Cardiovascular Activity of the Chemical Constituents of Essential Oils

Cardiovascular diseases are a leading cause of death in developed and developing countries and decrease the quality of life, which has enormous social and economic consequences for the population. Recent studies on essential oils have attracted attention and encouraged continued research of this group of natural products because of their effects on the cardiovascular system. The pharmacological data indicate a therapeutic potential for essential oils for use in the treatment of cardiovascular diseases. Therefore, this review reports the current studies of essential oils chemical constituents with cardiovascular activity, including a description of their mechanisms of action.


Introduction
Non-communicable diseases (NCD) are the leading causes of death worldwide and are responsible for approximately 68% of all global deaths in 2012. The main causes for NCD are cardiovascular diseases (CVD), which account for 46.2% of NCD-related deaths. CVD are responsible for 17.3 million deaths per year, a number that is expected to grow to more than 23.6 million by 2030 [1]. Although a wide range of pharmacological agents are available for the treatment of CVD, the control and prevention of these diseases continues to be a challenge. The cost of treatment continues to increase, which makes CVD even more expensive and impactful to the budget of public health systems around the world [2]. Therefore, new tools for the treatment of CVD are necessary for a cost that is reasonable for health systems. Among the sources of drug candidates available for the treatment of CVD, natural products have been reported to have a potential role in the therapeutic effects of such diseases [3]. The evaluation of the chemical constituents of plants has enriched the pharmacological arsenal used in the treatment of diseases, and it has helped to understand their pathological mechanisms [4].
It is well established that oxidative stress influences the pathogenesis of heart diseases, such as hypertension, atrial fibrillation, and atherosclerosis, and studies have demonstrated the implication of this stress in these diseases [5]. There is substantial epidemiological and experimental evidence that antioxidants in the diet can be preventive for heart disease [5]. The failure of antioxidants found in foods, such as vitamins C and E, to prevent these disorders has led to the exploration of the ROS-suppressive effects of drugs used in the treatment of cardiovascular disease [6,7]. Moreover, many natural products have antioxidant and various other pharmacological properties [8]. Some of their actions on oxidative stress are associated with pharmacological effects [9][10][11][12]. Natural products with antioxidant and/or vasorelaxant effects have been shown to positively affect many cardiovascular conditions [13,14] once the redox status or the vascular function has worsened and is

Thymoquinone
Thymoquinone is the main monoterpene of the volatile oil obtained from the seeds of Nigella sativa L. (Ranunculaceae). It exhibits several pharmacological activities, such as acting as an anti-inflammatory [26], antitumor agent [29] and as an analgesic [21]. Antioxidant and vascular relaxant effects of thymoquinone (TQ) have been documented in different experimental models of cardiovascular diseases. Aydin et al. [33] observed that treatment with TQ was associated with the reduction in the oxidative stress systemically measured after abdominal aorta ischemia or reperfusion injury in rats. This reduction in oxidative stress was associated with less severe lesions in the hearts of rats that received TQ intraperitoneally. The antioxidant mechanism of TQ involves reactive oxygen species (ROS), redox-related enzymes, and cytokine profiles. Nemmar et al. [34] observed that TQ improved the superoxide dismutase activity and reduced the interleucin-6 content in mice, which prevented cardiovascular side effects induced by a pollutant. TQ induced a dose-dependent reduction in plasmatic lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS), and glutathione reductase (GR), whereas SOD activity in the plasma and the myocardial reduced or oxidized glutathione ratio (GSH/GSSG) were increased in rats with an isoproterenol-induced myocardial infarction that were then treated with TQ. These actions protect the heart from the injury resulting from isoproterenol [35]. Oxidative stress is also implicated in vascular dysfunction by blunting both nitric oxide (NO)-and endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in the arteries of ageing animals. TQ could reverse the age-related down-regulation of the endothelial NO synthase (eNOS) and increased the vascular formation of ROS in the mesenteric artery. In addition to the effects on oxidative stress, TQ also affects components of the renin-angiotensin aldosterone system (RAS) and increases the expression of the small and intermediate conductance Ca 2+ -activated K + channel (SKCa and IKCa, respectively), resulting in the incremental NO-and EDFH-induced mesenteric relaxation. These actions determined the improvement of endothelial function in ageing animals after 14 days of TQ treatment [36]. In addition, Ghayur et al. [37] observed that the relaxant effect of TQ in the aortas of rats should also involve the blockade of voltage-operated Ca 2+ channels (VOCC). Taken together, these studies indicate that TQ has broad actions on the cardiovascular system, including the redox system, ion channels, the RAS system, endothelial-related relaxant agents, and cytokines. These actions result in antioxidant and vascular relaxant effects which work to protect the cardiovascular system.

Cinnamaldehyde
This aromatic aldehyde is an active constituent isolated from the stem bark of cinnamon trees such as Cinnamomum cassia Presl. and others plants [38]. El-Bassossy et al. [39] showed that cinnamaldehyde normalized the vascular contractility and prevented the development of hypertension in insulin deficient or resistant animals, also prevented the hyper-responsiveness to vasoconstrictor agents (Phenylephrine or KCl) and the hypo-responsiveness to vasodilatory agents (Ach) in the aortic rings. In insulin-deficient animals, cinnamaldehyde prevented the inhibition of NO release, while in insulin resistant rats, cinnamaldehyde prevented the elevated influx of Ca 2+ . Through an antioxidant action and the preservation of the NO levels, cinnamaldehyde protected the endothelium relaxation in the aortic rings of hyperglycemic mice. This antioxidant mechanism involved the up-regulation of the endogenous antioxidant enzyme NF-E2-related factor 2 (Nrf2) [40], which is known to regulate the generation of ROS [41]. Additionally, Raffai et al. [42] demonstrated that cinnamaldehyde also induced vascular relaxation in porcine coronary arteries through an endothelium-independent mechanism by inhibiting Ca 2+ sensitivity and Ca 2+ influx. When carried in micelles, cinnamaldehyde was also able to induce endothelium-dependent vascular relaxation by NO-and H 2 O 2 -dependent means. This was also demonstrated by Xue et al. [43], who showed that this relaxant effect of cinnamaldehyde was likely mediated by changes in calcium influx or in its release from intracellular stores. Additionally, Alvarez-Collazo et al. [44] studied the mechanism of action of this compound and showed that CA promoted relaxation in vascular smooth muscle cells (VSMC) and ventricular cardiac myocytes (VCM), at least in part by inhibition of the L-Type Ca 2+ channel. Additionally, these studies do not exclude subtype 1 of the Transient Receptor Potential Ankyrin (TRPA1).
Song et al. [14] evaluated the cardioprotective properties of cinnamaldehyde against the ischemic injury precipitated by isoproterenol. The pre-treatment for 14 days with cinnamaldehyde resulted in decreased cardiac injury (hypertrophy and histological changes), decreased pro-inflammatory cytokines (TNF-α and IL-6), increased serum NO and SOD levels on the heart, and reduced ST segments generated by myocardial ischemia. Together, these results show that cinnamaldehyde has cardioprotective effects that can be attributed to antioxidant and anti-inflammatory proprieties.

Cinnamic Acid
This compound is an aromatic carboxylic acid with carbonic structure C6-C3 appearing naturally in the plant kingdom. In addition, cinnamic acids are formed in the biosynthetic pathway leading to various natural product classes, such as phenylpropanoids, flavonoids, coumarins, lignans, anthocyanins, and tannins [45]. In vitro analysis of vasorelaxant proprieties of cinnamic acid (CA) was conducted by Kang et al. [46] who used the thoracic aortas of rats. They showed that CA promoted vasorelaxation in a dose-and endothelium-dependent manner, once both NO inhibition by L-NAME and endothelium removing reduced its relaxant effect. The increases of e-NOS and pe-NOS after CA incubation on the cell cultures of human endothelium strongly reinforced this hypothesis. Additionally, the participation of Protein Kinase G (PKG) as a mediator was demonstrated due to the increase of cGMP observed after the incubation of cells with CA. Together, these results demonstrate that CA promotes vasorelaxant effects by changing the endothelium-NO release mechanism. Lastly, the mediation of intracellular Ca 2+ release by PKG could be involved with those observations. Song et al. [14] studied the effects of CA on myocardial injury (MI), using an in vivo model. CA treatment deceased the biochemical (CK-MB and LDH) and inflammatory markers of MI (TNF-α and IL-6) and increased the NO levels, which resulted in the reduction of cardiac histological abnormalities induced by isoproterenol. These benefits were related, at least in part, to the improvement of NO synthesis and the antioxidant effect of this compound.

Cinnamyl Alcohol
Cinnamyl alcohol is a phenylproppanoid that occurs in numerous natural products in free state or as an ester in plants, such as cinnamon leaf, narcissus, and gardenia. This compound can also be obtained by the hydrogenation of cinnamic aldehyde. The vasodilatory propriety of cinnamyl alcohol (CAL) was evaluated by Kang et al. [47]. They used aortic rings, the cell cultures of human aortic smooth muscle cells and human umbilical vein endothelial cells. The results on the aortic rings showed an endothelium-dependent vasodilation. This effect was reduced by L-NAME, glibenclamide and methylene blue pre-treatment, which indicated the role of NO, K + channel and guanylylcyclase, respectively, on the vasodilatory activity of CAL. It was also demonstrated that CAL promoted cGMP accumulation and the augmentation of PKG1 levels, and interfered with the Rho-kinase pathway. Therefore, the endothelium-dependent vasodilation induced by CAL is related with the NO-cGMP-PKG pathway in rat thoracic aorta, resulting in activation of K + channels and an inhibition of the Rho-kinase pathway.

α-Bisabolol
α-Bisabolol is a monocyclic sesquiterpene tertiary alcohol, which has a weak sweet, floral aroma. It is found in substantial amounts in the essential oils of Matricaria chamomilla, Salvia runcinata, Eremanthus erythropappus, Myoporum grassifolium, and Vanillosmopsis sp [48]. Studies that evaluated the vasorelaxant proprieties of (−)-α-bisabolol (BS) were concentrated on the aortic and mesenteric arteries. De Siqueira et al. [49] observed the relaxant action of BS in a wide range of smooth muscle preparations, with a higher pharmacological potency in the mesenteric vessels. Pre-contracted aortic rings also showed relaxation with BS administration. Later, the same group demonstrated the BS-induced vascular relaxation mechanism involved with the calcium influx through voltage-dependent channels [50]. Calcium-dependent vascular relaxation was also observed in porcine coronary and splenic arteries once the withdrawal of the calcium from the medium completely eliminated the BS-induced vascular relaxation [51]. Therefore, the studies that were conducted have demonstrated that BS promoted vasorelaxation by inhibiting the calcium influx through voltage-dependent channels. The evaluation of the molecular model of the β-subunit isoform of voltage-gated L-type Ca 2+ channel (Cavβ2a) demonstrated that BS interacted preferentially with this channel subunit and promoted the uncoupling of the Cavβ2a subunit from the α-interaction domain (AID). However, the authors do not exclude that BS could have also acted as a negative allosteric inhibitor.

Carvacrol
Carvacrol is a monoterpene phenol found in many essential oils. The compound is an isomer of thymol. Shabir et al. [52] observed that carvacrol decreased the hypercontraction induced by lead (Pb II) in the aortic rings of rats at a concentration of 100 µmol/L. The incubation of carvacrol with apocynin, which is an inhibitor of NADPH oxidase enzyme, did not promote any change in the vasodilatory response. However, co-incubation with L-NAME decreased the effect of carvacrol, which indicated that the relaxant effect of this compound was mediated by an increase in NO synthesis. Pires et al. [13] used cell cultures from parenchymal arterioles and tested the effect of carvacrol on calcium permeability on the transient receptor potential vanilloid (TRPV). The authors showed that carvacrol promoted an increased influx of calcium by activating the TRPV3 channel. Therefore, this calcium influx through the TRPV3 channel, which is important to activate intermediate (IK) and small-conductance Ca 2+ -activated K + (SK) channels and causes hyperpolarization, may contribute to carbachol-endothelium dependent vascular relaxation. In vivo studies conducted by Dantas et al. [53] demonstrated that carvacrol induced hypotension and bradycardia in non-anesthetized Wistar rats. The mechanism apparently involved vasorelaxation through the reduction of Ca 2+ influx by changes in voltage-dependent, transient receptor potentials and store/receptor operator channels (SOCs/ROCs). Taken together, these studies demonstrate that Carvacrol can cause vascular relaxation by an endothelium-dependent mechanism that involves the NO and Ca 2+ pathways.

Borneol
Borneol is a cyclic monoterpene alcohol extracted from Cinnamomum camphora (L.) and other plants [54]. Silva-Filho et al. [55] demonstrated that borneol promoted the relaxation of aortic rings that were pre-contracted with phenylephrine or KCl − in a concentration-dependent and endothelium-independent manner. Additionally, the pre-incubation with K + channel blockers attenuated the borneol-induced vasorelaxation. Borneol also interfered with intracellular calcium mobilization. Bai et al. [56] observed that a borneol-rich extract at a concentration of 1 mg/mL promoted relaxation, with total relaxation that was obtained at 10 mg/mL. It was observed that a Suxiao Jiuxin Pill was able to promote vasorelaxation by both endothelium-dependent and -independent mechanisms. Wu et al. [57] conducted an in vivo study to determine if borneol had neuroprotective properties against ischemic stroke. The anti-inflammatory proprieties of borneol were demonstrated in this study. Borneol alone (0.8 mg/kg) was able to promote a reduction on the protein expression of pro-inflammatory markers (TNF-α, iNOS, IL-1β and COX-2). Additionally, borneol promoted a reduction of the infarct area in a dose-dependent manner (IC 50 : 0.36 mg/kg). Together, these results demonstrated the neuroprotective effects of borneol and promoted an indirect increase of the scavengers of ROS, and once the expression of iNOS was reduced the production of NO decreased.

Carvone
Carvone is a monoterpene ketone and the main active component of the oil of Mentha spicata. The carvones ((+)-and (−)-forms) are probably the most versatile terpene chirogens and suitable starting materials in stereoselective synthesis, especially terpenes [58]. The most well-known source of (−)-(R)-carvone is spearmint oil. Its enantiomer is a constituent of dill and caraway oils [59]. To investigate the effect of carvone on conductance arteries, Kundu et al. [60] demonstrated that this terpenoid was capable of promoting vasorelaxation on pre-contracted aortic rings, even when the artery was exposed to metals (arsenic and mercury). The antioxidant proprieties of carvone contributed to this vasorelaxant effect. However, the effect of carvone on calcium voltage-dependent channels was more important than its ROS scavenger or NO synthesis actions. Using aortic rings and guinea pig tracheas, De Sousa et al. [61] showed that there was no difference in the pharmacological action of (+)-and (−)-enantiomers of carvone, both forms presented a vasorelaxant action. Furthermore, it seems that the action was directly on the smooth muscle, since it was not reduced in the endothelium deprived rings.

Eugenol
This phenylpropanoid is used as an ingredient in cosmetics, perfumes, and pharmaceutical and dental preparations [62]. Kundu et al. [60] demonstrated that eugenol presented antioxidant proprieties and could promote a vasorelaxant effect, and a calcium blockade in high concentrations. The protective effect was observed in arteries that were exposed to heavy metal (As and Hg). Along the same line, Shabir et al. [52] examined that the effects of Eugenol were examined in Pb(II)-hypercontracted aortic rings. The authors observed that Pb(II) induced hypercontraction through the depletion of NO and by increased reactive oxygen species (ROS). Eugenol promoted relaxation of Pb(II) hypercontracted aortic rings by increased NO bioavailability. This effect was probably mediated by the antioxidant proprieties of this compound. Peixoto-Neves et al. [63] showed that Eugenol promoted a concentration-dependent dilation of the cerebral arteries by an inhibition of Calcium voltage-dependent channel, which was confirmed by patch-clamp studies.

1-Nitro-phenylethane
The 1-nitro-phenylethane (NP) is the first nitro compound isolated from essential oil, and one of the few natural products containing this functional group [64]. The cardiovascular effect of this compound, isolated from A. canelilla essential oil and others plants, was tested in vivo by Interaminense et al. [65]. NP promoted bradycardic and hypotensive responses after a bolus injection. That response was completely eradicated after cervical bivagotomy. The tests that were made with capsaicin and methylatropine suggested that the mechanism of action used by NP was mediated by both a vagal reflex and a cholinergic mechanism. Additionally, the application of NP directly on the heart shows that an effect of pulmonary C-fibers could also be involved.

Auraptene
Auraptene is a coumarin contained in the peels of citrus fruits such as Citrus paradise [66]. Razavi et al. [67] studied the effect of the chronic administration of auraptene on heart rate and blood pressure after eight weeks of treatment of normo-and hypertensive rats using the DOCA-Salt model of hypertension. They observed a dose-and time-dependent decrease in blood pressure in hypertensive rats and no changes in heart rate. While promising, the study failed to provide mechanisms since a biomolecular study was not performed.

Citral
Citral is a mixture of the isomeric aldehydes geranial and neral, which occurs in plants and citrus fruits. Pereira et al. [68] used aortic rings to investigate the vasorelaxant proprieties of this monoterpene. The authors showed that this compound promoted vasodilation in phenylephrine pre-contracted rings using an endothelium-independent mechanism. The results suggested that citral promoted relaxation by changing calcium dynamics, which is an effect that occurs once citral-inhibited contractions by both high K + and phenylephrine manifest. However, the study did not investigate the effects of citral on calcium receptors.

Citronellal
The monoterpene citronellal is a major component of the essential oils in various aromatic species, such as Cymbopogon winterianus Jowitt (Java citronella), Corymbia citriodora (Hook.) K.D. Hill, and C. nardus L. [69]. Cardiovascular properties of citronellal were evaluated in an NO-inhibition model of experimental hypertension. Mean arterial pressure (MAP) was reduced by oral acute citronellal administration. Citronellal also induced vasorelaxation of the mesenteric arteries of rats using an endothelium-independent mechanism. Although the exact mechanism of the vasodilatory action of citronellal was not conclusive, it is possible to state that the hypotensive effect should be related to its vasodilatory action.

Farnesene
Farnesene is one of the major compounds of the German essential oil chamomile. The action of this sesquiterpene on vascular tone was investigated using porcine coronary and splenic arteries. It was demonstrated that farnesene did not promote a vasorelaxant effect even when concentrations up to 30 µM were used [51].

Limonene
Limonene is a monoterpene found in citrus fruits, especially in orange and lemon, with high concentration in their essential oils [70,71]. De Sousa et al. [61] investigated the effects of limonene in guinea pig tracheas and rat aortas. The authors observed that the compound produced relaxant effects on the tracheas and aortic rings independent of the endothelium. In this study, both (+)-limonene and (−)-limonene enantiomers were used, and no differences were observed. This indicated that limonene could promote antispasmodic effects on the smooth muscle of the trachea.

Linalool
The monoterpene linalool (LO) is the major constituent (87.7%) of Rosewood Oil (EOAR). De Siqueira et al. [72] observed that EOAR induced hypotension and bradycardia in awakened animals that were abolished by pre-treatment with methylatropine. Additionally, dose-dependent EOAR blunted the phenylephrine-induced contraction of the aortic rings. Isolated LO reduced the hypercontraction of aortic segments induced by heavy metals, such as As and Hg, and involved the enhancement of NO synthesis and the blockade of voltage-dependent calcium channels [60]. Deep investigation of the mechanism of action of LO indicated further participation of soluble guanylyl cyclase and K + channel on its vasorelaxant effects [73].

Linalyl Acetate
The monoterpene ester linalyl acetate (LA) mobilized the intracellular calcium concentration ([Ca]i) in cultured vascular endothelial (EC) or in mouse vascular smooth muscle (MOVAS) cells. In EC, LA induced a transient increase followed by a sustained decrease in [Ca]i, whereas in MOVAS the increase remained unchanged. LA blocks the extracellular calcium influx in EC, but not in MOVAS. Therefore, LA differently affects the endothelium and smooth muscle cells and its effect on EC may explain its protective effect against endothelium dysfunction associated with cardiovascular diseases [74].

Menthol
Menthol is a monoterpene alcohol found in Mentha species such as M. piperita and M. arvensis [75]. Cheang et al. [76] used different arterial segments (aortae, coronary and mesenteric) to investigate the proprieties of the menthol to produce vasorelaxation. This monoterpene produced concentration-dependent and endothelium independent vasorelaxation. The contraction induced by CaCl 2 was suppressed by menthol in a similar way as nifedipine (an L-type Ca 2+ channel inhibitor) and indicated that menthol could affect this kind of channel. This study demonstrated that the vasorelaxant proprieties of menthol were not affected by cGMP or NO. Therefore, the vasorelaxation induced by menthol was probably caused by direct action on calcium dynamics.

N-Butylidenephthalide
N-Butylidenephthalide (BP) is obtained from the volatile oil of Angelica sinensis [77]. The effects of this compound in angiogenesis and cell proliferation in vitro and ex vivo were evaluated by Yeh et al. [77]. The researchers showed that this compound was capable of a concentration-dependent inhibition of endothelial proliferation, endothelial wound healing, and endothelial tube formation on human umbilical vein endothelial cells (HUVEC). The researchers also investigated the mechanism of action and determined that BP promoted apoptosis and an increased maintenance of the cell cycle during the G0-G1 phase. Additionally, BP decreased the capillary sprouting of the aorta and vascularization of zebrafish. Together, these results indicate the anti-angiogenic effect of BP.

Rotundifolone
Several studies using the essential oil of Mentha x villosa showed its hypotensive effect in a dose-dependent manner in hypertensive rats (DOCA-salt hypertensive rats), which is probably associated with a vasorelaxative activity [78,79]. Similarly, hypotensive properties also were observed with the monoterpene rotundifolone, the main constituent of the essential oil of Mentha x villosa, comprising approximately 63% of its content. Rotundifolone promotes a concentration-dependent vasorelaxant effect on the superior mesenteric arteries of rats. The mechanism by which rotundifolone promoted this relaxation was investigated using patch-clamp techniques. The experiment demonstrated that rotundifolone probably acted by calcium-activated potassium (BK Ca ) channel activation, once tetraethylammonium (TEA) eradicated the observed relaxation. However, this mechanism of action seemed to be more important at low doses and on conducting arteries (aorta). Additionally, changes on the L-type Ca 2+ channels at high concentrations could also precipitate the mechanism by which rotundifolone caused vascular relaxation.

α-Terpineol
The in vivo effect of the monoterpene α-terpineol was evaluated by Sabino et al. [80] who used the model of hypertension induced by L-NAME. Therefore, it was demonstrated that α-terpineol was capable of inducing a dose-dependent hypotension in awake animals. Likewise, when mesenteric rings were used, the researchers showed that this compound produced vasorelaxant effects independent of the endothelium. Those vasorelaxant effects could be attributed, at least in part, to the inhibition of voltage-dependent calcium channels. Additionally, treatment with α-terpineol for seven days promoted an induced antioxidant effect in the animals treated with L-NAME. The values of SOD, catalase and glutathione peroxidase activity were restored to values similar to the control groups, which indicated the antioxidant capacity of α-terpineol.
The in vitro and in vivo cardiovascular effects of the chemical constituents of essential oils are shown in Tables 1 and 2. capable of inducing a dose-dependent hypotension in awake animals. Likewise, when mesenteric rings were used, the researchers showed that this compound produced vasorelaxant effects independent of the endothelium. Those vasorelaxant effects could be attributed, at least in part, to the inhibition of voltage-dependent calcium channels. Additionally, treatment with α-terpineol for seven days promoted an induced antioxidant effect in the animals treated with L-NAME. The values of SOD, catalase and glutathione peroxidase activity were restored to values similar to the control groups, which indicated the antioxidant capacity of α-terpineol.
The in vitro and in vivo cardiovascular effects of the chemical constituents of essential oils are shown in Tables 1 and 2. capable of inducing a dose-dependent hypotension in awake animals. Likewise, when mesenteric rings were used, the researchers showed that this compound produced vasorelaxant effects independent of the endothelium. Those vasorelaxant effects could be attributed, at least in part, to the inhibition of voltage-dependent calcium channels. Additionally, treatment with α-terpineol for seven days promoted an induced antioxidant effect in the animals treated with L-NAME. The values of SOD, catalase and glutathione peroxidase activity were restored to values similar to the control groups, which indicated the antioxidant capacity of α-terpineol.
The in vitro and in vivo cardiovascular effects of the chemical constituents of essential oils are shown in Tables 1 and 2. capable of inducing a dose-dependent hypotension in awake animals. Likewise, when mesenteric rings were used, the researchers showed that this compound produced vasorelaxant effects independent of the endothelium. Those vasorelaxant effects could be attributed, at least in part, to the inhibition of voltage-dependent calcium channels. Additionally, treatment with α-terpineol for seven days promoted an induced antioxidant effect in the animals treated with L-NAME. The values of SOD, catalase and glutathione peroxidase activity were restored to values similar to the control groups, which indicated the antioxidant capacity of α-terpineol.
The in vitro and in vivo cardiovascular effects of the chemical constituents of essential oils are shown in Tables 1 and 2.

1-Nitro-phenylethane
Spontaneously hypertensive rats (SHR) 1-10 mg/kg Promotes bradycardic and hypotensive responses after in bolus application. The mechanism suggested is by cholinergic and vagal reflex activation [65] Molecules 2017 , 22, 1539  8 of 19 capable of inducing a dose-dependent hypotension in awake animals. Likewise, when mesenteric rings were used, the researchers showed that this compound produced vasorelaxant effects independent of the endothelium. Those vasorelaxant effects could be attributed, at least in part, to the inhibition of voltage-dependent calcium channels. Additionally, treatment with α-terpineol for seven days promoted an induced antioxidant effect in the animals treated with L-NAME. The values of SOD, catalase and glutathione peroxidase activity were restored to values similar to the control groups, which indicated the antioxidant capacity of α-terpineol.
The in vitro and in vivo cardiovascular effects of the chemical constituents of essential oils are shown in Tables 1 and 2.

1,8-Cineole
Systolic blood pressure measured in rats 0.1 mg/kg Antihypertensive activity associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine [83]

1,8-Cineole
The effect of cyclic monoterpene 1,8-cineole was investigated on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. The dose of 0.1 mg/kg of this monoterpene significantly reduced SBP, while, at the dose of 1.0 mg/kg, there was an increase of plasma nitrite concentrations. At doses of 0.01 mg/kg and 0.1 mg/kg, 1,8-cineole also antagonized nicotine-induced lipid peroxidation. It has been suggested that the regulation of nitric oxide and oxidative stress in rats should contribute to the antihypertensive effect of 1,8-cineole [83].

1,8-Cineole
Systolic blood pressure measured in rats 0.1 mg/kg Antihypertensive activity associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine [83]

1,8-Cineole
The effect of cyclic monoterpene 1,8-cineole was investigated on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. The dose of 0.1 mg/kg of this monoterpene significantly reduced SBP, while, at the dose of 1.0 mg/kg, there was an increase of plasma nitrite concentrations. At doses of 0.01 mg/kg and 0.1 mg/kg, 1,8-cineole also antagonized nicotine-induced lipid peroxidation. It has been suggested that the regulation of nitric oxide and oxidative stress in rats should contribute to the antihypertensive effect of 1,8-cineole [83].

Thymoquinone
Airway inflammation by acute exposure to diesel exhaust particles (DEP) 0.01-0.1 mg/mL Pre-treatment with thymoquinone prevents the worse effects promoted by DEP such as leukocytosis, increase of IL-6 and decrease of SOD plasma activity. The platelet numbers and prothrombotic events were also decreased [34] Isoproterenol model of myocardial ischemia 12.

1,8-Cineole
Systolic blood pressure measured in rats 0.1 mg/kg Antihypertensive activity associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine [83]

1,8-Cineole
The effect of cyclic monoterpene 1,8-cineole was investigated on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. The dose of 0.1 mg/kg of this monoterpene significantly reduced SBP, while, at the dose of 1.0 mg/kg, there was an increase of plasma nitrite concentrations. At doses of 0.01 mg/kg and 0.1 mg/kg, 1,8-cineole also antagonized nicotine-induced lipid peroxidation. It has been suggested that the regulation of nitric oxide and oxidative stress in rats should contribute to the antihypertensive effect of 1,8-cineole [83].

1,8-Cineole
Systolic blood pressure measured in rats 0.1 mg/kg Antihypertensive activity associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine [83] 2.

1,8-Cineole
The effect of cyclic monoterpene 1,8-cineole was investigated on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. The dose of 0.1 mg/kg of this monoterpene significantly reduced SBP, while, at the dose of 1.0 mg/kg, there was an increase of plasma nitrite concentrations. At doses of 0.01 mg/kg and 0.1 mg/kg, 1,8-cineole also antagonized nicotine-induced lipid peroxidation. It has been suggested that the regulation of nitric oxide and oxidative stress in rats should contribute to the antihypertensive effect of 1,8-cineole [83].

Conclusions
Essential oils are a new option of bioactive substances in animal models that are being used in the study of new candidates for cardiovascular drugs. Due to the diversity of chemical structures and mechanisms of action, such as blockade of voltage dependent L-type Ca 2+ channels, cholinergic and vagal reflex activation, and participation of muscarinic receptors, it is not possible to establish a principal chemical characteristic of cardiovascular activity. The lipid solubility and volatility are common properties of these substances. However, several compounds have high pharmacological potency, for example 1,8-cineole and borneol. Pharmacological evaluation of the synthetic derivatives of these constituents appears to be an interesting way to optimize the pharmacologic profile and advance the knowledge to promote accomplishing prototypes for new cardiovascular drugs. In addition, the simplicity of the chemical structures of the bioactive compounds may result in the preparation of low cost drug candidates.