Odmienności w podawaniu leków będących donorami tlenku azotu w praktyce położniczej
Evgeniya B. Radzishevskaya1, Oleksandr A. Vyhivskyi2, Violetta B. Kalnytska1
1Kharkiv National Medical University, Kharkiv, Ukraine
2M.V. Lomonosov Moscow State University, Moscow, Russian Federation
Introduction: Endothelial dysfunction is a universal mechanism for the development of many pathological conditions of the body. In obstetric practice, endothelial dysfunction underlies the development of many pathological conditions. Nitric oxide (NO) deficiency is a key element in endothelial dysfunction.
The aim: To summarize the literature data on the effect of NO donor drugs on the state of fetoplacental complex in pregnancy complicated by obstetric and concomitant extragenital pathology, as well as their effect on the outcome of pregnancy.
Materials and methods: The article presents an assessment of 39 literary sources, discussing the peculiarities of the use of various NO donor drugs. The study allowed the authors to characterize main functions of nitric oxide and pathogenesis of endothelial dysfunction. Modern methods for the correction of endothelial dysfunction in obstetrics are described.
Conclusions: The presented review showed the role of nitric oxide in the development of endothelial dysfunction in various critical situations in obstetrics and therapeutic efficacy of administration of NO donor drugs in the correction of these disorders. Nitric oxide donors have a wide range of indications for use in obstetrics, and determination of their therapeutic possibilities requires further research.
Wiad Lek 2018, 71, 9, 1765-1769
Endothelial dysfunction is a universal mechanism for the development of many pathological conditions of the body. In obstetric practice, endothelial dysfunction underlies the development of many pathological conditions. NO deficiency is the key link of endothelial dysfunction. The main functions of NO are regulation of vascular tone and oxidative processes, suppression of adhesion and aggregation of platelets, proliferation and apoptosis, lymphocyte aggregation . Obstetric pathologies associated with impaired NO synthesis and / or release include preeclampsia (PE), placental dysfunction (PD), premature detachment of the normally located placenta, fetal hypoxia, intrauterine growth retardation, spontaneous abortion.
To summarize the literature data on the effect of NO donor drugs on the state of fetoplacental complex in pregnancy complicated by obstetric and concomitant extragenital pathology, as well as their effect on the outcome of pregnancy.
Materials and methods
The article presents an assessment of 39 literary sources, discussing the peculiarities of the use of various NO donor drugs. The study allowed the authors to characterize main functions of nitric oxide and pathogenesis of endothelial dysfunction. Modern methods for the correction of endothelial dysfunction in obstetrics are described.
Review and discussion
Pathogenesis of endothelial dysfunction is triggered by a generalized vasospasm with increased peripheral resistance, as well as a disruption of vascular and intravascular coagulation component. One of the main regulators of the vascular wall relaxation mechanisms is the endothelin relaxant factor (ERF), a substance secreted mainly by endothelial cells and having NO as its active principle [2, 3]. In 1987 scientists proved that ERF is identical to NO . In normal pregnancy the level of NO increases, which is biologically justified, since it reduces the response of the immune system to exogenously introduced or endogenously synthesized vasopressors. Thus, it turns on mechanism aimed at protection of the pregnant from excessive stress [2, 5]. Pathological conditions of pregnancy, for instance pre-eclampsia, develop secondary to a significant reduction in NO synthesis by endothelial cells, which leads to arteriolospasm and microcirculation disorders .
L-arginine is the only substrate for NO synthesis in the human body. NO is formed from L-arginine by NO synthase enzyme, which is mainly found in endothelial cells (Fig. 1).
It is practically impossible to artificially influence the activity of NO-synthase, therefore, the introduction of NO-arginine substrate into the body is optimal [7, 8].
Given all of the above, it is logical to assume that an increase in the level of nitric oxide in the body of a pregnant woman should contribute to the restoration of the functional capacity of the endothelium, thereby reducing hemodynamic and microcirculatory disorders. This is possible with the introduction of NO from outside due to a phenomenon known as the “arginine paradox”: L-arginine restores endothelial NO synthesis to normal levels, contributing to the normalization of vascular function without causing excessive vasodilation .
Currently, the most effective pathogenic method of endothelial dysfunction correction in obstetrics is the use of a physiological donor of nitric oxide – L-arginine, which contributes to the improvement of the endothelium and thus normalizes blood circulation both in the systemic and utero-placental blood flow. Therefore, arginine drugs have found wide application in obstetrics . Due to vasodilating and antihypoxic properties, nitrogen donors improve maternal and fetal hemodynamics and reduce intrauterine fetal hypoxia . During pregnancy, they exhibit antitoxic and hepatoprotective activity, acting as a nonspecific metabolic regulator of metabolic processes. Administration of L-arginine reduces the level of immune complexes circulating in the blood, reduces the severity of the syndrome of “metabolic” intoxication and immunotoxicosis, increases compensatory-adaptive reactions of the body without embryotoxic, gonadotoxic, mutagenic and teratogenic effects, does not cause allergic and immunotoxic reactions. Relative contraindications for administration include feverish states, increased excitability and severe disturbances in the filtration function of the kidneys [11, 12].
The effectiveness of the drug with arginine glutamate (AGT) as the active substance in the treatment of PE in pregnant women has been confirmed by several studies. I.A. Zhabchenko et al.  conducted an open, randomized, controlled clinical study of 108 patients with preeclampsia showing high efficiency of treatment in the group of patients with PE, where AGT was included in the therapy complex, in comparison with the group receiving only conventional therapy. The effectiveness of the treatment involved faster rates of elimination or reduction of clinical and laboratory signs of PE (edema, blood pressure level, etc.), improvement in the well-being of patients and the state of fetus.
I.A. Tuchkina et al. showed the ability of AGT to reduce endothelin-1 and increase the level of S-nitrosothiols, which helped to eliminate the cause of PE progression, improved the overall condition of pregnant women, preventing the development of complications of the gestational process .
A clinical trial involving 60 pregnant women at high risk of developing PE showed the effectiveness of a set of measures to prevent the onset and progression of this obstetrical pathology aimed at eliminating endothelial dysfunction in women at high risk of its occurrence. Women of the main group additionally took the drug with the active substance arginine hydrochloride (AHC) for the prevention of PE for 4 weeks at gestation period of 12-16 weeks. The results of the study showed a decrease in the manifestation of endothelial dysfunction, a 1.5-fold decrease in the frequency of PE and in the development of its severe forms (8.3% vs. 20.0%), other complications of pregnancy (threatened preterm labor, PD, fetal distress and intrauterine growth retardation), in the frequency of caesarean section and preterm labor, absence of perinatal mortality, an increase in the biophysical profile of fetus and newborn .
The efficacy of L-arginine in the prevention of PE in high-risk pregnancies was demonstrated by a randomized, double-blind, placebo-controlled clinical trial. A group of patients receiving L-arginine showed fewer cases of PE, higher birth-rate and less number of preterm deliveries .
Imbalance of arginine in the body of a pregnant woman can cause the development of PD, which was revealed in the study by V.A. Linde . The action of NO synthase leads to generation of arginine nitric oxide, a potent endogenous vasodilator and a mediator of various physiological processes. The level of arginine in blood serum is known to change during pregnancy, significantly increasing to its middle term and returning to the initial values before birth. Placenta is an important “supplier” of arginine in pregnancy, providing amino acid replenishment not only for regulation of the processes of cell differentiation, the state of the vascular wall and blood flow, but also for maintaining the growth and development of the fetus, for which arginine is an almost indispensable amino acid.
L-arginine donors have a pronounced effect on the vascular tone of both uterine and umbilical arteries, contributing to normalization of hemodynamics in the mother-placenta-fetus system [18, 19]. V.V. Simrok and T.F. Koryavaya conducted a study on the efficacy of L-arginine in the complex therapy of PD in 126 pregnant women with PE in combination with hepatobiliary disease. The main group (41 pregnant women), in addition to standard therapy, received a 4.2% solution of AHC, 100 ml once a day for 5 days successively and then 10 ml 3 times a day for 10-15 days, depending on the effect achieved. The main group, according to clinical and ultrasound monitoring, was found to have an improvement in blood circulation in the mother-placenta-fetus system, whereas in the comparison group in more than half of the patients these signs persisted . Positive effects of AHC were noted in the treatment of hemodynamic disorders of the fetoplacental complex in pregnant women with hypamnion at the term of 32-36 weeks. Biophysical profile of the fetus following AHC treatment showed no case of pathological or doubtful fetal status . The literature data indicate that the use of L-arginine in complex basic therapy of PE of medium and severe severity allows faster and safer stabilization of hemodynamic parameters .
The use of AHC in the complex therapy of PE and correction of the revealed disorders in the uterus-placenta-fetus complex positively influences the growth of the fetus and its functional state, which makes it possible to prolong the pregnancy until the optimal period of delivery. Moreover, L-arginine was shown to have a positive effect on the outcome of labor and adaptation of newborns in the early neonatal period .
Data on the use of AHC in the therapy of placental dysfunction in pregnant women suffering from epilepsy are given. In 70% of patients normalization of hemodynamic parameters in the uterine artery basin was noted, 66.7% of patients with hemodynamic disorders in the umbilical artery had complete normalization of the systolic-diastolic ratio, which indicated a significant decrease in the vascular resistance index .
PD often develops secondary to bacterial and viral infections, causing a number of complications, both in the mother and in the fetus. N.H. Muminova conducted a study on the quality of treatment of chronic PD in bacterial and viral persistence with the use of the NO donor drug (AHC) in comparison with standard drug therapy. The group included 44 pregnant women with acute pyelonephritis, 17 with community-acquired bilateral pneumonia and 6 with bronchopneumonia. AHC as part of complex therapy was administered intravenously by 100 ml No. 5, with the transition to oral administration later. L-arginine contributed to a faster elimination of pathological process, improvement of both clinical, laboratory and hemodynamic parameters (blood pressure, pulse), improved daily diuresis, which is important in renal and pulmonary pathology. This indicates the advisability of using AHC in the treatment and prevention of PD in pregnant women with infectious inflammatory processes .
T.P. Leshchinskaya et al. presented the results of a study on lipid metabolism in 47 pregnant women with preterm labor. The examined patients were found to have hyperlipidemia secondary to endothelial dysfunction, which gave the authors grounds to consider these changes as one of the causes of preterm labor. Administration of AHC in the complex treatment of this group of patients significantly reduced the lipid spectrum and stabilized the endothelial function .
The effectiveness of AHC administration in the correction of placental dysfunction with concomitant extragenital pathology was confirmed by clinical studies conducted by O.M. Gopchuk. The study involved 30 pregnant women at the term of 32-34 weeks with a disturbance of placental circulation secondary to diabetes mellitus and chronic pyelonephritis. All patients were prescribed AHC in a dose of 100 ml IV for 10 days to correct the revealed pathologies. At the end of treatment the patients were found to have an improvement in the general condition, stabilization of blood pressure and repeated Doppler study of blood flow in the mother-placenta-fetus system confirmed the improvement of circulation .
The combination of PD and extragenital pathology during pregnancy is a serious obstetric problem. Concomitant diseases complicate the course of pregnancy, childbirth and the postpartum period, which leads to an increase in maternal morbidity and mortality. Endothelial dysfunction developing in pregnant women suffering from diabetes mellitus, hypertension, autoimmune diseases, leads to microcirculation disturbance in the placenta and prevents the normal course of pregnancy.
The conducted studies proved the safety and high efficiency of the use of nitric oxide donor AHC in the treatment of pregnant women with arterial hypertension and endothelial dysfunction, as evidenced by normalization of endothelial function, which persisted throughout pregnancy, improvement in the parameters of pregnancy, delivery, fetus and newborn [28, 29]. These data support the analysis of controlled Cochrane studies, Pubmed data and the Australian International Register of Clinical Trials. In women with diagnosed hypertension (a sample of 884 pregnant women), L-arginine reduced the manifestation of PE and reduced the risk of preterm labor .
A study involving 40 pregnant women with II-III degree heart failure secondary to cardiovascular diseases, which were further treated with AHC with basic therapy for heart failure showed that combination therapy led to an improvement in the quality of life and overall well-being of pregnant women, increased tolerance to physical activity, increased glomerular filtration, and reduced levels of the important vasoconstrictor endothelin. All this significantly improved the results of treatment of heart failure during pregnancy . Attention is drawn to the fact of a significant improvement in the fetal condition in patients .
L-arginine drug AGT helps improve rheological parameters of blood in pregnant women with hypertension. The authors recommend combining the use of antihypertensive drugs with AGT in order to prevent complications of pregnancy .
The efficacy of L-arginine (arginine aspartate (AAS)) drugs was studied in the complex therapy of patients with placental dysfunction in the presence of varicose vein disease. Based on the results obtained, the researchers suggest that all pregnant women with varicose veins should prevent placental AAS dysfunction, proceeding from the morphologically confirmed decrease in compensatory reactions of the placenta .
A study on the use of AGT in the treatment of iron deficiency anemia during pregnancy is also of particular interest. The study showed a decrease in the indices of phagocytic activity of monocytes, which indicated a decrease in the functional activity of the macrophage phagocytosis system as a whole. In the opinion of T.P. Leshchinskaya et al., the inclusion of AGT in the complex of therapeutic measures in pregnant women with this pathology is effective and pathogenically justified . It was shown that the inclusion of the NO donor (AHC) in the complex of preventive, diagnostic and therapeutic measures in the pharmacological correction of endothelial dysfunction secondary to iron deficiency anemia made it possible to reduce the frequency of fetal hypoxia during pregnancy and childbirth, and to reduce the number of perinatal complications .
According to the literature, to improve the effectiveness of specific and preventive treatment of pregnant women with syphilis and antenatal intrauterine infection of the fetus, the patients were administered combined treatment comprising AGT and a drug containing soybean phospholipids (SP) or AAS and SP with a 2-week course simultaneously with penicillin agents. During treatment, there was a subjective improvement in the general condition of pregnant women, normalization of motor activity of the fetus, the number of amniotic fluid and the time course of increasing the height of the uterine fundus, improving the structure of the placenta, cardiotocographic parameters of the fetus and Apgar score of newborns, as well as favorable neonatal period during prophylactic treatment of newborns .
Yu. V. Davidova et al. recommend the use of AHC for the prevention of endothelial dysfunction in pre-conception period, as well as at early gestation, which can prevent the development of placental syndromes in later pregnancy.
Recently, the literature has described the effective use of nitric oxide donors in the treatment cycle before the cycle of using assisted reproductive technologies. The study found that AHC improves uterine blood flow and restores morphofunctional state of the endometrium, significantly increases the implantation ability of the endometrium, which in turn increases the incidence of pregnancy .
Thus, the presented review showed the role of nitric oxide in the emergence of endothelial dysfunction in various critical situations in obstetrics and therapeutic effectiveness of NO group donor drugs in correcting these disorders. Nitric oxide donors have a wide range of indications for use in obstetrics, and the disclosure of their therapeutic potential requires further research.
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According to the order of the Authorship.
Conflict of interest:
The Authors declare no conflict of interest.
Oleksandr O. Vyhivskyi
M.V. Lomonosov Moscow State University
Moscow, Russian Federation
Figure 1. Chemical formula of arginine