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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 5  |  Page : 204-210

Tocolytic effect of the monoterpenic phenol isomer, carvacrol, on the pregnant rat uterus


1 Department of Pharmacology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of the State of Hidalgo, México
2 Department of Geriatrics, Academic Area of Gerontology, Institute of Health Sciences, Autonomous University of the State of Hidalgo, México

Date of Submission19-Jul-2020
Date of Acceptance17-Sep-2020
Date of Web Publication27-Oct-2020

Correspondence Address:
Dr. Mario I Ortiz
Department of Pharmacology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of the State of Hidalgo, Eliseo Ramirez Ulloa 400, Doctores, 42090, Pachuca, Hidalgo
México
Dr. Victor Manuel Munoz-Perez
Department of Pharmacology, Academic Area of Medicine, Institute of Health Sciences, Autonomous University of the State of Hidalgo, Eliseo Ramirez Ulloa 400, Doctores Pachuca, 42090, Hidalgo
México
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Source of Support: This work was financially supported by the Perfíl Deseable del Programa para el Desarrollo Profesional Docente (PRODEP): No. 244033-PRODEP-SEP, Mexico., Conflict of Interest: None


DOI: 10.4103/CJP.CJP_56_20

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  Abstract 

Despite the wide application of carvacrol (CAR) in different biological and medical areas, there is still insufficient electrophysiological data on the mechanisms of action of CAR, particularly in the pregnant uterine function. The aim of this study was to evaluate the in vitro tocolytic effect of CAR on the contractility of isolated pregnant rat uterus in the presence of a calcium channel antagonist (nifedipine) and a cyclooxygenase inhibitor (indomethacin). The uteri were isolated from pregnant Wistar rats at 16–18 days of pregnancy and suspended in an isolated organ bath chamber containing a Ringer's physiological solution and aerated with 95% O2 and 5% CO2. Samples were used in functional tests to evaluate the inhibitory effect of CAR at increasing concentrations on the rhythmic spontaneous, oxytocin-induced phasic, K+-induced tonic, and Ca2+-induced contractions. The differences in inhibitory concentration-50 and Emax among the compounds were determined using the one-way ANOVA followed by a post hoc Student-Newman-Keuls or Bonferroni test, in all cases P < 0.05 was considered statistically significant. Nifedipine was used as positive controls where required. CAR caused a significant concentration-dependent inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. We showed that the inhibitory effects of CAR depends on the type of muscle contraction stimuli, and that it acts stronger in spontaneous rhythmic activity and in contractions of isolated rat uterus induced by Ca2+. Nifedipine was more potent than CAR and indomethacin on the uterine contractility (P < 0.05), but none of them was more effective than nifedipine. Therefore, the tocolytic effect induced by CAR was associated with the blockade of the calcium channels in the pregnant rat uterus. This property placed CAR as a potentially safe and effective adjuvant agent in cases of preterm labor, an area of pharmacological treatment that requires urgent improvement.

Keywords: Calcium channels, carvacrol, pregnancy, preterm labor, tocolytic


How to cite this article:
Munoz-Perez VM, Ortiz MI, Gerardo-Muñoz LS, Cariño-Cortés R, Salas-Casas A. Tocolytic effect of the monoterpenic phenol isomer, carvacrol, on the pregnant rat uterus. Chin J Physiol 2020;63:204-10

How to cite this URL:
Munoz-Perez VM, Ortiz MI, Gerardo-Muñoz LS, Cariño-Cortés R, Salas-Casas A. Tocolytic effect of the monoterpenic phenol isomer, carvacrol, on the pregnant rat uterus. Chin J Physiol [serial online] 2020 [cited 2020 Nov 29];63:204-10. Available from: https://www.cjphysiology.org/text.asp?2020/63/5/204/299250


  Introduction Top


Pre-term birth (PTB) is one of the main clinical problems in gynecological and obstetrical practice. The most common causes include infections and chronic conditions such as diabetes and high blood pressure, among others.[1] Tocolytics are also known as anti-contraction medications or labor suppressants that are used to suppress or inhibit the premature labor; in fact, the tocolytic therapy is provided when delivery would result in premature birth.[2] Currently, tocolytic drugs, such as calcium channel blockers, beta-adrenergic receptor agonists, and cyclooxygenase inhibitors are used for the treatment of PTB as a first-line therapy.[3],[4],[5] These drugs have different mechanisms of actions, such as inhibiting calcium channels, reducing the number of some inflammatory mediators, and increasing the intracellular concentrations of some second messengers related to the uterine relaxation mechanisms.[5],[6] Despite the availability of several tocolytic drugs that can inhibit the premature uterine contractions, the pharmacotherapy of PTB is inappropriate.[7] Their use has been strongly associated with several serious adverse effects in both fetus and mother.[5],[8] In addition, some tocolytics suppress only partially the contractions or are ineffective.[9] Due to the growing interest in the discovery and development of new drugs for the pharmacological treatment of PTB, it is important to identify new molecular targets involved in the uterine contraction; in fact, it has been considered to find new drugs derived from the medicinal plants with potential tocolytic properties, including calcium agonist and prostaglandin inhibitors.[10] The combination therapy between tocolytic drugs and plant extracts for the treatment and/or prevention of the PTB could be an interesting and alternative strategy and deserves to be studied further to explore its advantages and disadvantages.[10],[11],[12] Carvacrol (CAR) is a liquid phenolic monoterpenoid, 2-methyl-5-(1-methylethyl) phenol and is present in essential oils obtained from different plants, such as oregano (Origanumvulgare), marjoram (Origanummajorana), and Mexican oregan (Lippiagraveolens), among others.[13] CAR possess a wide range of biological activities including anti-inflammatory, antibacterial, antifungal, antioxidant, anticarcinogenic, antiplatelet, and vasorelaxant.[13],[14] Despite the fact that the mechanisms of action of CAR are not well clarified and not well understood, some of them have been related to the reduction of the membrane potential which effect promoted a rise of the intracellular calcium concentration by inducing PLC-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry through PKC-sensitive, non-store-operated Ca2+ channels.[15],[16] Other findings have suggested that CAR possesses a vasorelaxant property that was tested in the rat aorta which effect has also been related to some mechanisms involving a transduction pathway between Ca2+ release from sarcoplasmic reticulum and/or regulation of the Ca2+ sensitivity of the contractile system.[14],[17] However, no data are available in the international literature regarding the effects of CAR on the female reproductive system, particularly on the contractility of the uterine smooth muscle (myometrium) that is a critical structure in the physiopathology of the PTB. Therefore, the present study was aimed to investigate the tocolytic effect of CAR on the pregnant rat uterus and to assess the possible mechanisms underlying this effect.


  Materials and Methods Top


Animals

Thirty pregnant female Wistar rats weighing 200–220 g (70–80 days old) were used in this study. Pregnancy was corroborated daily, and the female rat was cataloged as pregnant when a copulation plug was observed in the vagina (considered as the 1st day of pregnancy). Four animals per cage were housed under the following conditions: temperature (20°C–25°C), humidity (40%–60%), 12 h of light/12 h of dark and ad libitum water, and food intake.[18] Animals received humane care according to the respective institutional guidelines, the Mexican Official Norm (NOM-062-ZOO-99) regarding technical specifications for the production, care and use of laboratory animals, and the criteria outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, 1985).[19]

Drugs and solutions

CAR (phenol monoterpenoid), nifedipine (calcium channel blocker), indomethacin (a nonselective inhibitor of cyclooxygenase), dimethyl sulfoxide, and oxytocin (uterine motility inductor), were purchased from Sigma-Aldrich, Mexico.

Functional studies of the in vitro contractility

Animals were sacrificed by CO2 inhalation between days 16 and 18 of gestation to study the relaxant effect of CAR as tocolytic agent. Uterus extraction and its preparation for the in vitro experiments were carried out as reported.[18] The removed uterus horns were placed in a Ringer physiological solution (mM: NaCl 144, NaHCO3 30, KCL 6.2, KH2 PO4 1, MgSO4 0.5, CaCl2 2.5) glucose 11.1, pH 7.4 bath to wash blood rests. Uterine strips, 10 mm × 3 mm, were cut from the antimesium side of the pregnant uterus and vertically mounted in chambers with 3 mL of Ringer that was changed repeatedly until the basal tension record was uniform to 1 g. Uterine strips were maintained in the Ringer solution bath at 37°C with constant bubbling of 5% CO2 in O2 before starting with the experimental protocols on the spontaneous, oxytocin-induced phasic,[20] K+-induced tonic, and Ca2+-induced contractions. The changes of the contractile activity from the isometric tension was recorded with a FT03C force transducer coupled to an RPS-312 RM model polygraph (Grass Telefactor, West Warwick, RI, USA). The recorded data were analyzed using the software PolyVIEW version 2.5, and the uterine contractions (integral activity) were measured considering the area under the curve (AUC) defined by the graphic isometric register over a 15-min period after stabilization. The inhibitory effects of CAR, nifedipine, and indomethacin on the phasic and tonic uterine contractions were expressed as follows:[18]

% Inhibition = 100% – (AUCr/AUCi) × 100

AUCr represents the remaining AUC after uterine strip exposition to drug, and AUCi is the AUC of the integral activity before any compound addition. Before and after exposition to drugs, 15 min was considered enough to obtain stable and representative biological activity. All concentration-response curves were built for CAR, nifedipine, and indomethacin using increased concentrations: 10, 23, 56, 70, 100, 150, and 230 μM for CAR, 1, 3.2, 10, 18, 23, 56, and 100 nM for nifedipine and 3, 10, 30, 42, 56, 100, 300, 420, and 560 μM for indomethacin.

Statistical analysis

Data obtained from the inhibitory effect of the compounds on phasic and tonic contractions underwent a concentration-response curve analysis, which was performed using Sigma Plot version 14.0 notebook software (Systat Software Inc., San Jose, CA, USA) to obtain the inhibitory concentration-50 (IC50) values, a drug concentration that reaches 50% of the maximum inhibitory effect (potency), and the Emax, a maximum inhibitory response produced by the highest concentration of the tested compound (efficacy). All the data are expressed as the means ± standard error of the mean (SEM) from the determinations for each concentration (n = 6). The differences in IC50 and Emax values of the drugs were determined by the one-way ANOVA followed by a Student-Newman-Keuls or a Bonferroni post hoc tests using Sigma Stat Software version 3.1 (Systat Software Inc., San Jose, CA, USA). In all cases, P < 0.05 was considered statistically significant.


  Results Top


Carvacrol inhibits phasic and tonic contractions of the pregnant rat uterus

Influence of different types of uterine activation (spontaneous rhythmic activity, oxytocin-induced phasic and K+-induced tonic, and Ca2+-induced contractions) on the relaxant effect of CAR. [Figure 1]a shows the concentration-dependent sigmoid curves of the inhibitory effect on the spontaneous contractions of the pregnant rat uterus induced by CAR that were compared with nifedipine and indomethacin. Nifedipine sigmoid curve totally appears leftward in order between the 10−9 and 10−8 M concentrations and reached a maximal inhibition of 98.6%, while the indomethacin sigmoid curve is observed in the order of μM, and its maximal inhibition value was 96.2%, thus indomethacin was less potent than nifedipine; in addition, the non-parallel slope and shape of both sigmoid curves suggest the different mechanisms of action of these drugs. The sigmoid curve of CAR and indomethacin is found very close to each other and even more rightward in the order between the 10−5 and 10−4 M, which indicates that CAR is significantly less potent than nifedipine that has been used as positive control; their order of potency was as follows: nifedipine was the most potent > CAR > indomethacin (P = 0.05). Regarding efficacy, the three compounds showed a significant similar efficacy value; in fact, CAR was more effective than indomethacin, and as effective as nifedipine, because the maximal inhibition of CAR was 100%. [Figure 1]b depicts a typical tracing of the inhibition of spontaneous phasic contractions of pregnant rat uterus by adding CAR and control drugs. Interestingly, the percentage of inhibition induced by CAR is dependent on the increasing concentrations used in each experiment. In [Figure 2]a, the sigmoid curve of CAR appears to overlap the sigmoid curve of indomethacin which shows to be more potent than CAR, but with similar efficacy. [Figure 2]b represents a typical tracing of the inhibition of oxytocin-induced phasic contractions by adding CAR and control drugs. In fact, we observed a very similar pattern in the distribution and shape of the concentration-dependent sigmoid curves of CAR and indomethacin on the K+-induced tonic and Ca2+-induced contractions; their sigmoid curves are always found very close to each other and more rightward in the order between the 10−5 and 10−4 M, contrary to the sigmoid curve of nifedipine in the 10−9 M [Figure 3]a and [Figure 4]a. Their typical recordings represent the experimental inhibition of the K+-induced tonic and Ca2+-induced contractions by increasing the concentrations of CAR [[Figure 3]b and [Figure 4]b, respectively]. A summary of the values related to the pharmacological parameters, the IC50 and the Emax, for all three drugs are represented in [Table 1]. In this case their order of potency is the most potent nifedipine > CAR > indomethacin, except in the oxytocin sigmoid curve in where indomethacin was more potent than CAR. Each value was derived from a concentration-response curve analysis.
Figure 1: Inhibitory effect of carvacrol, indomethacin, and nifedipine on the spontaneous contractions. (a) Concentration-response curves of pregnant uterine strips of pregnant rat. Each point in the graph indicates the mean of six experiments (n = 6) for carvacrol, nifedipine, and indomethacin; the vertical bars represents the standard error of the mean (±standard error of the mean). (b) Typical recording of spontaneous phasic contractions inhibited by carvacrol in concentration-dependent manner; *Different from nifedipine, P < 0.05.

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Figure 2: Inhibitory effect of carvacrol, nifedipine, and indomethacin on oxytocin-induced contractions. (a) Concentration-response curves of pregnant uterine strips of pregnant rat. Each point in both graphs represents the mean of six experiments (n = 6) for carvacrol, nifedipine, and indomethacin; the vertical bars represents the standard error of the mean (±standard error of mean). (b) Typical recording of oxytocin-induced phasic contractions inhibited by carvacrol in concentration-dependent manner; *Different from nifedipine, P < 0.05.

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Figure 3: Inhibitory effect of carvacrol, nifedipine, and indomethacin on KCl-induced tonic contractions. (a) Concentration-response curves of pregnant uterine strips of pregnant rat. Each point in both graphs represents the mean of six experiments (n = 6) for carvacrol, nifedipine, and indomethacin; the vertical bars represents the standard error of the mean (±standard error of mean). (b) Typical recording of KCl-induced tonic contractions inhibited by carvacrol in concentration-dependent manner; *Different from nifedipine, P < 0.05.

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Figure 4: Inhibitory effect of carvacrol, nifedipine, and indomethacin on Ca2+-induced tonic contractions. (a) Concentration-response curves of pregnant uterine strips of pregnant rat. Each point in both graphs represents the mean of six experiments (n = 6) for carvacrol, nifedipine, and indomethacin; the vertical bars represents the standard error of the mean (±standard error of the mean). (b) Typical recording of Ca2+-induced tonic contractions inhibited by carvacrol in the concentration-dependent manner; *Different from nifedipine, P < 0.05.

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Table 1: Inhibitory concentration-50 and maximum inhibitory effect values of carvacrol, indomethacin, and nifedipine

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  Discussion Top


Annually, an estimated 15 million babies are born preterm whose complications are the leading cause of death among infants under 5 years and are responsible for around 1.1 million of deaths.[21] Many survivors face a lifetime of disability, including visual, hearing problems, and learning disabilities; in fact, this condition is an important contributor to perinatal morbidity and mortality and an economic burden on society.[18],[21] Tocolytics are the most used drug in the clinic for the treatment of PTB. Unfortunately, their use has been frequently associated with adverse reactions and low efficacy.[5],[6] In fact, the search for new drugs for the treatment of PTB tries to identify target molecules involved in the signaling pathways that lead to uterine contractions. Currently, new drugs and herbal extracts are being used in both in vivo and in vitro PTB models to explore their possible therapeutic benefits.[18],[22],[23] Some aromatic plants-derived organic compounds that may be involved in the defense of plants against phytopathogenic bacteria, fungi, viruses, among others.[24] One of these compounds is CAR which can exhibit numerous bioactive properties in in vitro and in vivo models,[13] such as the neuroprotective property of CAR in conscious rodents through the activation of the receptor potential vanilloid 3 (TRPV3) channels.[25] Hence, to evaluate if the inhibition of the uterine contractions was a direct consequence of the inactivation of the receptor/voltage-operated Ca2+ channels or of the inhibition of the synthesis of prostaglandins, controls of nifedipine, and indomethacin were used for comparison, since both tocolytic drugs inhibit the uterine contraction by blocking Ca2+ channels and by inhibiting the cyclooxygenase, an enzyme that catalyzes the production of prostaglandins that are also known as a potent utero-tonic agent, respectively.[26],[27] In this study, CAR was able to induce a significant utero-relaxant effect on the phasic and tonic contractions of strips isolated from pregnant rat uterus. To date, this constitutes the first report on the tocolytic effect of CAR in pregnant uterus. The myometrium consists mainly of uterine smooth muscle cells, also known as uterine myocytes, whose main function is to regulate the uterine quiescence and contractility during pregnancy and labor.[28],[29] There are several receptors on the surface of the myometrial cells that affect the contractility, such as L-type calcium channels,[30] which regulate the transport and exchange of calcium from the extracellular space into the intracellular compartment;[30],[31] in fact, the oxytocin receptors and beta adrenergic receptors can act as contractility agonist or antagonist, respectively.[32] Currently, the calcium channels play an important role in the progression of normal labor;[33] for that reason, they are an important molecular target for the pharmacological treatment of PTB.[34],[35] Our results are similar to the findings of the study in which CAR was able to act as a potent vasodilator on the arteries from both non-pregnant and pregnant rat by inhibiting the voltage-sensitive calcium channels in the vascular smooth muscle cells.[36] Another tocolytic approach; CAR was also able to modulate the cardiac electrical activity by inhibiting the cardiac and vascular TRPM7 and L-type Ca2+ channels in white rabbits.[37] These data are consistent with the results obtained from this research; CAR can inhibit the rhythmic spontaneous, oxytocin-induced phasic, K+-induced tonic and Ca2+-induced contractions in the pregnant rat uterus, an effect which could also be related to the blockade of the calcium channels, as reported in the studies mentioned above. On the other hand, the concentration-response curves for CAR and indomethacin are similar. Indomethacin is a nonsteroidal anti-inflammatory drug and works by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.[3] Indomethacin is an effective tocolytic agent and can delay premature labor by reducing uterine contractions through the inhibition of prostaglandin synthesis in the uterus and possibly through calcium channel blockade.[37] In this sense, it has been reported that indomethacin is able to inhibit or alter the expression and the activity of some ion proteins, such as Kv potassium channels, transient receptor potential, and Na, K-ATPase in in vitro and in vivo models.[38],[39],[40] It is possible that CAR may probably regulate the activity of different ion channels to inhibit the uterine contraction, such as the voltage-operated potassium (Kv) channels that contribute to endothelium-dependent vasorelaxation induced by CAR on the rat aorta.[41] However, the exact mechanism of action of CAR responsible for inhibiting the uterine contractions is yet to be completely clarified because, to date, there is not sufficient electrophysiological data on the mechanisms of action of CAR, particularly with regard to the function of the pregnant myometrium. However, some researchers suggest that the relaxant effect, particularly on the smooth muscle, of some essential oils derived from the medicinal plants could be involved in the modulation and/or blockade of calcium channels,[40],[41],[42],[43] an effect which could also be related to the tocolytic effect induced by CAR. Further studies are required to evaluate, in detail at molecular level, the mechanisms of action of CAR involved in the blockade of the voltage-gated calcium channels and/or L-type calcium channels in the pregnant uterine smooth muscle. In light of the possible side effects of CAR, some reports have shown this compound to be non-toxic in both in vivo and in vitro models.[44],[45],[46] In conclusion, the tocolytic or utero-relaxant property of CAR, as a probable Ca2+-channel blocker, place CAR as a potentially safe and effective tocolytic agent in a field that urgently needs new and improved pharmacological treatments, as in cases of preterm labor.

Acknowledgments

This work was supported by the Perfíl Deseable del Programa para el Desarrollo Profesional Docente (PRODEP): No. 244033-PRODEP-SEP, Mexico. The authors thank the head of the animal care house (Bioterio – Instituto de Ciencias de la Salud) of the Autonomous University of the State of Hidalgo, “Ing. Daniel Ramírez Rico” for the logistical support of the animal care house.

Financial support and sponsorship

This work was financially supported by the Perfíl Deseable del Programa para el Desarrollo Profesional Docente (PRODEP): No. 244033-PRODEP-SEP, Mexico.

Conflicts of interest

There are no conflicts of interest.



 
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