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Anxiety and depression are mental disorders that have been exponentially increasing over the last decades. Psychopharmacology emerged to try to alleviate the symptoms of these disorders; however, the side effects and the time it takes to achieve the desired effect are factors that decrease the search for and adherence to treatment. To remedy this situation, new compounds capable of improving the performance of these medications and reducing their adverse effects have been sought. The use of medicinal plants has been widely employed for this purpose. Mauritia flexuosa F.L., a palm tree with high incidence in Brazil, has been heavily targeted as all its parts are usable. The objective of this study is to evaluate the effects of fixed oil from the fruit of the buriti palm in models of depression and anxiety. The phytochemical profile of this oil and its toxicity were also investigated. The experiments conducted included the open field, rotarod, forced swim, and elevated plus maze tests. As a result, it was observed that the fixed oil from buriti palm presented 18 compounds, with elaidic acid being the major one, and showed no signs of toxicity. However, it demonstrated a possible stimulating activity in the open field test and had no effect on the motor system in the rotarod test. Furthermore, it exhibited an antidepressant-like effect in the forced swim test but an anxiety-like effect in the elevated plus maze test. Therefore, buriti oil may potentially be used in new formulations to assist in the treatment of anxiety and depression., Competing Interests: Declaration of competing interest The authors confirm that they have no conflicts of interest with respect to the work described in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Limonene, a monoterpene found in essential oils, has various activities, such as antifungal, antioxidant, neuroprotective, gastroprotective and vasorelaxant. However, the observation of limonene's biphasic effect in preclinical studies provides crucial information about its dose-dependent actions. Understanding this behavior is essential for optimizing therapeutic doses and anticipating possible side effects prior to clinical trials. The objective of this study is to provide a more detailed characterization and investigation of the mechanisms of action of limonene on the contractile tonus of isolated aorta.The experiments were carried out on aortic rings isolated from rats, subjected to isometric recording of contractions in their circular smooth muscle and exposed to different concentrations of limonene. It was found that limonene blocked the contraction induced by KCl (60 mM), but had a biphasic effect on the contraction induced by phenylephrine (0.1 μM). At lower concentrations, limonene was able to amplify the contraction induced by phenylephrine, while at higher concentrations, it inhibited it. The nitric oxide synthase blockers L-NAME and ruthenium red, a TRP ion channel blocker, did not significantly interfere with the biphasic character of limonene. However, indomethacin, a blocker of arachidonic acid derivatives, completely blocked the amplification of contraction induced by phenylephrine. In addition, limonene promoted relaxation in contractions induced by BAY-K 8644, a calcium channel agonist and by Ba 2+ . Limonene has complex effects on aortic tone, amplifying or inhibiting contractions, suggesting that the therapeutic window should be carefully studied to optimize clinical results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Citral is a low-toxicity monoterpene that has a vasodilator effect on various smooth muscles, and The present study aimed to evaluate its vasorelaxant effect on umbilical vessels of normotensive parturients (NTP) and with preeclampsia parturients (PEP)., Method: Segments of human umbilical artery (HUA) and vein (HUV) of NTP or PEP were mounted in a bath to record the force of contraction, under tension of 3.0 gf and contracted with the contracting agents: K + (60 mM), 5 -HT (10 μM) and Ba 2+ (1-30 mM). Next, the effect of citral (1-3000 μM) on these contractions and on basal tone was evaluated., Results: In HUA and HUV, citral (1-1000 μM), in NTP condition, inhibited contractions evoked by K + (IC 50 of 413.5 and 271.3, respectively) and by 5-HT (IC 50 of 164.8 and 574.3). In the PEP condition, in HUA and HUV, citral also inhibited the contractions evoked by K + (IC 50 of 363.3 and 218.3, respectively) and 5-HT (IC 50 of 432.1 and 520.4). At a concentration of 1000 μM, citral completely or almost completely (>90 %) inhibited all contractions. At a concentration of 100-1000 μM, citral, in general, was already able to reduce the contraction induced by 1-3 mM Ba 2+ in both AUH and VUH, under NTP and PEP conditions., Discussion: Citral has been shown to be an effective HUA and HUV vasodilator in NTP and PEP. As its toxicity is low, it suggests that this substance can be considered a potential therapeutic agent., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied., Objective: The study aimed to characterize the effect of POH on human umbilical arteries (HUA)., Methods: Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated., Results: POH (1-1000 μM) altered the basal tone of HUA and completely relaxed HUA rings precontracted with KCl (60 mM) or 5-HT (10 μM), obtaining greater potency in the pharmacomechanical pathway (EC 50 110.1 μM), suggesting a complex interference in the mobilization of extra- and intracellular Ca 2+ . POH (1000 μM) inhibited contractions induced by BaCl 2 (0.1-30 mM) in a similar way to nifedipine (10 μM), indicating a possible blockade of L-type VOCC. In the presence of potassium channel blockers, tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (10 μM), an increase in the EC 50 value of the POH was observed, suggesting a modulation of the activity of BK Ca , K V , and K ATP channels., Conclusion: The data from this study suggest that POH modulates Ca 2+ and K + ion channels to induce a relaxant response in HUA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Pre-eclampsia (PE) is a disease of high incidence in parturients, that adversely affects both mother and fetus. Although PE prevalence is high, there are few studies on literature describing its etiology or its mechanism of action. Thus, the aim of this study was to elucidate PE-induced alterations of contractile reactivity in umbilical vessels., Method: Segments of human umbilical artery (HUA) and human umbilical vein (HUV) from neonates of normotensive or PE parturients were obtained and contractile responses measured with a myograph. The segments were allowed to stabilize (2 h) under 1.0, 2.0 and 3.0 g force (gf) at pre-stimulation and, then, were stimulated with high isotonic K + concentrations ([K + ] o ; 10-120 mM)., Results: All preparations responded to increases in isotonic K + concentrations. In HUA and HUV of neonates of normotensive parturients, and in HUV of neonates of PE parturients, the contraction saturated at nearly 50 mM [K + ] o , while in HUA of neonates of PE parturients, saturation occurred at 30 mM [K + ] o . Additionally, several differences between contractile responses of HUA and HUV from neonates of normotensive parturients and those from neonates of parturients with PE were observed. PE alters the contractile response of the HUA and HUV to increased [K + ] o , and its contractile modulation by the pre-stimulus basal tension. Moreover, in HUA of PE, reactivity is decreased for 2.0 and 3.0 gf basal tensions and increased for 1.0 gf; in the HUV of PE condition, it is increased for all basal tensions., Discussion: In conclusion, PE promotes several alterations in HUA and HUV contractile reactivity, vessels in which important circulatory alterations are known to occur., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Naturally occurring bioactive compounds have a plethora of biological effects., Objective: In this study, we examined a pharmacological screening of natural products on the human umbilical artery (HUA)., Methods: HUA preparations were used to follow contractions by KCl (60 mM) and tested at different concentrations (1-5000 μg/mL and μM) of the Lippia alba (EOLa) and Lippia origanoides (EOLo) essential oils, terpenes (citral, limonene perilic alcohol) and phenylpropanoids (eugenol, methyl eugenol). Discussion/Results: The reduction corresponded to approximately 100%, except for limonene (80±1.2 %). When evaluating the concentration of the natural product that promotes 50 % relaxation of the HUA contracted by KCL, EC50 values were: 424.3 μg/mL (EOLa); 468.7±6.7 μg/mL (EOLo); 264.2 ± 8.2 μM (citral); 677.8±5.4 μM (limonene); 186.3±6.4 μM (peryl alcohol); 986.4±7.9 μM (eugenol); and 279.1±4.4 μM (methyl-eugenol). Perillyl alcohol had a lower EC50 (consequently it has a higher pharmacological potency)., Conclusion: The plant extracts have a promising vasorelaxing effect in HUAs, paving the way for future investigations: as applications in diseases related to these vessels, such as preeclampsia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Lippia alba is popularly known as lemon balm, with its essential oil (EO) cited for displaying antimicrobial, sedative, and vasorelaxant effects. Yet, its action on isolated human vessels has not been described in the literature. Thus, we evaluated the vasorelaxant effect of essential oil of L. alba (EOLa) on human umbilical arteries (HUA) isolated in organ baths. HUA rings were isolated, subjected to contractions induced by potassium chloride (KCl), serotonin (5-HT), or histamine (HIST) to record the isometric tension, and then treated with EOLa (30-1000 µg/mL). The EOLa showed a more prominent inhibitory effect on the pharmacomechanical coupling contraction via HIST with an EC 50 value of 277.1 ± 8.5 µg/mL and maximum relaxant effect at 600 µg/mL. The addition of tetraethylammonium (TEA) or 4-aminopyridine (4-AP) in HUA preparations did not inhibit EOLa total relaxant effect at 1000 µg/mL. In the presence of gliblenclamide (GLI), the oil relaxed the HUA rings by 90.8% at maximum concentration. The EOLa was also investigated for its effects on voltage-operated calcium channels (VOCCs), where the HUA preincubation with this oil at 1000 μg/mL inhibited BaCl 2 (0.1-30 mM)-induced contractions. This study demonstrates for the first time that EOla has a vasorelaxant effect on HUA and its particular blockade of VOCCs.

Eugenol (EUG) is a phenylpropanoid widely used in the food and cosmetic industries. It is commonly referred to in the literature by its biological activities such as antioxidant, anti-inflammatory, antimicrobial, and relaxing in organs of laboratory animals, especially in rodent vessels. However, its vasorelaxant potential in human tissue, has not been investigated. Thus, this study characterizes the vasodilatory effect of EUG in the human umbilical artery (HUA). HUAs were isolated, cleaned, sectioned (3-4 mm) and placed in an organ bath (10 mL Krebs Henseleit, 37 °C; and carbogenic mixture). EUG (100-1400 μM), obtained total relaxation of electromechanical contractions induced by KCl (60 mM), and pharmacomechanical contractions (30-1200 μM), induced by serotonin (10 μM) and by histamine (10 μM), showing statistically significant concentrations: 600 μM, 400 μM and 200 μM, and EC 50 values: 759.8 ± 6.5 μM, 229.9 ± 7.9 and 279.0 ± 3.4 μM, respectively. EUG (1200 and 1400 μM) prevented the contraction promoted by BaCl 2 (0.1-30 mM), similar to the effects of nifedipine (10 μM), sugesting the involvement of EUG in blocking VOCCs. In the presence of tetraethylammonium (10 μM), EUG (30-1200 μM) did not produce a total relaxation (88.6%), suggesting that an alternative pathway where potassium channels, may partially mediate EUG effect. In the presence of 4-aminopyridine (1 mM), glibenclamide (10 μM), and tetraethylammonium (1 mM), EUG relaxed HUAs 100%, although the pharmacological potency was statistically altered, demonstrating the participation of K + channels (Kv, KATP, BKCa). Our data indicates that EUG has a vasorelaxant effect on HUAs, had a greater pharmacological potency in the serotoninergic pathway, showing effective participation of VOCCs and a partial modulation of K + channels. These data suggest new possibilities for the use of EUG in human vascular dysfunctions, such as preeclampsia. More studies are necessary to confirm the safety and effectivity in future treatments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Alternative methods for the use of animals in research have gained increasing importance, due to assessments evaluating the real need for their use and the development of legislation that regulates the subject. The principle of the 3R's (replacement, reduction and refinement) has been an important reference, such that in vitro, ex vivo and cord replacement methods have achieved a prominent place in research., Methods: Therefore, due to successful results from studies developed with these methods, the present study aimed to evaluate the myorelaxant effect of the Dysphania ambrosioides essential oil (EODa) using a Sus scrofa domesticus coronary artery model, and the toxicity of both the Dysphania ambrosioides essential oil and its major constituent, α-terpinene, against Drosophila melanogaster in toxicity and negative geotaxis assays., Results: The EODa relaxed the smooth muscle of swine coronary arteries precontracted with K + and 5-HT in assays using Sus scrofa domesticus coronary arteries. The toxicity results presented LC 50 values of 1.546 mg/mL and 2.282 mg/mL for the EODa and α-terpinene, respectively, thus showing the EODa and α-terpinene presented toxicity to these dipterans, with the EODa being more toxic., Conclusions: Moreover, the results reveal the possibility of using the EODa in vascular disease studies since it promoted the relaxation of the Sus scrofa domesticus coronary smooth muscle.

Caffeic acid is a phenolic compound widely found in commonly consumed foods such as pears, apples and coffee, and is pharmacologically known for its antioxidant, anti-inflammatory and anti-asthmatic properties. However, its relaxant activity in the aorta, uterus and ileum smooth muscle has not been investigated. This study aimed to comparatively evaluate the effect of caffeic acid on smooth muscle from different organs (aorta, uterus and ileum), and the contractions of this different organ were induced by different agonists. The organ bath technique was used, where the organs were placed in different cuvettes with 10 mL of Tyrode solution for 1 h to stabilize, then, myometrial, intestinal strip and aortic ring contractions were evoked using different contractile agonists (KCl 60 mM, PHE 0.1 μM, OT 10-2 IU/mL, CCh 10 -6  M and BaCl 2 0.1-30 mM); increasing concentrations of caffeic acid (0.03-7 mM) were administered in the experimental preparations. In the presence of KCl (60 mM), caffeic acid caused relaxations with the following EC 50 values: 2.7 ± 0.26 mM/mL (aorta), 5.7 ± 0.71 mM/mL (uterus) and 2.1 ± 0.39 mM/mL (ileum). When in the presence of different agonists, PHE (0.1 μM) for the aorta, OT (10 -2 IU/mL) for the uterus and CCh (10 -6  M) for the ileum, caffeic acid caused relaxations with EC 50 values of: 2.7 ± 0.31 mM/mL; 2.2 ± 0.34 mM/mL and 2.0 ± 0.28 mM/mL, respectively. The inhibitory effect of caffeic acid on serotonergic (aorta and uterus) and muscarinic receptors (uterus and ileum), as well as its possible involvement with L-type Ca 2+ channels, was also observed. This study reports the pharmacological characterization of caffeic acid on smooth muscle from different organs, for which caffeic acid was more potent in the ileum. A diverse understanding of its performance as a possible therapeutic product is attributed to its relaxant effect., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Carveol is a monoterpene present in the structure of many plant products. It has a variety of biological activities: antioxidant, anticancer and vasorelaxation. However, studies investigating the effect of monoterpenoids on human vessels have not yet been described. Thus, the present study aimed to characterize the effect of (-)-carveol on human umbilical arteries (HUAs). HUA ring preparations were isolated and subjected to isometric tension recordings of umbilical artery smooth muscle contractions. (-)-Carveol exhibited a significant vasorelaxant effect on KCl and 5-HT-induced contractions, obtaining EC 50 values of 344.25 ± 8.4 and 175.82 ± 4.05 µM, respectively. The participation of calcium channels in the relaxation produced by (-)-carveol was analyzed using vessels pre-incubated with (-)-carveol (2000 µM) in a calcium-free medium, where the induction of contractions was abolished. The vasorelaxant effect of (-)-carveol on HUAs was reduced by tetraethylammonium (TEA), which increased the (-)-carveol EC 50 to 484.87 ± 6.55 µM. The present study revealed that (-)-carveol possesses a vasorelaxant activity in HUAs, which was dependent on the opening of calcium and potassium channels. These results pave the way for further studies involving the use of monoterpenoids for the vasodilatation of HUAs. These molecules have the potential to treat diseases such as pre-eclampsia, which is characterized by resistance in umbilical arteries.

This study aimed to investigate the myorelaxant action of the Dysphania ambrosioides essential oil (EODa) and its major constituent α-terpinene on tracheal smooth muscle isolated from rats. In tracheal smooth muscle ex vivo, in organ baths, isometric contractions recordings were done in order to evaluated the effect of EODa (1-1000 μg/mL) and α-terpinene (1-3000 μg/mL) on the following parameters: basal tone, contractions evoked by potassium (KCl 60 mM), acetylcholine (ACh 10 μM) or serotonin (5-HT 10 μM). The EODa and its major constituent α-terpinene, did not statistically alter basal tone; however, they induced myorelaxant effects on top of contractions induced by KCl, ACh and 5-HT. EODa and α-terpinene also inhibited the contractions induced by barium in presence of High [K + ] (80 mM). The data suggest that the relaxation induced by these agents is caused by the inhibition of L-type VGCC, inhibiting the inward Ca 2+ current through these channels, but does not exclude the possibility of participation of other mechanisms. Results from this study also suggest the EODa, due to their efficacy on relaxation of the respiratory tract, posses a therapeutic potential as a antispasmodic agent for respiratory tract., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This research evaluated the anxiolytic and antidepressant-like effects of a hydroethanolic extract from the leaves of Annona coriacea (EHFAC) and caffeic acid (CA). Mice were intraperitoneally treated with saline, EHFAC (1, 10, 20 mg/kg) or CA (0.15 mg/kg) and subject to the elevated plus-maze, open field, rota-rod, forced swimming and reserpine-induced akinesia tests. Pro-convulsant and anticholinergic effects were also evaluated. EHFAC presented anxiolytic-like effect on the elevated plus-maze, which was partially reversed by flumazenil. A similar effect was observed with CA. In the forced swimming test, EHFAC and CA reduced the immobility time of mice; such effect was potentiated when EHFAC or CA were associated with imipramine, bupropion and fluoxetine. The antidepressant-like effect was reinforced as EHFAC partially reversed the reserpine-induced akinesia. In addition, a pre-treatment with EHFAC and CA did not decrease the latency to 1st seizure of animals that received a sub-convulsive dose of PTZ, nor reduced the intensity of oxotremorine-induced tremors. Taken together, the results indicate that EHFAC and CA have anxiolytic and antidepressant-like effects, which involve important neurotransmitter systems, such as GABAergic and monoaminergic ones, being devoid of side effects, commonly associated with classical psychotropic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The species Lippia alba (Mill.) N. E. Brown belongs to the Verbenaceae family. It is abundant and grows spontaneously throughout the Brazilian territory. Popularly known as "erva-cidreira", it is widely used because of its sedative, carminative and analgesic properties. The objective of this study was to investigate the mechanism of action of the L. alba essential oil (EOLa) and its major constituents citral and limonene, on isolated rat uterus muscle. To evaluate the EOLa, citral and limonene effect, cumulative concentrations curves for EOLa and citral (1-600 μg/mL) and for limonene (1-1200 μg/mL) were constructed from contractions of rat uterine strips under a 1 g tension. EOLa, citral and limonene dose-dependently relaxed myometrial preparations pre-contracted with 60 mM KCl, 10-2 IU/mL oxytocin, serotonin (10 μM), or ACh (10 μM). The results demonstrate that the EOLa, citral and limonene cause relaxation of the uterine smooth muscle. These results suggest that the relaxation induced by EOLa, citral and limonene is caused by inhibition of L-type VOCC, inhibiting the Ca 2+ current through these channels, although other mechanisms of action are likely to contributing to relaxant activity. There was no involvement of K + channels (BKca, K ATP , K V ) or cyclooxygenase on the relaxation promoted by EOLa. Then studies of the tocolytic effects of EOLa, citral and limonene may yield new insights into their therapeutic use., (Copyright © 2018 Elsevier B.V. All rights reserved.)