Corrigendum to "The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses" [Heliyon 9, Issue 12, December 2023, Article e22488].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e22488.].

The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses.

Aims: Our aims were to investigate the uterus relaxant effect of sildenafil alone and co-administered with ß2-mimetic terbutaline in an isolated organ bath and to perform in vivo smooth muscle electromyographic studies in pregnant rats. The modifications in uterine cAMP/cGMP levels were also detected. Main methods: Contractions of non-pregnant and 5/15/18/20/22-day pregnant uterine rings were measured in an isolated organ bath system in the presence of sildenafil alone or with terbutaline. The uterine levels of cAMP and cGMP were determined by commercial ELISA assays. The in vivo efficacy of the combination was measured by smooth muscle electromyography. Key findings: Sildenafil reduced uterine contractions in vitro and in vivo; additionally, terbutaline significantly increased the uterorelaxant effect of sildenafil in the lower concentration or dose ranges. Terbutaline enhanced the cGMP level increasing effect of sildenafil. Significance: The co-administration of sildenafil and terbutaline could be a promising tocolytic combination to reduce maternal and foetal adverse events and increase efficacy.

Combined uterorelaxant effect of magnesium sulfate and terbutaline: Studies on late pregnant rat uteri in vitro and in vivo.

INTRODUCTION: Preterm delivery and its complications are among the biggest challenges and health risks in obstetrical practice. Several tocolytic agents are used in clinical practice, although the efficacy and side effect profiles of these drugs are not satisfying. The aim of this study was to investigate the uterus relaxant effect of the coadministration of ß2 -mimetic terbutaline and magnesium sulfate (MgSO4 ) in an isolated organ bath and to perform in vivo smooth muscle electromyographic (SMEMG) studies in pregnant rats. In addition, we also investigated whether the tachycardia-inducing effect of terbutaline can be reduced by the presence of magnesium, due to the opposite heart rate modifying effects of the two agents. MATERIAL AND METHODS: In the isolated organ bath studies, rhythmic contractions of 22-day- pregnant Sprague-Dawley rats were stimulated with KCl, and cumulative dose-response curves were constructed in the presence of MgSO4 or terbutaline. The uterus-relaxing effects of terbutaline were also investigated in the presence of MgSO4 in both normal buffer and Ca2+ -poor buffer. The in vivo SMEMG studies were carried out under anesthesia with the subcutaneous implantation of an electrode pair. The animals were treated with MgSO4 or terbutaline alone or in combination in a cumulative bolus injection. The implanted electrode pair also detected the heart rate. RESULTS: Both MgSO4 and terbutaline reduced uterine contractions in vitro and in vivo, furthermore, the administration of a small dose of MgSO4 significantly enhanced the relaxant effect of terbutaline, especially in the lower range. However, in Ca2+ -poor environment, MgSO4 was not able to increase the effect of terbutaline, indicating the role of MgSO4 as a Ca2+ channel blocker. In the cardiovascular studies, MgSO4 significantly decreased the tachycardia-inducing effect of terbutaline in late pregnant rats. CONCLUSIONS: The combined application of MgSO4 and terbutaline may have clinical significance in tocolysis, which must be confirmed in clinical trials. Furthermore, MgSO4 could substantially reduce the tachycardia-inducing side effect of terbutaline.

Non-genomic uterorelaxant actions of corticosteroid hormones in rats: An in vitro and in vivo study.

AIMS: We aimed to identify the short-term effects of a glucocorticoid (GC) and a mineralocorticoid (MC) on non-pregnant and late pregnant rat uterine contractions to estimate their tocolytic potential. METHODS: The in vitro contractility studies were performed with uterine tissues from non-pregnant and 22-day pregnant SPRD rats. The cumulative dose-response of fludrocortisone (FLU) and dexamethasone (DEX) was measured alone or in the presence of steroid receptor antagonist mifepristone (MIF) or spironolactone (SPR). [35S]GTPγS and cAMP immunoassays were carried out to detect the activated G-proteins and cAMP, respectively. The in vivo uterine action of single doses of FLU and DEX was measured by smooth muscle electromyography. The results were statistically analyzed with an unpaired t-test. RESULTS: FLU and DEX relaxed both pregnant (33 and 34%) and non-pregnant (37 and 34%) uteri in vitro. MIF inhibited the relaxing effect of DEX, especially in the pregnant uterus, but reduced the effect of FLD only in non-pregnant tissues. GTPγS studies showed a MIF-sensitive elevation in activated G-proteins both in pregnant and non-pregnant uteri by DEX, whereas FLU induced activation only in non-pregnant samples. DEX relaxed pregnant and non-pregnant uteri in vivo in a MIF-sensitive way. SIGNIFICANCE: DEX can inhibit contractions in the late pregnant uterus in a non-genomic manner, while FLU seems to be ineffective. Its action is mediated by a G-protein-coupled receptor that can be blocked by mifepristone. Further investigations are necessary to determine the required dose and duration of GCs in the therapy of premature birth.

High Fat High Sucrose Diet Modifies Uterine Contractility and Cervical Resistance in Pregnant Rats: The Roles of Sex Hormones, Adipokines and Cytokines.

BACKGROUND: In obesity, the adipose tissue becomes a very significant endocrine organ producing different factors called adipokines, such as leptin, adiponectin and kisspeptin; however, no data are available about their actions on uterine contraction in obese pregnant rats. Our aim was to study the impact of obesity on pregnant uterine contraction in a rat model. METHODS: Obesity was induced by the consumption of a high fat high sucrose diet (HFHSD) for 9 weeks, including pregnancy. Glucose tolerance, sex hormone, cytokine and adipokine levels were measured. Uterine contractions and cervical resistance, as well as their responses to adipokines, were tested along with the expressions of their uterine receptors. RESULTS: HFHSD increased body weight, and altered glucose tolerance and fat composition. The uterine leptin and kisspeptin pathway affect increased. The levels of proinflammatory cytokines were reduced, while the plasma level of progesterone was increased, resulting in weaker uterine contractions, and improving the uterine relaxing effects of adipokines. HFHSD reduced cervical resistance, but the core effect of adipokines is difficult to determine. CONCLUSIONS: Obesity in pregnant rats reduces uterine contractility and cytokine-induced inflammatory processes, and therefore obese pregnant rat methods are partially applicable for modelling human processes.

The ontogenies of endometrial and myometrial leptin and adiponectin receptors in pregnant rats: Their putative impact on uterine contractility.

AIMS: Limited data are available about the functions and expressions of leptin and adiponectin receptors (LEPR, AdipoRs) in the uterus. Our aim was to investigate the effects of leptin and adiponectin on the contractions of intact and denuded nonpregnant and pregnant uteri, as well as the changes in mRNA and protein expressions of LEPR and AdipoRs during the gestational period. MAIN METHODS: Contractions of nonpregnant and 5-, 15-, 18-, 20- or 22-day pregnant uterine rings were measured in an isolated organ bath system. The tissue contractions were stimulated with KCl and modified by cumulative concentrations of leptin or adiponectin. The mRNAs, protein expressions and localizations of LEPR and AdipoRs were determined by RT-PCR, Western blot and immunohistochemistry, respectively. KEY FINDINGS: Both adipokines relaxed the nonpregnant intact uterus more effectively than the denuded myometrium. Leptin inhibited the contractions of endometrium-denuded uteri throughout pregnancy, while its action was weakened on intact uteri towards term. The changes in LEPR receptor densities were independent of the relaxing effect. Adiponectin inhibited contractions, but this effect ceased on pregnancy day 22, while a gradual decrease was detected towards term on denuded myometria. These modifications were in harmony with changes in the expressions of AdipoRs. SIGNIFICANCE: Both leptin and adiponectin play a role in the relaxation of the pregnant uterus, but their efficacy significantly decreases towards the end of gestation. Their endometrial receptors may have a fine-tuning role in uterine contractions, predicting the importance of these adipokines in uterine contractions under altered adipokine level conditions.