ARTIGO DE REVISÃO
COSTA, Vicenilma de Andrade Martins [1], SILVA, Daiane Pereira da [2], MOURA, Jhônata Costa [3], DIAS, Carlos José Moraes [4], COSTA, Herikson Araujo [5], BORGES, Antonio Carlos Romão [6], RIBEIRO, Rachel Melo [7]
COSTA, Vicenilma de Andrade Martins et al. Cardioprotective and vasorelaxant effects of carvacrol: a mechanistic approach. Revista Científica Multidisciplinar Núcleo do Conhecimento. Year 09, Ed. 07, Vol. 01, pp. 102-118. July 2024. ISSN: 2448-0959, Acess link: https://www.nucleodoconhecimento.com.br/education-physics-en/cardioprotective-and-vasorelaxant, DOI: 10.32749/nucleodoconhecimento.com.br/education-physics-en/cardioprotective-and-vasorelaxant
ABSTRACT
Cardiovascular disorders are the leading cause of morbidity and mortality worldwide. Therefore, it is beneficial to investigate new therapies for the control and treatment of these disorders. In this context, carvacrol emerges as a phytochemical with important therapeutic potential. Therefore, this article aims to discuss and describe the pharmacokinetic properties and main mechanisms that explain the effects of carvacrol on cardiovascular disorders. ADMET studies revealed that carvacrol has promising pharmacodynamic characteristics for cardiovascular treatments. Some studies showed that animals treated with carvacrol had a decrease in the infarct area, less collagen deposition, lower serum concentrations of cardiac injury markers, as well as a decrease in the expression of proteins involved in cellular apoptosis pathways, evidencing its cardioprotective role. However, most of the effects described are related to intraperitoneal and intravenous treatment in normotensive animals, being limited studies that investigated the effects of carvacrol by the oral route and demonstrating the need to continuation of the works with models of spontaneous hypertension, which would better mimic the systemic arterial hypertension observed in humans.
Keywords: Carvacrol, Hypotension, Vessel relaxation, Cardioprotective, Pharmacokinetics.
1. INTRODUCTION
Characterized as the main causes of morbidity and mortality in the world, Cardiovascular Diseases (CVDs) affect people all over the world, mainly affecting developing countries (Nascimento et al., 2018), providing too much cost to society with drug treatment, clinical hospitalizations and surgical procedures (Siqueira; Siqueira-Filho; Land, 2017). Therefore, the discovery of new interventions, especially those of a non-drug nature, that can help in the treatment and prevention of these disorders is salutary.
Currently, experimental epidemiological studies using medicinal plants, as well as their secondary metabolites, have demonstrated effectiveness in combating several comorbidities (Sofowora; Ogunbodede; Onayade, 2013; Rajput et al., 2018). Documents belonging to ancient civilizations point to the use of various plants for medicinal purposes, such as the Ebers Papyrus, dated 1550 BC, which highlights the use of various inputs coming from plant origin. Thus demonstrating that they are safe and profitable. For a long time, plants and their derivatives have been used in cooking or in the production of traditional medicines to combat various pathologies (Rahmani et al., 2014). Turmeric, oregano, thyme, olives and dates, to name a few, have been widely used for culinary purposes in diets and are also believed to have beneficial effects against numerous ailments (Rahmani et al., 2014).
In this context, carvacrol, characterized as a phenolic monoterpene (C10H14O), found in the essential oil extracted from various plants, such as oregano, thyme and basil. (Vera; Chane-Ming, 1999; Thompson et al., 2003), emerges as an alternative for studies, since some properties and mechanisms of action have already been described in the literature, namely: anti- inflammatory (Liu et al., 2019), antimicrobial (Reis et al., 2018), analgesic (Wang et al., 2019), anticancer (Arunasree, 2010; Baranauskaite et al., 2017), antioxidant (Bellés et al., 2018), vasorelaxant, hypotensive, antihypertensive and cardioprotective (Chen et al., 2017; Earley; Gonzales; Garcia, 2010) actions.
Regarding the properties of carvacrol on the cardiovascular system, it can be observed that the main mechanism of action is the blockade of the calcium channels, resulting in a relaxation of the vessel and reducing Blood Pressure (BP) (Aydin et al., 2007; Dantas et al., 2015). This mechanism may confer cardioprotection, since the control of hypertension may decrease the chances of cardiac remodeling (Chen et al., 2017). However, there are few original studies that have proposed to investigate the effect of carvacrol, as an isolated compound, on these variables, as well as it is scarce in the literature review articles describing the mechanisms behind the effects of this compound on cardiovascular responses. Therefore, the main objective of this review is to discuss and describe the pharmacokinetic properties and the main mechanisms that explain the effects of carvacrol on CDVs.
2. DATA EXTRACTION AND METHODOLOGY
Scientific search engines such as PubMed, Google Scholar, Scielo, and Bireme were used to find and collect literature. For the search of the articles analyzed, the word carvacrol was used along with the following descriptors: blood pressure, hypertension, hypotension, relaxation vessel, vascular, cardioprotection, heart attack, myocardial infarction, and ischemic injury, including all original articles, In Vivo and In Vitro published until December 2022, while review articles, articles that did not address in the abstract the effect of carvacrol on the variables represented by the other descriptors and articles that used plant extract instead of the isolated compound, carvacrol, were excluded.
3. RESULTS
3.1 CARVACROL CARDIOVASCULAR PROPERTIES
3.1.1 HEMODYNAMIC EFFECTS
There are still few works that investigate the hemodynamic effects of carvacrol (Table 1), some studies show both antihypertensive and hypotensive effects (Aydin et al., 2007; Dantas et al., 2015; Feketa; Marrelli, 2015). Therefore, with the exception of surveys carried out by Barreto Da Silva et al. (2020), Costa et al. (2021) and Dias et al. (2022), the other studies were conducted using normotensive animals, however, the absence of a systemic arterial hypertension model limits investigations on antihypertensive effects.
The first study to demonstrate an effect of carvacrol on BP pressure was a study conducted by Aydin et al. (2007). Were administered several doses of carvacrol (1, 10, 20 50, 100 and 500 µg/kg) intraperitoneal route, observing hypotensive and antihypertensive effect only at the dose of 100 µg/kg; the dosage of 500 µg/kg has been described as toxic to animals. In this experiment, an immediate reduction of Mean Arterial Pressure (MAP) and Systolic Blood Pressure (SBP) was demonstrated both in the control group (reduction below normal values) and in the group that had hypertension induced by L-NAME (return to baseline SBP after five minutes of carvacrol administration), thus characterizing the hypotensive and antihypertensive effects of carvacrol.
In the research conducted by Dantas et al. (2015), bradycardia and dose-dependent reduction of BP, after being administered into the vein the doses of 1, 5, 10 e 20 mg/kg of carvacrol. This study indicated only at the hypotensive effect of carvacrol, this response being attributed mainly to the relaxation of blood vessels through Voltage-Dependent Calcium Channel block (CAVs), without explaining how carvacrol promoted bradycardia.
Already in the study of Feketa e Marrelli (2015), the hypothesis that carvacrol could promote hypothermia was tested, however, in order to evaluate the toxicity of this compound they were able to observe effects on BP in CD-1 mice. Therefore, they administered carvacrol in the dosage of 100 mg/kg intraperitoneal rout and 25, 50 e 100 mg/kg intravenous rout. The authors did not observe effects on BP when the route of administration of carvacrol was intraperitoneal, however, when administered intravenously, a dose-dependent reduction can be observed (-26 ± 4, -36 ± 4 and -58 ± 5 mmHg, respectively). It is worth emphasizing that all the studies used direct BP measurement, via a catheter, increasing the reliability of the results discussed.
Barreto Da Silva et al. (2020), were the first researchers to propose a design using a model with Spontaneously Hypertensive Rats (SHR), aiming to evaluate the effects of 21 daysof treatment with carvacrol (oral route), formulations of Carvacrol Encapsulated in β – Cyclodextrin (CARV/ β-CD). These authors also pointed out significant reductions in vascular tension and evidenced an anti-inflammatory property of carvacrol, when observing a reduction in pro-inflammatory mediators (IL-1β) and an increase in anti-inflammatory cytokines (IL-10).
In the study by Costa et al. (2021), spontaneously hypertensive animals treated with 20 mg/kg of carvacrol orally had their BP levels normalized after four weeks, resembling the normotensive group and the group treated with amlodipine (20 mg/kg), antihypertensive used as a positive control of carvacrol. Similar to this study, Dias et al. (2022), also observed an antihypertensive effect of carvacrol (20 mg/kg/day) when treating rats (SHR) for four weeks. The hemodynamic variables in this study, SBP, DBP and MAP, were like the normotensive group and the group treated with 50 mg of losartan/day in the last week of treatment.
Table 1. Effects of carvacrol on blood pressure
3.1.2 VASORELAXANT EFFECT
Previous studies attribute a vasorelaxant effect to carvacrol as the main mechanism for the hypotensive and antihypertensive effects presented by this phytochemical. However, other mechanisms at the vascular level attributed to carvacrol are already known. Table 2 shows some works that aimed to study some of these mechanisms. Liu et al. (2020), compared the effects of treatment with two doses of carvacrol (10 and 20 mg/kg) on hyperglycemia-induced hypercontractility in the aorta of mice, with the main results being the reduction in the number of layers of vascular smooth muscle cells with a concomitant decrease in the thinned morphological pattern presented in untreated animals. Furthermore, these authors suggest that the reduction in vascular hypercontractility observed through exposure of the aortic rings to different concentrations of phenylephrine is due to the activation of the P13K/Akt signaling pathway. In this study there was no difference between the doses of carvacrol used.
Zhao et al. (2020), treated diabetic mice for six weeks with oral carvacrol (05 and 10 mg / kg) to try to mitigate the deleterious effects of hyperinsulinemia on the endothelium of the thoracoabdominal artery. The findings of Zhao et al. (2020), show significant reductions in the inflammatory profile, as observed in serum levels of IL-1β, IL-6, IL-18, TNF-α and NF-kB expression, as well as demonstrated reductions in parameters related to diabetic disorders, such as p-InsR, p-IRS-1, expression of TRL4 and insulin. All these changes were more pronounced at the dose of 05 mg/kg and resulted in a significant decrease in lesions and consecutively vascular fibrosis.
Carvacrol has also been discussed as an agonist and antagonist of different receptors in the superfamily of TRP receptors (Transient Potential Receptors), as well as CAVs (Dantas et al., 2015), evaluated carvacrol in the mesenteric artery of pre-contracted rats with PHE (10 µM). The carvacrol (10-8 and 3×10-4M) induced vasorelaxation in mesenteric artery rings with and without functional endothelium. Carvacrol reduced concentration – dependent contractions induced by Bay K 8644 (200 nM), suggesting involvement of CAVs. These authors also observed that in arteries depolarized by 60 mM KCL, against nifedipine, a CAV blocker, and/or cyclopiazonic acid, a Ca2+ -ATPase (SERCA) reserve inhibitor, carvacrol showed a reduction of CaCl2 -induced contraction. In this same study, it was also possible to observe a carvacrol response related to calcium influx by inhibiting SOCs (Store-Operated Calcium) and involvement of TRPM7 (Transient Potential Receptor, Subfamily M, Member 7), a functional component of SOCs.
Posteriorly, Lee et al. (2015), based on the property of carvacrol on oxidative stress, verified the ability of monoterpene to affect the migration and proliferation of aortic VSM cells from rats. In the same study, the effect of carvacrol (0.03 – 3μM) on the neoformation of the carotid intima – layer of rats after induced injury was evaluated. The results together suggest a potential inhibitory effect on migration and proliferation of VSM cells, probably by regulation of the MAPK pathway.
Carvacrol is also being assigned an angiogenic potential (Matluobi et al., 2018), however, this response has been verified in human mesenchymal stem cells through In Vitro studies, demonstrating that low doses of carvacrol (25-200 μM) are able to increase the survival of mesenchymal stem cells and their migration rate. These authors have revealed that carvacrol induces neovascularization by detecting increased Expression of Vascular Endothelial Transcription Factor (VEGF) and the Von Willebrand Factor (FvW), an important glycoprotein in the regulation of vascular homeostasis, being involved in inflammation pathways.
Table 2. Effects of carvacrol on vascular smooth muscle
3.1.3 CARDIOPROTECTIVE EFFECTS
Carvacrol also has cardioprotective properties. Table 3 brings a summary of the articles that proposed to investigate these properties.
Adapala et al. (2013), were the first researchers to show In Vitro that the molecular mechanisms that led to the increase of fibroblast cell differentiation had as key points the expression of the potential channels of the Voltage-Dependent Transient Receptor (TRPV4), channels calcium-sensitive to influx, showing that the increase in the expression of TRPV4 was related to the increase in the release of TGF-β1 in the ECM. These investigators, when inhibiting TRPV4 channels, using carvacrol, found that TGF-β1-induced fibroblast differentiation was not inhibited, however, the reduction in ECM stiffness was correlated with a lower differentiation of these cells, concluding that the TRPV4 channels participate in the cardiac remodeling process, either by mechanical mechanisms, interfering in the ECM rigidity, or by soluble mechanisms (interfering in the release of TGF-β1).
Table 3. Effects of carvacrol on ischemic disorders
In another study, conducted by Yu; Liu; Zhu (2013), the objective was to show the cardioprotective property of carvacrol at an event of myocardial infarction. Therefore, the researchers conducted the experiments on adult Wistar rats (250-300 grams), inducing infarction via ligation of the left anterior descending coronary artery and treating them with 25, 50 and 100 mg/kg of carvacrol by seven consecutive days. The first results demonstrated in this study, indicated a reduction of the area of infarction in the animals treated with 25, 50 and 100 mg/kg of carvacrol, having an infarct area equal to 31.64%, 26.76% and 23.99% respectively. In the control group, the infarct area was 37.33%. Carvacrol treatment was also effective in dramatically decreasing serum concentrations of Creatine Kinase (CK), Creatine Kinase – Cardiac isoform (CK – MB), Cardiac Troponin (cTnT) and Lactate Dehydrogenase Enzyme (LDH) when compared to the control group. It was also possible to observe antioxidant and antiapoptotic effects of carvacrol, the first being demonstrated by the reduction in the treated groups of the activity of Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione Non-Exudative Enzyme (GSH), as well as Glutathione Peroxidase (GSH-PX), and the antiapoptotic effect was evidenced by the reduction of the expression of the proteins caspases-3 and Bax, as well as by increased levels of the protein Bcl-2, cell apoptosis markers. These results indicate that carvacrol was effective in attenuating the damage caused by acute myocardial infarction. Using the same protocol for infarction induction, Chen et al. (2017), observed results similar to those of the previously mentioned research. However, cardioprotection was only conferred, regarding the reduction of the infarct area, to the animals treated with the doses of 50 and 100 mg/kg of body mass, and there was no significant difference in those treated with 25 mg/ kg, when compared to the control group.
Chen et al. (2017), also showed an antioxidant effect, with increased activity of SOD and Catalase (CAT) enzymes, and reduction of MDA levels. The cardioprotective efficiency of carvacrol was also analyzed in vitro, indicating better viability of the cardiomyocytes of infarcted animals that were treated with carvacrol (Chen et al., 2017). These authors are still committed to investigate the cellular apoptosis pathway MAPK/ERK, demonstrating that in animals treated with carvacrol increased the Phosphorylation of ERK (p-ERK), thus deactivating the cell apoptosis pathway, while inhibiting ERK with PD-98059 the cardioprotective property of carvacrol was reversed, demonstrating the involvement of the MAPK-ERK pathway in the antiapoptotic mechanisms of carvacrol (Chen et al., 2017).
Jamhiri et al. (2019), through in vivo and in vitro assays, they observed reductions in cardiac fibrosis and in the gene expression of the atrial natriuretic peptide, a key factor for the cardiac remodeling pathway. While Costa et al. (2021), presented qualitative results that evidence a cardioprotective role of carvacrol on cardiac remodeling imposed by arterial hypertension. In the experimental design proposed by them, the rats (SHR) were treated (oral) with 20 mg/kg of carvacrol for four weeks. Another property inherent to carvacrol was described in the work of Almanaitytė; Jurevičius; Mačianskienė (2020), who demonstrated antiarrhythmic activity, when they found that carvacrol increased the QRS interval and promoted atrioventricular block in hearts explanted from rabbits and humans through a Langerdorff perfusion system. Fig. 1 below, presents a summary of the previously discussed mechanisms of action of carvacrol.
Fig. 1. Mechanisms of action of carvacrol
4. CONCLUSIONS AND FUTURE PERSPECTIVES
In conclusion, ADMET analyzes revealed that carvacrol has promising pharmacodynamic properties for the treatment of CDVs. In addition, carvacrol has hypotensive and antihypertensive action, especially when used at doses of 50 and 100 mg/kg. This hemodynamic response seems to be mainly associated with voltage-dependent calcium channel block, reducing vascular contraction tone, and mitigating endothelial dysfunction in diabetes models. We also conclude that carvacrol promotes cardiac protection, acting in the pathways of cardiac remodeling and apoptosis, reducing cardiac fibrosis and deposition of collagen, as well as reduction of infarct area and expression of apoptotic molecular markers and hypertrophic in normotensive rats and / or with angiotensin II-induced hypertension treated with carvacrol. However, there is a need for further studies using spontaneous hypertension models that can combine carvacrol with other antihypertensive therapies, such as drugs already consolidated for this purpose or even non-drug interventions such as physical exercise, which may reveal its real antihypertensive potential.
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Material received: July 24, 2023.
Peer-Approved Material: October 17, 2023.
Edited material approved by the authors: July 5, 2024.
