Sildenafil citrate: function and its potential use in pregnant human and animal
Introduction and purpose
The aim of this paper is to review background material about sildenafil citrate (SC) in order to identify research questions that possibly become the basis of further research. This review will be focused on the use of sildenafil citrate in human and animal with the emphasis in its function and effect in particular tissues and organ. Although sildenafil citrate is known to be an effective vasodilator and erectile dysfunction (ED) drug in human, the use of this drugs and its effect on pregnant animals is still considered new.
Common function of sildenafil citrate
Viagra® is the current largely known brand name for SC, which is well known for its effect in treating ED in men. It improves the erectile activity in male penile by indirectly induce the relaxation of smooth muscle in corpus cavernosum, consequently, this activity increases the penile blood flow and triggers the penile erection (Boolell et al., 1996, Ballard et al., 1998). Insufficient vascular blood flow to the penile is the major cause of ED in men, however, this problem can be successfully treated by taking sildenafil citrate orally (Goldenberg, 1998, Levinson et al., 2003). The ability of SC to increase blood flow in penile therefore attracting researchers to find its possible use in female reproductive tract blood vessel with a hope that it may enhance pregnancy in pregnant individual.
Actions of sildenafil citrate in vasculature
The action of SC in blood vessel smooth muscle is it can efficiently enhancing nitric oxide (NO) activity, which indirectly increases the blood flow. Normally, the rising amount of NO in vasculature will increase cyclic guanosine monophosphate (cGMP) that induce vasodilation of blood vessels (Scaglione et al., 2017). SC acts as an selective inhibitor for cGMP-specific phosphodiesterase enzyme type-5 (PDE-5) (Boolell et al., 1996, Moreland et al., 1998, Glossmann et al., 1999, Umrani and Goyal, 1999, Scaglione et al., 2017) which catalyze inactivation of cGMP to guanosine monophosphate (GMP) (Ballard et al., 1998). Inhibition of PDE-5 will keep the cGMP in active state and increase in intracellular concentration, thus it enhances the nitric oxide (NO) activity in vasodilating blood vessels and increase the blood flow to the penile (Glossmann et al., 1999, Hatzimouratidis, 2006, Scaglione et al., 2017). Hence, this mechanism where SC enhances the activity of NO further become the basic theory for another SC action in blood vessels which use NO as the promotor.
Besides having vasodilatory effect on blood vessels, SC also has ability to promotes the growth of blood vessels from the existing vasculature (angiogenesis) by enhancing NO activity. NO has proven to induce the proliferation of smooth muscle cells in blood vessel (Paulis et al., 2008), therefore, SC is able to enhance NO by inhibiting PDE-5 which involve in the new growth of blood vessels (neovascularization). In vitro studies on cultured endothelium of chicken chorioalantoic membranes (CAMs) shows that SC administration may stimulates neovascularization through protein kinase G/ mitogen activated protein kinase pathway (PKG/AMPK) by inhibiting PDE-5 (Pyriochou et al., 2007). Furthermore, it also has been reported by an in vivo studies that SC is able to generate new vessels and increase vascularization in myocardial blood vessels in rats (Koneru et al., 2008). Therefore, these findings may be used as basic theory that SC has the ability to promotes angiogenesis in vasculature in human and animal tissues, especially those who contain PDE-5.
Sildenafil citrate effect in female
In female individual, SC increases local blood flow to the female reproductive tract. In non-pregnant individual, SC has been reported to have successfully increases the blood flow in clitoris and uterus of non-pregnant postmenopausal women (Alataş and Yağci, 2004), as well as uterine blood flow non-pregnant nulliparous women (Hale et al., 2010). Likewise, in non-pregnant ewes, SC also shown to rise blood flow to uterus (Zoma et al., 2004). In addition, study in pregnant women indicates that SC shows vasodilatory effect in myometrial arteries and utero-placental blood vessels (Wareing et al., 2005) which possibly happen as enhanced NO caused the relaxation of smooth muscle and increase the blood flow to the uterus (Herraiz et al., 2012). These findings show that the action of SC increases the blood flow in reproductive tract of pregnant and non-pregnant females has the same mechanism with sildenafil vasodilatory action in male penile blood vessels.
Similarly, the mechanism by which SC affect blood flow and neovascularization in female reproductive tract is more likely through inhibition of PDE-5 and enhance NO activity. A study in pregnant single bearing ewes shows that PDE-5 is found in all over the urogenital tract. In this study, PDE-5 mRNA is most prominent in maternal myometrium, while its protein are localized in the smooth muscle of blood vessels (Coppage et al., 2005). Inhibition of PDE-5 by SC will enhance NO activity (Glossmann et al., 1999, Pellicer et al., 2011, Scaglione et al., 2017) .In addition to its effect in growing new blood vessels, SC also has reported to promote the neovascularization in the uterus of pregnant rat by increase plasma level of NO, the promotor of angiogenesis (Soobryan et al., 2017). These findings lead to further study about the possibility of sildenafil citrate use in enhancing pregnancy in suboptimal condition.
Sildenafil citrate in pregnant individuals
The use of SC in female has giving a hope that it may have potential therapeutic uses in pregnant individuals who need enhancement in blood supply to fetus. A study in normotensive pregnant rats shown that SC is effectively increase the utero-placental blood supply, increase fetal weight and support placental growth (Pellicer et al., 2011). Similarly, supplementation of SC as vasodilatory promoter has improved placental blood flow and placental growth which affect the fetus survival and growth in intrauterine growth restriction ewes (Oyston et al., 2016, Satterfield et al., 2010). Thus, it may protect sheep fetus from pregnancy toxemia in triplets bearing ewes (Peterson et al., 2016). In support of this, a meta-analysis study has identified that the treatment with SC during uterine retarded growth pregnancy may increase the fetal growth by which increasing approximately 10% of fetal weight (Paauw et al., 2017). Therefore, SC may have a positive impact in maintaining or even increasing maternal blood supply to the utero-placental circulation which then support the placental and fetal development.
Side effects of sildenafil citrate administration
Although SC has many functions in male and female reproductive tract, it also has several adverse effects. It is reported that SC may cause side effect on human retina such as causing blue nuance to vision and the eyes become more sensitive to light (Stockman et al., 2007, Kerr and Danesh‐Meyer, 2009). In rat, long-term administration of SC caused toxic effect on the structure of retina and optic nerves (Eltony and Abdelhameed, 2017). Furthermore, it is reported that short term administration of SC may mildly increase risk of unfavorable effects such as severe headaches, flushing, dyspepsia and visual disturbance to treat in men with ED, women with sexual arousal disorder, and pregnant women (Tsertsvadze et al., 2009, Basson et al., 2002, Dunn et al., 2017). Despite the use of SC is proven to be effective in treating male and female sexual disorder, the severe adverse effect need to be given a serious attention in terms of long term use of this compound.
Conclusion and research questions
The use of SC in pregnant women indeed shows a promising hope to increase the survival and fetal growth during suboptimal pregnancy in human and animal. Vasodilatory effect of SC in both pregnant and non-pregnant uterus have been reported (Wareing et al., 2005, Zoma et al., 2004, Hale et al., 2010, Herraiz et al., 2012, Pellicer et al., 2011, Soobryan et al., 2017). Besides vasodilatory effect, SC administration also shown angiogenesis ability in uterus and placenta of rats (Oyston et al., 2016, Soobryan et al., 2017). However, limited studies has been done on safety for the females during pregnancy (Paauw et al., 2017) probably because this approach is considered new. Effects of long-term supplementation of SC in pregnant female organ other than reproductive tract will be valuable to gain information safety in the use of SC in pregnancy.
As one of the most prominent adverse effect in human is that short-term use of SC may cause severe headache in male, non-pregnant women and pregnant women, further possible research can be done is the effect of animal’s brain which chronically administered with SC during pregnancy. Research question that appear for this research will be “ Is the long term effect of SC during pregnancy may cause permanent change in the brain of animal?” and “ How SC may cause the change in the brain, especially the blood supply?”. These two research questions eventually might answer another question “Is it safe to use SC in long term period for pregnant individuals?”. The histological study in this area might give an overview and describe what are the changes might happen in long term use of SC in pregnant individuals. This research is considered important because currently the approach of using SC in pregnant individuals is considered new and the research in this area is developing largely. The result of this research may help to determine the safety of the long-term use of SC in animal and human.
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