arteries from NP women and women whose pregnancies are complicated by FGR. Data are expressed as active effective pressure production in kPa. All data are mean ± SEM; the x axis shows concentration of agonist x 10–x. {blacktriangleup}, NP (n = 13, top; n = 14, bottom); {triangleup}, FGR pregnancy (n = 10, top; n = 6, bottom). Statistical test was repeated-measures ANOVA.

 
The effect of PDE5 inhibition on agonist-induced vasoconstriction is shown in Table 2Go. In NP, myometrial small arteries incubated with 100 nmol/liter sildenafil showed decreased constriction to AVP (P = 0.002, paired t test). A similar trend was seen in vessels constricted with U46619, although this did not achieve statistical significance (P = 0.14, paired t test). In women with pregnancies complicated by FGR, myometrial small arteries incubated with 100 nmol/liter sildenafil showed decreased constriction with either AVP or U46619 (P = 0.002 and P = 0.04, respectively, paired t test). Additionally, 10 nmol/liter sildenafil showed decreased constriction with AVP-constricted small arteries (P < 0.05, paired t test). These data suggest that sildenafil limits the vasoconstriction of myometrial small arteries from NP women and from women whose pregnancies are complicated with FGR.


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  		TABLE 2. Effect of incubation with sildenafil citrate on agonist-induced constriction of myometrial small arteries

 
Wire myography: relaxation responses of small arteries from myometrium

Alteration of endothelial function in pregnancies complicated by FGR. U46619-constricted myometrial small arteries from NP women exhibited dose-dependent relaxation to increasing concentrations of BK (Fig. 2Go, top). This relaxation was significantly attenuated in arteries from women whose pregnancies were complicated by FGR (residual constriction, 43 ± 8% in FGR vs. 30 ± 5% in NP; IC50, 84 ± 15 nmol/liter in FGR vs. 14 ± 9 nmol/liter in NP; P = 0.001, repeated-measures ANOVA). A similar relationship was seen with arteries constricted with AVP (residual constriction, 45 ± 12% in FGR vs. 80 ± 3% in NP; IC50, 21 ± 12 nmol/liter in FGR vs. 15 ± 7 nmol/liter in NP; P = 0.0009, repeated-measures ANOVA; Fig. 3Go, top).



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  		FIG. 2. Endothelium-dependent relaxation of U46619-constricted myometrial small arteries. Data are expressed as percent maximal response to U46619. All data are mean ± SEM; x axis shows concentration of BK x 10–x. Top, Arteries from NP ({blacktriangleup}; n = 14) and arteries from FGR pregnancy ({triangleup}; n = 16 vessels from 12 patients); bottom, arteries from FGR pregnancy, BK-only control (•; n = 10), and arteries from FGR pregnancy, BK with 100 nmol/liter sildenafil citrate ({circ}; n = 10). Data were compared before and after sildenafil by repeated-measures ANOVA.

 


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  		FIG. 3. Endothelium-dependent relaxation of AVP-constricted myometrial small arteries. Data are expressed as percent maximal response to AVP. All data are mean ± SEM; x axis shows concentration of BK x 10–x. Top, Arteries from NP ({blacktriangleup}; n = 14) and arteries from FGR pregnancy ({triangleup}; n = 8); bottom, arteries from FGR pregnancy, BK-only control (•; n = 6), and arteries from FGR pregnancy, BK with 100 nmol/liter sildenafil citrate ({circ}; n = 6). Data were compared before and after sildenafil by repeated-measures ANOVA.

 
Effect of PDE5 inhibition. The effect of PDE5 inhibition on human myometrial small arteries was studied using U46619- and AVP-induced constriction. BK-induced relaxation of myometrial small arteries from NP women, preconstricted with U46619, was not significantly altered by preincubation with 0, 10, or 100 nmol/liter sildenafil [residual constriction, 30 ± 9% (control) vs. 35 ± 8% (10 nmol/liter) and 30 ± 5% (100 nmol/liter); n = 10; P > 0.05, repeated-measures ANOVA]. Similar data were seen when AVP (n = 7) was used to constrict arteries from NP women [residual constriction, 16 ± 3% (control) vs. 27 ± 9% (10 nmol/liter) and 28 ± 9% (100 nmol/liter); n = 7; P > 0.05, repeated-measures ANOVA].

In U46619-constricted arteries from women whose pregnancies were complicated by FGR, preincubation with sildenafil enhanced BK-induced relaxation [residual constriction, 40 ± 10% (control) vs. 47 ± 11% (10 nmol/liter) and 22 ± 10% (100 nmol/liter)]. This improvement in relaxation attained significance at 100 nmol/liter (IC50, 20 ± 9 nmol/liter (100 nmol/liter) vs. 79 ± 38 nmol/liter (control); P < 0.008, repeated-measures ANOVA; Fig. 2Go, bottom).

In AVP-constricted arteries from women whose pregnancies were complicated by FGR, preincubation with sildenafil enhanced BK-induced relaxation [residual constriction, 49 ± 14% (control) vs. 39 ± 14% (10 nmol/liter) and 34 ± 14% (100 nmol/liter)]. This improvement in relaxation attained significance at 100 nmol/liter [IC50, 20 ± 14 nmol/liter (100 nmol/liter) vs. 16 ± 11 nmol/liter (control); P < 0.05, repeated-measures ANOVA; Fig. 3Go, bottom].

In U46619-constricted arteries from women whose pregnancies were complicated by FGR, preincubation with 100 nmol/liter of the related PDE5 inhibitor UK-343664, also significantly enhanced relaxation [IC50, 10 ± 7 nmol/liter (100 nmol/liter) vs. 93 ± 53 nmol/liter (control); P < 0.05, repeated-measures ANOVA; Fig. 4Go].



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  		FIG. 4. Endothelium-dependent relaxation of U46619-constricted myometrial small arteries. Data are expressed as percent maximal response to U46619. All data are mean ± SEM; x axis is concentration of BK x 10–x. Arteries are from FGR pregnancy, BK-only control ({blacktriangleup}; n = 6), and from FGR pregnancy, BK with 100 nmol/liter UK-343664 ({triangleup}; n = 6). Data were compared before and after UK-343664 by repeated-measures ANOVA.

 
PDE5 inhibition thus significantly enhanced endothelium-dependent vasorelaxation.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have previously demonstrated that, in contrast to NP, myometrial small arteries from women with preeclampsia show attenuated BK-induced endothelium-dependent relaxation (26, 27) and that relaxation was entirely mediated by NO (28). In this study, we have demonstrated for the first time that, as in preeclampsia (26, 27, 28), there is aberrant myometrial small artery function in pregnancies complicated by FGR. Myometrial small arteries from pregnancies complicated by FGR show increased vasoconstriction and reduced endothelium-dependent relaxation compared with that seen in NP. The decreased uteroplacental flow, suggested by abnormal uterine artery Doppler in a significant number of women whose pregnancies are complicated by FGR (15) may be a direct result of this inappropriately increased vasoconstriction/reduced endothelium-dependent relaxation.

Here, we hypothesized that inhibition of PDE using the PDE5-specific inhibitor sildenafil citrate would enhance NO-mediated relaxation in small myometrial arteries isolated from women with pregnancies complicated by fetal growth restriction. The rationale behind this hypothesis stems from the similarities between the pathophysiologies associated with preeclampsia and FGR: a poorly modified uteroplacental vasculature (35) leading to a relative placental hypoperfusion and possible endothelial cell dysfunction (18, 19, 22, 23, 24). We have demonstrated that the PDE5 inhibitor sildenafil citrate limits the effects of vasoconstrictors in both NP and FGR. A similar phenomenon has been suggested in the peripheral vasculature where sildenafil displays the characteristics of a mild NO donor (36); however, the major effects of sildenafil have been clearly demonstrated to be primarily a result of increases in cytosolic GMP (36, 37, 38).

We have also demonstrated that whereas sildenafil citrate does not significantly modify BK-induced endothelium-dependent relaxation in myometrial small arteries in NP women, there is a striking improvement in relaxation of small arteries from FGR pregnancies. Incubation with sildenafil citrate effectively enhanced endothelium-dependent relaxation to levels seen in NP vessels. Similar data were seen with UK-343664, a related PDE5-specific inhibitor. These data suggest that sildenafil citrate used as a therapeutic agent may improve myometrial perfusion in FGR pregnancies by promoting myometrial small artery vasodilatation, decreasing peripheral resistance, and increasing flow within the uteroplacental bed.

We originally calculated the dose of sildenafil citrate to use in this study from erectile dysfunction clinical trials data (e.g. Refs.36, 39). Pharmacokinetic data suggest that a 100-mg oral dose of sildenafil citrate produces a plasma concentration in excess of 100 nmol/liter for 4–5 h after oral dosage (40). We therefore decided to use 100 nmol/liter as the maximum dose in our study, as we believed that these concentrations would be attainable in the myometrial circulation in vivo. This concentration is still 100-fold less than that required for nonspecific inhibition of other PDE isoforms by sildenafil citrate (which is suggested to be in the 1–10 µmol/liter range) (41).

It may be that administration of sildenafil citrate may not be an appropriate therapeutic strategy in all cases where growth restriction is apparent. However, we suggest that in cases where an inappropriately small fetus has been identified, with no genetic abnormalities and where there are abnormal uterine Doppler waveforms present, the findings of our study justify a clinical trial investigating whether sildenafil citrate administration may lead to improved uteroplacental blood flow, improved placental perfusion, and prolongation of pregnancy. This may be particularly important in women at 24–28 wk gestation where extending pregnancy by 7–10 d has significant gains in immediate postnatal and long-term sequelae (42); indeed, at extremes of prematurity, every day that pregnancy is prolonged is associated with a 3% improvement in perinatal mortality.

Common adverse reactions including headaches (7–32%), flushing (7–33%), dyspepsia (1–13%), rhinitis (0–19%), and abnormal vision/visual disturbances (0–10%) have been reported from clinical trials for the use of sildenafil in erectile dysfunction, and they may also apply to its prospective use in pregnancy (40). Additionally, sildenafil has been suggested to produce significant hypotension during coadministration with nitrates (43), and dual usage is therefore contraindicated. Other studies have also suggested adverse cardiovascular events with sildenafil administration, and thus the American College of Cardiology has issued guidelines regarding the use of sildenafil in men with cardiovascular disorders (40).

Another important consideration when administering drugs in pregnancy is the large increase in circulating plasma volume, which may alter the drug pharmacokinetics of sildenafil. Any trial that is to be conducted should take this into account as part of its dosage regime. It is not known whether sildenafil crosses the placenta thereby affecting fetal hemodynamics; from structural data one would expect sildenafil to cross the syncytiotrophoblast. As yet, there is only one case report of a woman with pulmonary hypertension who received sildenafil treatment during pregnancy, with no reported adverse effects on fetal well-being (44).

In summary, we have demonstrated that 1) myometrial small arteries from women whose pregnancies are complicated by FGR show increased constriction in response to agonist-induced vasoconstriction compared with that seen in NP; 2) incubation with sildenafil citrate limits the effects of vasoconstrictors on myometrial small arteries from NP women and from women whose pregnancies are complicated with FGR; 3) myometrial arteries from women whose pregnancies are complicated by FGR show compromised endothelium-dependent relaxation to BK; and 4) BK-induced endothelium-dependent relaxation of myometrial small arteries from women whose pregnancies are complicated by FGR is improved by incubation with 100 nmol/liter sildenafil in both AVP- and U46619-constricted arteries.

We suggest that use of sildenafil citrate in vivo may potentially improve uteroplacental blood flow in pregnancies complicated by FGR.


   Footnotes
 
This work was supported by Tommy’s: The Baby Charity and Pfizer, USA. M.W. and J.E.M. are supported by the British Heart Foundation.

First Published Online February 15, 2005

Abbreviations: AVP, Arginine vasopressin; BK, bradykinin; FGR, fetal growth restriction; IBR, individualized birthweight ratio; NP, normal pregnancy; PDE5, phosphodiesterase-5.

Received September 15, 2004.

Accepted February 4, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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