Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth Muscle and on Systemic Blood Pressure: Pharmacological Studies and Perspective of Therapeutic Use

*Ana Carolina Cardoso-Teixeira, Klausen Oliveira-Abreu, Levy Gabriel de Freitas Brito, Andrelina Noronha Coelho-de-Souza and José Henrique Leal-Cardoso*

#### **Abstract**

Terpenes are a class of chemical compounds with carbon and hydrogen atoms in their structure. They can be classified into several classes according to the quantity of isoprene units present in its structure. Terpenes can have their structure modified by the addition of various chemical radicals. When these molecules are modified by the addition of atoms other than carbon and hydrogen, they become terpenoids. Terpenes and terpenoids come from the secondary metabolism of several plants. They can be found in the leaves, fruits, stem, flowers, and roots. The concentration of terpenes and terpenoids in these organs can vary according to several factors such as the season, collection method, and time of the day. Several biological activities and physiological actions are attributed to terpenes and terpenoids. Studies in the literature demonstrate that these molecules have antioxidant, anticarcinogenic, anti-inflammatory, antinociceptive, antispasmodic, and antidiabetogenic activities. Additionally, repellent and gastroprotective activity is reported. Among the most prominent activities of monoterpenes and monoterpenoids are those on the cardiovascular system. Reports on literature reveal the potential effect of monoterpenes and monoterpenoids on systemic blood pressure. Studies show that these substances have a hypotensive and bradycardic effect. In addition, the inotropic activity, both positive and negative, of these compounds has been reported. Studies also have shown that some monoterpenes and monoterpenoids also have a vasorelaxing activity on several vascular beds. These effects are attributed, in many cases to the blocking of ion channels, such as voltagegated calcium channels. It can also be observed that monoterpenes and

monoterpenoids can have their effects modulated by the action of the vascular endothelium. In addition, it has been shown that the molecular structure and the presence of chemical groups influence the potency and efficacy of these compounds on vascular beds. Here, the effect of several monoterpenes and monoterpenoids on systemic blood pressure and vascular smooth muscle will be reported.

smooth muscle", or "toxicity". For easiness of posterior consultation, we presented the information related to a substance under a heading, which was the common name of the substance and organized the most important information on a table

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

**Dose (mg/kg)/ concentration (μM)**

2159.1 203.62 <sup>μ</sup>MC

*Lippia alba* Vasorelaxant 941.6 28.02 <sup>μ</sup>MB

[10]

19]

1–20 mg/kg [14, 23] 2.7 g/kg (v.o

[23]

*bergamia* Hypotensive

100–200 mg/kg [23, 25]

–6.4 10<sup>3</sup> M

443.3 66.83 <sup>μ</sup>MC

1333.3 225.20 <sup>μ</sup>M<sup>C</sup>

menthol

Vasorelaxant 100–500 mMA [33]

Vasorelaxant 1–2 mM<sup>A</sup> [27]

,

;

*Lippia alba* Vasorelaxant [18] 6.4 <sup>10</sup><sup>4</sup> to 1.9 M [18]

Limonene Hypotensive 20–40 mg/kg<sup>A</sup> [12] 4.4–5.1 g/kg

α-Pinene Hypotensive 1–20 mg/kg<sup>A</sup> [14] >2.0 g/kg

β-Pinene Hypotensive 1–20 mg/kg<sup>A</sup> [14] >2.0 g/kg

p-Cymene Vasorelaxant 5.8 1.6 <sup>10</sup><sup>5</sup> MC [16] 4.7 g/kg

Geraniol Vasorelaxant [21] 10–300 μM <sup>A</sup> [21] 3.6 g/kg (v.o.

Citronellol Hypotensive 1–20 mg/kg [14, 18,

**Ref. LD50 Plant source**

*Citrus limon*,

*Eucalyptus tereticornis*, *Citrus lemon*

*Eucalyptus tereticornis*, *Citrus lemon*

*Eucalyptus camaldulensis*, *Origanum acutidens*

*Cymbopogon winterianus*,

*Cymbopogon martinii*, *C. nardus*, *C. winterianus*.

*Dracocephalum kotschyi*

*Citrus reticulata*, *Anethum graveolens*

*Mentha* genus

*Lavandula angustifólia*, *Ocimum basilicum*, *Citrus*

(v.o—rats); 5.6–6.6 g/kg (v.o—mice) [13]

(v.o.—mice) [15]

(v.o.—mice) [15]

(v.o—rat); >5 g/kg (v.o —rabbit) [17]

3.45 g/kg (v.o —rats) [20]

—rats)[22]

—rats) [24]

[10] 2.1 g/kg (v.o —rats) [26]

[10] 3.0 g/kg (v.o. —rats) [28]

[29, 30] 2.9–6 g/kg (v. o—mice and rats) [31, 32]

**Substance Pharmacological**

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

Linalool Hypotensive

(normotensive animals)

(hypertensive animals)

Perillyl alcohol Vasorelaxant[10] 277.7 5.46 <sup>μ</sup>MB

Carveol Vasorelaxant 662.1 32.85 <sup>μ</sup>MB

Menthol Antihypertensive Diet plus 0.5%

**97**

Vasorelaxant [23] 6.4 <sup>10</sup><sup>6</sup>

**cardiovascular activities**

**Keywords:** terpenes, terpenoids, arterial pressure, pharmacological effect, toxicity, perspective of therapeutic use, anti-hypertensive

#### **1. Introduction**

#### **1.1 Terpenes and terpenoids**

Terpenes and terpenoids are names frequently interchangeably used. Most frequently terpene is defined as a hydrocarbon with one or several isoprene units. When terpene molecules are modified by the addition of atoms other than carbon and hydrogen, they are more appropriately named terpenoids [1].

Terpenes and terpenoids come from the secondary metabolism of several plants. They can be found in the leaves, fruits, stem, flowers, and roots [2]. They can be classified into several classes according to several criteria: 1—the quantity of isoprene units present in its structure, among which we can mention the monoterpenes, diterpenes, sesquiterpenes, and others; 2—the number of cyclic components in their molecular structure, according to which we have the acyclic, monocyclic, and bicyclic monoterpenes [1, 3, 4].

Studies in the literature demonstrate that the natural (present in essential oils— EO) monoterpenes and monoterpenoids have one or several biological/pharmacological activities, among which the most frequently reported are antioxidant, anticarcinogenic, anti-inflammatory, repellent, gastroprotective, antinociceptive, antispasmodic, and antidiabetogenic activities [4, 5].

Among the most prominent and therapeutically potentially promising activities of natural monoterpenes and monoterpenoids are those on the cardiovascular system [6]. Reports on literature, here reviewed and discussed, reveal their effect on heart (rate and inotropism), systemic blood pressure (SBP), and blood vessels (direct (myogenic) and indirect (endothelium mediated)) [7–10].

These effects are frequently attributed to activity on ion channels, such as voltage-dependent Ca2+ channels (VDCC) [11]. These substances can affect the contractions mediated by electromechanical excitation-contraction coupling (EMC; ex.: the KCl-induced contraction) or pharmacomechanical excitationcontraction coupling (PMC; ex.: the Phenylephrine-induced contraction). In addition, it has been shown that the molecular structure and the presence of chemical groups influence the potency (pharmacodynamic potency) and efficacy (pharmacodynamic efficacy) of these compounds on vascular beds [10]. Here we will call simply maximum efficacy when, at appropriate concentration, total blockade of a response is induced (it is: complete blockade of contraction or Emax = 100%).

Here, we described the effects of monoterpenes and monoterpenoids on SBP and vascular smooth muscle (VSM). This research was carried out predominantly using articles present in the Pubmed and Pubchem databases. The search included articles published between 2000 and 2020. The search included 42 monoterpenes and monoterpenoids. The words used in the research include "monoterpenes", "monoterpenoids" and the name of the compounds associated with "cardiovascular", "vasorelaxant", "hypotension", "hypotensive", "antihypertensive", "vascular

smooth muscle", or "toxicity". For easiness of posterior consultation, we presented the information related to a substance under a heading, which was the common name of the substance and organized the most important information on a table


monoterpenoids can have their effects modulated by the action of the vascular endothelium. In addition, it has been shown that the molecular structure and the presence of chemical groups influence the potency and efficacy of these compounds on vascular beds. Here, the effect of several monoterpenes and monoterpenoids on

**Keywords:** terpenes, terpenoids, arterial pressure, pharmacological effect, toxicity,

Terpenes and terpenoids are names frequently interchangeably used. Most frequently terpene is defined as a hydrocarbon with one or several isoprene units. When terpene molecules are modified by the addition of atoms other than carbon

Terpenes and terpenoids come from the secondary metabolism of several plants. They can be found in the leaves, fruits, stem, flowers, and roots [2]. They can be classified into several classes according to several criteria: 1—the quantity of isoprene units present in its structure, among which we can mention the monoterpenes, diterpenes, sesquiterpenes, and others; 2—the number of cyclic components in their molecular structure, according to which we have the acyclic, monocyclic,

Studies in the literature demonstrate that the natural (present in essential oils— EO) monoterpenes and monoterpenoids have one or several biological/pharmacological activities, among which the most frequently reported are antioxidant, anticarcinogenic, anti-inflammatory, repellent, gastroprotective, antinociceptive,

Among the most prominent and therapeutically potentially promising activities of natural monoterpenes and monoterpenoids are those on the cardiovascular system [6]. Reports on literature, here reviewed and discussed, reveal their effect on heart (rate and inotropism), systemic blood pressure (SBP), and blood vessels

These effects are frequently attributed to activity on ion channels, such as voltage-dependent Ca2+ channels (VDCC) [11]. These substances can affect the contractions mediated by electromechanical excitation-contraction coupling (EMC; ex.: the KCl-induced contraction) or pharmacomechanical excitationcontraction coupling (PMC; ex.: the Phenylephrine-induced contraction). In addition, it has been shown that the molecular structure and the presence of chemical groups influence the potency (pharmacodynamic potency) and efficacy (pharmacodynamic efficacy) of these compounds on vascular beds [10]. Here we will call simply maximum efficacy when, at appropriate concentration, total blockade of a response is induced (it is: complete blockade of contraction or

Here, we described the effects of monoterpenes and monoterpenoids on SBP and vascular smooth muscle (VSM). This research was carried out predominantly using articles present in the Pubmed and Pubchem databases. The search included articles published between 2000 and 2020. The search included 42 monoterpenes and monoterpenoids. The words used in the research include "monoterpenes", "monoterpenoids" and the name of the compounds associated with "cardiovascular", "vasorelaxant", "hypotension", "hypotensive", "antihypertensive", "vascular

systemic blood pressure and vascular smooth muscle will be reported.

and hydrogen, they are more appropriately named terpenoids [1].

perspective of therapeutic use, anti-hypertensive

**1. Introduction**

Emax = 100%).

**96**

**1.1 Terpenes and terpenoids**

*Terpenes and Terpenoids-Recent Advances*

and bicyclic monoterpenes [1, 3, 4].

antispasmodic, and antidiabetogenic activities [4, 5].

(direct (myogenic) and indirect (endothelium mediated)) [7–10].


(**Table 1**). In order to allow some basis for evaluation of the therapeutic potential of these compounds, we include information on toxicity (LD50 values in mammals;

Monoterpenes are compounds with two isoprene units in their structure. They can be subdivided according to the number of cycle components in its structure into acyclic, monocyclic, and bicyclic [68, 69]. Of the natural monoterpenes studied, we have not found, in any publications, report of cardiovascular effects for myrcene, ocimene (acyclic), terpinenes, phellandrenes, terpinolene, thujene (monocyclic) and, 3-carene, camphene, sabinene (bicyclic), and tricyclene on SBP and VSM. However, several studies in the literature demonstrate that EO containing these

compounds have interesting cardiovascular effects.

**Table 1**).

**99**

**Table 1.**

*B*

**2. Monoterpenes**

**Substance Pharmacological**

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

**cardiovascular activities**

Citral Vasorelaxant 110.80 μg/ml

**Dose (mg/kg)/ concentration (μM)**

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

ml (652.56 μM)<sup>C</sup>

, 99.34 μg/

(727.8 μM)B

Citronellal Antihypertensive 200 mg/kg, v.o. [55] 2.42 g/kg (v.

Rotundifolone Hypotensive 1–30 mg/kg, i.v. [58] Not available

Vasorelaxant pD2 = 4.0 [60] 1,8-cineole Antihypertensive 0.1 mg/kg, i.p. [61] 2.48 g/kg

Hypotensive 0.3–10 mg/kg, i.v. [62]

Vasorelaxant 3.6 <sup>10</sup><sup>4</sup> MC [67]

*IC50 for KCl-induced contraction (electromechanical coupling) in presence of endothelium. CIC50 for phenilephrine-induced contraction (pharmacomechanical coupling) in presence of endothelium.*

(1.11 mM)<sup>C</sup> μg/ml

, 663.2 μg/ml (4.22 mM)C

Vasorelaxant 184 (1.1 mM)<sup>B</sup> and 185

Linalyl acetate Antihypertensive 10–100 mg/kg, i.p. [64] 10.0 g/kg

Vasorelaxant 1.09 mMB

*Monoterpenes and monoterpenoids with hypotensive and vasorelaxant effects.*

*Ref., Reference. ip, Intraperitoneally. v.o, Orally. i.v., Intravenous.*

*ARange of doses or concentration employed.*

Hypotensive 10–40 mg/kg, i.v. [55] Vasorelaxant 10<sup>6</sup> - 10<sup>1</sup> M [55] Carvone Vasorelaxant 6.2 2.6 <sup>10</sup><sup>4</sup> <sup>M</sup><sup>C</sup> [57] 1.6 g/kg (v.o.

**Ref. LD50 Plant source**

*Lippia alba e Pectis brevipedunculata*

*Cymbopogon winterianus*; *Cymbopogon citrates*

*Mentha spicata*, *Carum carvi*

*Mentha rotundifolia*, *M. spicata L*., *and M. x villosa*

*Croton nepetaefolius*; *Alpinia zerumbet*

*Lavandula angustifolia* and

[53, 54] 4.9 g/kg (v.o. —rats) [17]

o.—rats) [56]

—rats) [17]

(for mammals)

(rat, v.o); >5 g/kg (v.o, rabbit) [17]

(v.o—rats); 13.3 g/kg (v.o—mice) [24]

[58, 59]

[62, 63]

*Salvia sclarea* Hypotensive 10–100 mg/kg [64–66]


*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

*Ref., Reference. ip, Intraperitoneally. v.o, Orally. i.v., Intravenous.*

*ARange of doses or concentration employed.*

*B*

*IC50 for KCl-induced contraction (electromechanical coupling) in presence of endothelium. CIC50 for phenilephrine-induced contraction (pharmacomechanical coupling) in presence of endothelium.*

#### **Table 1.**

**Substance Pharmacological**

*Terpenes and Terpenoids-Recent Advances*

**cardiovascular activities**

Borneol Vasorelaxant 3 <sup>10</sup><sup>9</sup>

**Dose (mg/kg)/ concentration (μM)**

802.50 13.8 <sup>μ</sup>M<sup>C</sup>

α-Terpineol Hypotensive 1–30 mg/kg<sup>A</sup> [34] 3.0 g/kg (v.o.

Terpinen-4-ol Hypotensive 1–10 mg/kgA, i.v. [7, 37] 4.3 g/kg (v.o

Carvacrol Hypotensive 100 μg/kg, i.p [41] 0.8 g/kg (v.o

Vasorelaxant 78.80 11.91 <sup>μ</sup>M<sup>B</sup>

Anethole Antihypertensive 125–250 mg/kg<sup>A</sup> [45] <3.0 g/kg

Hypotensive 5–10 mg/kg, i.v.<sup>A</sup> [47] Vasorelaxant 9.01 2.44 <sup>10</sup><sup>4</sup> <sup>M</sup><sup>C</sup> [48]

Estragole Hypotensive 5–10 mg/kg, i.v.<sup>A</sup> [47] 1.8 g/kg (v.o

Eugenol Hypotensive 1–10 mg/kg, i.v.<sup>A</sup> [49–51] 2.6 g/kg (v.o

Vasorelaxant 323.3 14.0 μMB [11]

Cinnamaldehyde Vasorelaxant 334 30 μM [52] 2.22 g/kg (v.o

**98**

Vasorelaxant 4.34 0.3 <sup>10</sup><sup>4</sup> <sup>M</sup> <sup>C</sup> [48]

Vasorelaxant 10<sup>8</sup>

Thymol Vasorelaxant 64.40 4.41 <sup>μ</sup>MB

Hypotensive 1–20 mg/kg i.v. [43]

145.40 6.07 <sup>μ</sup>M<sup>C</sup>

106.40 11.37 <sup>μ</sup>M<sup>C</sup>

Vasorelaxant 10<sup>12</sup> – 10<sup>5</sup> M [34] Vasorelaxant 300 μg/ml (1.94 mM) [36]

**Ref. LD50 Plant source**

*Eucalyptus camaldulensis*, *Croton nepetaefolius*.

*Alpinia zerumbet*, *Croton*

*Salvia officinalis*, *Cinnamomum camphora*

*Thymus vulgaris*, *Origanium compactum*, *Lippia sidoides*

*Acalypha phleoides*, *Lippia sidoides*, *L. origanoides*

*Pimpinella anisum*, *Croton zehntneri*, *Foeniculum vulgare*

> *Croton Zehntneri*, *Ocimum basilicum*, *Artemisia dracunculus*

*Croton zehntneri*, *Ocimum*

*Cinnamomum osmophloeum*, *C. zeylanicum*

—mice) [35]

—rats) [32]

—rats) [40]

—rats) [42]

[44] 0.9 g/kg (v.o —rats) [44]

> (v.o—rats) [46, 17]

—rats) [32]

—rats) [17]

—rats) [17]

*sonderianus* Vasorelaxant 421.43 23.48 <sup>μ</sup>M<sup>B</sup> ;

;

–<sup>3</sup> <sup>10</sup><sup>4</sup> M [43]

;

*gratissimum* Vasorelaxant 0.31 0.05 mM [49]

[9]

–<sup>3</sup> <sup>10</sup><sup>4</sup> <sup>M</sup><sup>B</sup> [38, 39] 6.5 g/kg (v.o

[44]

*Monoterpenes and monoterpenoids with hypotensive and vasorelaxant effects.*

(**Table 1**). In order to allow some basis for evaluation of the therapeutic potential of these compounds, we include information on toxicity (LD50 values in mammals; **Table 1**).

#### **2. Monoterpenes**

Monoterpenes are compounds with two isoprene units in their structure. They can be subdivided according to the number of cycle components in its structure into acyclic, monocyclic, and bicyclic [68, 69]. Of the natural monoterpenes studied, we have not found, in any publications, report of cardiovascular effects for myrcene, ocimene (acyclic), terpinenes, phellandrenes, terpinolene, thujene (monocyclic) and, 3-carene, camphene, sabinene (bicyclic), and tricyclene on SBP and VSM. However, several studies in the literature demonstrate that EO containing these compounds have interesting cardiovascular effects.

#### **2.1 Limonene**

Limonene (LM) is one of the most common monoterpenes on nature. Studies have demonstrated that it has low toxicity and have suggested its promising effect [13]. The LM had a dose-dependent hypotensive effect, associated with bradycardia in rats (**Table 1**). LM is also reported to cause delayed ventricular relaxation and negative inotropism. It has been suggested that these effects are due to an action of LM on VDCC [12]. In spontaneously hypertensive rats (SHR) with cerebral ischemia, LM attenuated the elevation of the blood pressure of the animals [70].

in VSM without the participation of the NO and cyclooxygenase (COX) pathway [18]. In another study, in anesthetized and awake rats, citronellol (1–20 mg/kg, i.v.) also had a hypotensive effect, but associated with bradycardia. As a probable cause

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

of this discrepancy, the chirality of the compound was suggested [19]. In rat mesenteric arteries, citronellol had an endothelium-independent vasorelaxing effect. On the contraction induced by PHE (IC50 130 μM) and KCl, the effectiveness reached 100%. This monoterpenoid was able to block the influx of Ca2+ and contraction induced by caffeine and this finding led the authors to also

suggest that it acts on influx and the mobilization of Ca2+ stores [18, 19].

diabetic animals, the GER attenuated the cardiac changes caused by diabetes mellitus (DM). The authors suggested that the mechanism for this effect was the attenuation of changes caused by DM in contractility and systolic duration by

reduced tissue hyperresponsiveness to PHE [21].

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

Geraniol (GER) is an acyclic monoterpenoid with low toxicity (**Table 1**) [73]. In

In the aorta of normoglycemic animals, GER (30–300 μM) had a vasorelaxing effect on contractions induced by PHE and KCl. This effect was more effective on EMC, suggesting inhibition of Ca2+ channels in the plasma membrane of smooth cell. The authors demonstrated that the NO, COX, and K<sup>+</sup> channels do not participate in this vasorelaxant effect. In the aorta of diabetic rats, GER (30–300 μM)

Linalool (LN) is an acyclic tertiary alcohol. In normotensive animals, LN (1–20 mg/kg, i.v.) led to hypotension and tachycardia. Hypotension was attenuated

In the mesenteric bed of normotensive animals, LN showed an endotheliumindependent vasorelaxant effect on PMC and EMC, with maximum efficacy. Additionally, LN inhibited contractions induced by CaCl2 and caffeine, which led the authors to suggest that the mechanism of action involves the mobilization of Ca2+ from intracellular stores and the influx of Ca2+ through the plasma membrane. The direct relaxing effect of LN on VSM has been suggested to be responsible for the hypotensive effect of this compound. In the aorta of normotensive rats with endothelium, LN (100 μM) had a relaxing effect on PHE-induced contraction [23, 75].

Perillyl alcohol (POH) is a monocyclic alcohol. It had a reversible vasorelaxing effect in rat aorta, dependent on concentration and maximum efficacy on the KCl (IC50 277.7 5.46 μM) and PHE-induced (IC50 443.3 66.83 μM) contractions (**Table 1**). Among the contractions inhibited by POH, which also inhibited contractions induced by phorbol dibutyrate (PDB) or by BayK8644, the greatest pharmacological potency was over the contractions induced by KCl and BayK8644, which suggested that the mechanism of the relaxing effect of POH was inhibition of VDCCs. However, other mechanisms have not been ruled out [10]. POH (1–2 mM)

by Nω-Nitro-L-arginine methyl ester (L-NAME) and atropine but not by indomethacin, thus suggesting that the NO and muscarinic receptor pathways participate in promoting this effect [14, 23]. In Goldblatt hypertensive animals, LN (200 mg/kg) caused hypotension, of magnitude similar to nifedipine (NIF), without altering heart rate (HR) [23]. LN also had a hypotensive effect at a dose of

*3.1.2 Geraniol*

GER [74].

*3.1.3 Linalool*

100 mg/kg in SHR [25].

*3.1.4 Perillyl alcohol*

**101**

In rat aorta, the LM promoted a marked vasorelaxing effect when administered in presence of the contractions induced by a solution with a high concentration of K<sup>+</sup> or phenylephrine (PHE). The IC50 values were dependent on the endothelium and maximum efficacy was documented for both types of contraction. The potency in endothelium-intact arteries was greater in EMC than in PMC. LM was also able to relax the contraction induced by BayK8644, a VDCC activator [71], effect in which the LM presented the greatest potency, suggesting a possible effect of this monoterpene on VDCCs [10].

#### **2.2 Pinene**

α- and β-pinene are two isomeric bicyclic monoterpenes [72] which, in awake rats, induced arterial hypotension and tachycardia. ()-β-pinene was significantly more effective than (+)-α-pinene. The authors suggested that the exocyclic double bond of ()-β-pinene contributes more to the pharmacological effect than the endocyclic double bond of (+)-α-pinene. They explained tachycardia as a reflex response to the hypotension [14].

#### **2.3 p-cimene**

P-cymene is a monocyclic monoterpene that in rat's aorta showed a reversible vasorelaxant effect, with maximum efficacy and in a concentration-dependent manner. This effect, independent of the endothelium, indicated a myogenic effect. Additionally, the participation of K+ channels in the vasorelaxant effect of p-cymene has been suggested [16].

#### **3. Monoterpenoids**

Monoterpenoids are compounds found in several plant species (**Table 1**). Concerning their chemical functions, they can be: alcohols, phenolics, phenylpropanoids, aldehydes, ketones, ethers, or esters. For the following natural monoterpenoids, no studies were found that described effect on SBP and VSM: lavandulol, fenchol, chrysanthenol and nerol (alcohols); apiol, myristicin and safrole (phenylpropanoids).

#### **3.1 Alcohols**

#### *3.1.1 Citronellol*

Citronellol is a low toxicity acyclic monoterpenoid [20]. Regarding hemodynamic parameters, citronellol (1–20 mg/kg, i.v.) is reported to induce hypotension associated with tachycardia in non-anesthetized rats [18]. This hypotensive effect was interpreted to occur probably due to a direct vasorelaxant action of citronellol *Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

in VSM without the participation of the NO and cyclooxygenase (COX) pathway [18]. In another study, in anesthetized and awake rats, citronellol (1–20 mg/kg, i.v.) also had a hypotensive effect, but associated with bradycardia. As a probable cause of this discrepancy, the chirality of the compound was suggested [19].

In rat mesenteric arteries, citronellol had an endothelium-independent vasorelaxing effect. On the contraction induced by PHE (IC50 130 μM) and KCl, the effectiveness reached 100%. This monoterpenoid was able to block the influx of Ca2+ and contraction induced by caffeine and this finding led the authors to also suggest that it acts on influx and the mobilization of Ca2+ stores [18, 19].

#### *3.1.2 Geraniol*

**2.1 Limonene**

*Terpenes and Terpenoids-Recent Advances*

terpene on VDCCs [10].

response to the hypotension [14].

p-cymene has been suggested [16].

**3. Monoterpenoids**

safrole (phenylpropanoids).

**3.1 Alcohols**

*3.1.1 Citronellol*

**100**

**2.2 Pinene**

**2.3 p-cimene**

Limonene (LM) is one of the most common monoterpenes on nature. Studies have demonstrated that it has low toxicity and have suggested its promising effect [13]. The LM had a dose-dependent hypotensive effect, associated with bradycardia in rats (**Table 1**). LM is also reported to cause delayed ventricular relaxation and negative inotropism. It has been suggested that these effects are due to an action of LM on VDCC [12]. In spontaneously hypertensive rats (SHR) with cerebral ischemia, LM attenuated the elevation of the blood pressure of the animals [70].

In rat aorta, the LM promoted a marked vasorelaxing effect when administered in presence of the contractions induced by a solution with a high concentration of K<sup>+</sup> or phenylephrine (PHE). The IC50 values were dependent on the endothelium and maximum efficacy was documented for both types of contraction. The potency in endothelium-intact arteries was greater in EMC than in PMC. LM was also able to relax the contraction induced by BayK8644, a VDCC activator [71], effect in which the LM presented the greatest potency, suggesting a possible effect of this mono-

α- and β-pinene are two isomeric bicyclic monoterpenes [72] which, in awake rats, induced arterial hypotension and tachycardia. ()-β-pinene was significantly more effective than (+)-α-pinene. The authors suggested that the exocyclic double bond of ()-β-pinene contributes more to the pharmacological effect than the endocyclic double bond of (+)-α-pinene. They explained tachycardia as a reflex

P-cymene is a monocyclic monoterpene that in rat's aorta showed a reversible vasorelaxant effect, with maximum efficacy and in a concentration-dependent manner. This effect, independent of the endothelium, indicated a myogenic effect.

Additionally, the participation of K+ channels in the vasorelaxant effect of

Monoterpenoids are compounds found in several plant species (**Table 1**).

phenylpropanoids, aldehydes, ketones, ethers, or esters. For the following natural monoterpenoids, no studies were found that described effect on SBP and VSM: lavandulol, fenchol, chrysanthenol and nerol (alcohols); apiol, myristicin and

Citronellol is a low toxicity acyclic monoterpenoid [20]. Regarding hemodynamic parameters, citronellol (1–20 mg/kg, i.v.) is reported to induce hypotension associated with tachycardia in non-anesthetized rats [18]. This hypotensive effect was interpreted to occur probably due to a direct vasorelaxant action of citronellol

Concerning their chemical functions, they can be: alcohols, phenolics,

Geraniol (GER) is an acyclic monoterpenoid with low toxicity (**Table 1**) [73]. In diabetic animals, the GER attenuated the cardiac changes caused by diabetes mellitus (DM). The authors suggested that the mechanism for this effect was the attenuation of changes caused by DM in contractility and systolic duration by GER [74].

In the aorta of normoglycemic animals, GER (30–300 μM) had a vasorelaxing effect on contractions induced by PHE and KCl. This effect was more effective on EMC, suggesting inhibition of Ca2+ channels in the plasma membrane of smooth cell. The authors demonstrated that the NO, COX, and K<sup>+</sup> channels do not participate in this vasorelaxant effect. In the aorta of diabetic rats, GER (30–300 μM) reduced tissue hyperresponsiveness to PHE [21].

#### *3.1.3 Linalool*

Linalool (LN) is an acyclic tertiary alcohol. In normotensive animals, LN (1–20 mg/kg, i.v.) led to hypotension and tachycardia. Hypotension was attenuated by Nω-Nitro-L-arginine methyl ester (L-NAME) and atropine but not by indomethacin, thus suggesting that the NO and muscarinic receptor pathways participate in promoting this effect [14, 23]. In Goldblatt hypertensive animals, LN (200 mg/kg) caused hypotension, of magnitude similar to nifedipine (NIF), without altering heart rate (HR) [23]. LN also had a hypotensive effect at a dose of 100 mg/kg in SHR [25].

In the mesenteric bed of normotensive animals, LN showed an endotheliumindependent vasorelaxant effect on PMC and EMC, with maximum efficacy. Additionally, LN inhibited contractions induced by CaCl2 and caffeine, which led the authors to suggest that the mechanism of action involves the mobilization of Ca2+ from intracellular stores and the influx of Ca2+ through the plasma membrane. The direct relaxing effect of LN on VSM has been suggested to be responsible for the hypotensive effect of this compound. In the aorta of normotensive rats with endothelium, LN (100 μM) had a relaxing effect on PHE-induced contraction [23, 75].

#### *3.1.4 Perillyl alcohol*

Perillyl alcohol (POH) is a monocyclic alcohol. It had a reversible vasorelaxing effect in rat aorta, dependent on concentration and maximum efficacy on the KCl (IC50 277.7 5.46 μM) and PHE-induced (IC50 443.3 66.83 μM) contractions (**Table 1**). Among the contractions inhibited by POH, which also inhibited contractions induced by phorbol dibutyrate (PDB) or by BayK8644, the greatest pharmacological potency was over the contractions induced by KCl and BayK8644, which suggested that the mechanism of the relaxing effect of POH was inhibition of VDCCs. However, other mechanisms have not been ruled out [10]. POH (1–2 mM) when incubated overnight prevented KCl-, 5-HT-, and U46619-induced contractions in coronary arteries [27].

#### *3.1.5 Carveol*

Carveol (CV) is a monocyclic alcohol found in the mint EO. In rat aorta, the CV (10–5000 μM) had a vasorelaxing effect, over contractions induced by PHE (IC50 1333.3 225.20 μM) and KCl (IC50 662.1 32.85 μM), which was reversible and independent of the vascular endothelium. The CV also inhibited contractions induced by PDB and BayK8644. Due to the greater potency of CV on contractions induced by KCl and BayK8644, the mechanism of its relaxing effect was attributed to a probable inhibitory effect on VDCCs [10].

induced by BayK, BaCl2, and K<sup>+</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

contractile proteins to Ca2+ [9].

*3.1.9 Borneol*

**3.2 Phenolics**

*3.2.1 Carvacrol*

*3.2.2 Thymol*

**103**

the blocking of VDCCs [44].

mechanism of action [39].

, presenting IC50 values of 454.2 28.7,

450.5 71.1, and 421.43 23.48 μM, respectively. This suggest the possible inhibitory effect of 4TERP on VDCCs. It has been suggested that 4TERP also acts on other components of myocytes, such as the IP3 pathway and the sensitivity of

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

In ventricular myocytes isolated from rats, 4TERP (30 μM) promoted a small increase (10.6 2.6%) of L type Ca2+ currents. Above 300 <sup>μ</sup>M the effect was

<sup>1203</sup> 0.224 <sup>μ</sup>M). 4TERP increased the Ca2+ spark frequency at low concentrations and decreased the amplitude of Ca2+ transients at low and high concentrations [78]. Thus, among the effects of 4TERP on the cardiovascular system, the effect on ion

Borneol is a bicyclic alcohol. In rat aorta, borneol had a vasorelaxing effect on contraction induced by KCl and PHE. This effect was reduced by L-NAME and indomethacin, showing the involvement of the NO and COX pathway in its mechanism [38]. In another study, in rat aorta, borneol inhibited contraction induced by CaCl2, BayK8644, and caffeine and the authors suggested probable activities of this monoterpenoid on VDCCs or intracellular Ca2+ stocks as components of its

In anesthetized rats, carvacrol (100 μg/kg, i.p.) decreased HR, SBP, systolic and diastolic pressure [42]. In normotensive non-anesthetized rats, carvacrol

(1–20 mg/kg, i.v.), had a hypotensive and bradycardic effect [43].

On aorta of rats, on contractions induced by KCl and PHE, carvacrol (1–1000 μM) showed a reversible inhibitory effect, with maximum efficacy, concentration-dependent and not dependent on the endothelium. In addition, carvacrol inhibited contractions in a Ca2+-free medium. These data together suggested the hypothesis that the vasorelaxant mechanism of this monoterpenoid involves multiple mechanisms: the IP3 pathway, the sensitivity of contractile proteins to Ca2+, and the blocking of VDCCs [44]. In mesenteric arteries, carvacrol (10<sup>8</sup> – <sup>3</sup> <sup>10</sup><sup>4</sup> M) had a concentrations-dependent vasorelaxing effect on PHE-, U46619, and KCl-induced contractions. This effect was endothelium independent and probably involves VOCCs, receptor operator channels (ROC), and store operator channels (SOC) channels [43]. Carvacrol also has a vasorelaxing effect on cerebral parenchymal arteries. In this case, this effect was endothelium-dependent and promoted through the activation of TRPV3 channels that consequently activated the low and medium conductance Ca2+-activated K+ channels [79].

Thymol is a carvacrol isomer. In aorta of rats, thymol (1–1000 μM) has a reversible and concentration-dependent vasorelaxant effect (in contractions induced by KCl and PHE). The experiments to elucidate the mechanism of action showed results very similar to those of carvacrol and led to similar conclusions: the involvement of the IP3 pathway, the sensitivity of contractile proteins to Ca2+, and

reversed; 4TERP reduced the amplitude of these currents (IC50 of

channels was highlighted as a possible mechanism of action.

In the human umbilical artery, the CV (1–5000 μM) reduced the basal tone by approximately 72% and relaxed contractions induced by 5-HT (IC50 of 175.82 μM) and KCl (IC50 344.25 μM) [76].

#### *3.1.6 Menthol*

Menthol is a monocyclic alcohol. In hypertensive animals, menthol (0.5% dietary) attenuated the elevation of vasoconstriction (on PHE- and U46619-induced contraction), blood pressure, the production of reactive oxygen species (ROS), and mitochondrial dysfunction. This effect probably occur due to the TRPM8 activation by menthol and involve the calcium signaling–mediated RhoA/Rho kinase pathway [29, 30].

Menthol showed cutaneous vasorelaxing activity in individuals in normotensive or in essential hypertension condition, an activity that has been suggested to involve the endothelium derived hyperpolarizing factor (EDHF) and NO [33, 77].

#### *3.1.7 α-Terpineol*

α-Terpineol (1–30 mg/kg, i.v.), a monocyclic alcohol, induced a reduction in SBP and tachycardia. These effects were mitigated by L-NAME and suggested to involve the NO pathway [34].

In mesenteric arteries, α-terpineol induced an endothelium-dependent vasorelaxant effect on contractions induced by PHE. The vasorelaxant effect of α-terpineol was not affected by atropine and indomethacin, but by treatment with L-NAME and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxal in-1-one (ODQ), suggesting the involvement of the NO/cGMP pathway [34]. In a cannulated mesenteric bed contracted by perfusion with KCl, α-terpineol (300 μg/ml (1.94 mM)) increased (by 93%) the mesenteric flow. The vasorelaxant effect of α-terpineol was abolished by L-NAME, suggesting the participation of NO in this effect [36].

#### *3.1.8 Terpinen-4-ol*

Terpinen-4-ol (4TERP) is a monocyclic alcohol. In hypertensive DOCA-salt and normotensive animals, uninefrectomized or not, 4TERP (1–10 mg/kg, i.v.) induced a reduction in SBP and bradycardia, with a peak between 20–30 s after administration. This effect lasted 1–10 minutes for all doses [7, 37].

In VSM of rats, 4TERP showed vasorelaxing effect, reversible and with maximum effectiveness, on contractions mediated by EMC (IC50 421.43 23.48 μM) and PMC (IC50 802.50 13.8 μM). It has been suggested that this effect involves the NO and COX pathway. 4TERP relaxed, with similar potency, the contractions

#### *Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

induced by BayK, BaCl2, and K<sup>+</sup> , presenting IC50 values of 454.2 28.7, 450.5 71.1, and 421.43 23.48 μM, respectively. This suggest the possible inhibitory effect of 4TERP on VDCCs. It has been suggested that 4TERP also acts on other components of myocytes, such as the IP3 pathway and the sensitivity of contractile proteins to Ca2+ [9].

In ventricular myocytes isolated from rats, 4TERP (30 μM) promoted a small increase (10.6 2.6%) of L type Ca2+ currents. Above 300 <sup>μ</sup>M the effect was reversed; 4TERP reduced the amplitude of these currents (IC50 of <sup>1203</sup> 0.224 <sup>μ</sup>M). 4TERP increased the Ca2+ spark frequency at low concentrations and decreased the amplitude of Ca2+ transients at low and high concentrations [78]. Thus, among the effects of 4TERP on the cardiovascular system, the effect on ion channels was highlighted as a possible mechanism of action.

#### *3.1.9 Borneol*

when incubated overnight prevented KCl-, 5-HT-, and U46619-induced

Carveol (CV) is a monocyclic alcohol found in the mint EO. In rat aorta, the CV (10–5000 μM) had a vasorelaxing effect, over contractions induced by PHE (IC50 1333.3 225.20 μM) and KCl (IC50 662.1 32.85 μM), which was reversible and independent of the vascular endothelium. The CV also inhibited contractions induced by PDB and BayK8644. Due to the greater potency of CV on contractions induced by KCl and BayK8644, the mechanism of its relaxing effect was attributed

In the human umbilical artery, the CV (1–5000 μM) reduced the basal tone by approximately 72% and relaxed contractions induced by 5-HT (IC50 of 175.82 μM)

Menthol is a monocyclic alcohol. In hypertensive animals, menthol (0.5% dietary) attenuated the elevation of vasoconstriction (on PHE- and U46619-induced contraction), blood pressure, the production of reactive oxygen species (ROS), and mitochondrial dysfunction. This effect probably occur due to the TRPM8 activation by menthol and involve the calcium signaling–mediated RhoA/Rho kinase pathway

α-Terpineol (1–30 mg/kg, i.v.), a monocyclic alcohol, induced a reduction in SBP and tachycardia. These effects were mitigated by L-NAME and suggested to

Terpinen-4-ol (4TERP) is a monocyclic alcohol. In hypertensive DOCA-salt and normotensive animals, uninefrectomized or not, 4TERP (1–10 mg/kg, i.v.) induced a reduction in SBP and bradycardia, with a peak between 20–30 s after administra-

In VSM of rats, 4TERP showed vasorelaxing effect, reversible and with maximum effectiveness, on contractions mediated by EMC (IC50 421.43 23.48 μM) and PMC (IC50 802.50 13.8 μM). It has been suggested that this effect involves the NO and COX pathway. 4TERP relaxed, with similar potency, the contractions

In mesenteric arteries, α-terpineol induced an endothelium-dependent vasorelaxant effect on contractions induced by PHE. The vasorelaxant effect of α-terpineol was not affected by atropine and indomethacin, but by treatment with L-NAME and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxal in-1-one (ODQ), suggesting the involvement of the NO/cGMP pathway [34]. In a cannulated mesenteric bed contracted by perfusion with KCl, α-terpineol (300 μg/ml (1.94 mM)) increased (by 93%) the mesenteric flow. The vasorelaxant effect of α-terpineol was abolished

by L-NAME, suggesting the participation of NO in this effect [36].

tion. This effect lasted 1–10 minutes for all doses [7, 37].

Menthol showed cutaneous vasorelaxing activity in individuals in normotensive or in essential hypertension condition, an activity that has been suggested to involve the endothelium derived hyperpolarizing factor (EDHF) and

contractions in coronary arteries [27].

*Terpenes and Terpenoids-Recent Advances*

to a probable inhibitory effect on VDCCs [10].

and KCl (IC50 344.25 μM) [76].

*3.1.5 Carveol*

*3.1.6 Menthol*

[29, 30].

NO [33, 77].

*3.1.7 α-Terpineol*

*3.1.8 Terpinen-4-ol*

**102**

involve the NO pathway [34].

Borneol is a bicyclic alcohol. In rat aorta, borneol had a vasorelaxing effect on contraction induced by KCl and PHE. This effect was reduced by L-NAME and indomethacin, showing the involvement of the NO and COX pathway in its mechanism [38]. In another study, in rat aorta, borneol inhibited contraction induced by CaCl2, BayK8644, and caffeine and the authors suggested probable activities of this monoterpenoid on VDCCs or intracellular Ca2+ stocks as components of its mechanism of action [39].

#### **3.2 Phenolics**

#### *3.2.1 Carvacrol*

In anesthetized rats, carvacrol (100 μg/kg, i.p.) decreased HR, SBP, systolic and diastolic pressure [42]. In normotensive non-anesthetized rats, carvacrol (1–20 mg/kg, i.v.), had a hypotensive and bradycardic effect [43].

On aorta of rats, on contractions induced by KCl and PHE, carvacrol (1–1000 μM) showed a reversible inhibitory effect, with maximum efficacy, concentration-dependent and not dependent on the endothelium. In addition, carvacrol inhibited contractions in a Ca2+-free medium. These data together suggested the hypothesis that the vasorelaxant mechanism of this monoterpenoid involves multiple mechanisms: the IP3 pathway, the sensitivity of contractile proteins to Ca2+, and the blocking of VDCCs [44]. In mesenteric arteries, carvacrol (10<sup>8</sup> – <sup>3</sup> <sup>10</sup><sup>4</sup> M) had a concentrations-dependent vasorelaxing effect on PHE-, U46619, and KCl-induced contractions. This effect was endothelium independent and probably involves VOCCs, receptor operator channels (ROC), and store operator channels (SOC) channels [43]. Carvacrol also has a vasorelaxing effect on cerebral parenchymal arteries. In this case, this effect was endothelium-dependent and promoted through the activation of TRPV3 channels that consequently activated the low and medium conductance Ca2+-activated K+ channels [79].

#### *3.2.2 Thymol*

Thymol is a carvacrol isomer. In aorta of rats, thymol (1–1000 μM) has a reversible and concentration-dependent vasorelaxant effect (in contractions induced by KCl and PHE). The experiments to elucidate the mechanism of action showed results very similar to those of carvacrol and led to similar conclusions: the involvement of the IP3 pathway, the sensitivity of contractile proteins to Ca2+, and the blocking of VDCCs [44].

#### **3.3 Phenylpropanoids**

#### *3.3.1 Anethole*

Anethole (AN) is a phenylpropanoid with very low toxicity, it has been suggested to have great therapeutic potential [46].

AN (5–10 mg/kg, i.v.) induced, in a concentration-dependent manner, in conscious normotensive rats, hypotension and bradycardia (phase 1), followed by pressoric and bradycardic response (phase 2) [47]. In animals with nicotineinduced hypertension associated with immobilization stress, AN (125–250 mg/kg, i. p.) had an anti-hypertensive effect with efficacy similar to physical exercise and NIF [45].

blocking of Ca2+ channels without, however, altering the activity of the contractile intracellular machinery [85]. Similar results were also observed in canine myocytes, where EUG reduced the amplitude and changed the kinetics of the Ca2+ current of

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

Studies have also shown that endothelial TRP channels can participate in the vasorelaxant effect of EUG (5 mg/kg, i.v). EUG at low concentrations (100 μM) is able to activate TRPV4 currents in these cells, triggering actions that lead to

It is known that among the predominant pathological changes in DM are blood vessel alterations. Nangle et al. [87] demonstrated that the EUG (200 mg/kg/day, p.o.) was able to reverse the increase in sensitivity to PHE and the reduction of ACh-induced relaxation in the renal artery of diabetic rats. This mechanism

As EUG has low toxicity, affects several vascular beds and has an inhibitory effect on Ca2+ channels, it has therapeutic potential in treatment of DM and

In rat aorta, cinnamaldehyde has an endothelium-dependent relaxing effect on contraction induced by KCl, prostaglandin F2 (PGF2), and NE [88]. Endothelium dependence, however, has been refuted by Xue et al., since the vasorelaxant effect induced by cinnamaldehyde was not mitigated by pretreatment with L-NAME or ODQ [89]. In addition, these authors reported that COX, K+ channels, and

β-adrenergic receptors are not involved in the vasorelaxant effect of Cinnamaldehyde

In the coronary artery, cinnamaldehyde has a concentration-dependent and endothelium-independent relaxing effect of maximum efficacy on contractions

The cinnamaldehyde relaxation mechanism is suggested to occur due to alterations of the sensitivity of contractile proteins to Ca2+ and, mainly, by inhibiting VDCCs, as this monoterpenoid inhibited the contraction induced by BayK 8644 in the coronary artery [52, 90]. Additionally, cinnamaldehyde has been shown to reduce L-type Ca2+ currents in VSM cells (IC50 of 0.81 0.02 mM; maximum

In the aorta and mesenteric artery of diabetic mice, cinnamaldehyde added to the diet (% 0.02) improved the endothelial response to ACh without changing SBP. Additionally, cinnamaldehyde prevented the production of ROS and depletion of NO, with beneficial effect in DM [91, 92]. In DM, cinnamaldehyde (20 mg/kg/day) also protected against the elevation of diastolic pressure, the increase in respon-

Citral is a monoterpenoid considered to be non-toxic and of therapeutic relevance [54, 96]. Citral reversibly inhibited contractions induced by PHE (IC50 99.34 μg/mL) and KCl (IC50 110.80 μg/mL) in aorta of healthy rats with maximum efficacy. The authors suggested that this effect occurs due to the blockade of VDCCs, since citral inhibited contractions induced by BaCl2 and BayK 8644

siveness to contracting agents and the hyporesponsiveness to ACh [93].

VDCC L-type channel [86].

probably occurred through NO and EDHF.

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

vasorelaxation [51].

Hypertension.

**3.4 Aldehydes**

[52, 88, 89].

efficacy) [52].

*3.4.2 Citral*

[53, 54].

**105**

*3.4.1 Cinnamaldehyde*

induced by U46619 and KCl [90].

Soares et al. [48] reported, in relation to concentration, a biphasic effect of AN on the aortic artery. Between 10<sup>6</sup> to 10<sup>4</sup> M, AN induced an increase in basal tone and PHE-induced contraction in preparations with endothelium. Between 10<sup>4</sup> and 10<sup>3</sup> the Figure 2b [48] shows this contraction vanishes and full relaxation stablishes (maximum efficacy). It was suggested that the activity on VDCC (activation (10<sup>6</sup> to 10<sup>4</sup> M) and inhibition (10<sup>3</sup> to 10<sup>2</sup> M)) is the probable mechanism of this effect [48]. Another study with AN in aortic rings reported only vasorelaxing effects, with higher potencies (for EMC and PMC, IC50: 50–75 μg/ml (0.34– 0.51 mM))[80]. This discrepancy was not explained.

#### *3.3.2 Estragol*

Estragole (ES) is an isomer of AN which, at 5–10 mg/kg, i.v., induced effects on blood pressure very similar to those of AN (see above) [47, 81]. In the aorta artery of rats with intact endothelium, the ES also had a similar effect to the AN (predominantly vasorelaxant), except that the amplification effect of the contraction was smaller and without statistical significance [48].

#### *3.3.3 Eugenol*

Eugenol (EUG) is a phenylpropanoid with a long effect half-life and low toxicity [82]. EUG is probably the most investigated monoterpenoid with effects on the cardiovascular system. EUG (1–10 mg/kg, i.v.) caused reduction of SBP and HR, in dose-dependent manner, in normotensive animals (conscious or anesthetized) and in hypertensive animals (DOCA-salt model). It was suggested that the hypotensive effect is due to the direct vasorelaxing activity of the EUG [49, 50].

In blood vessels, EUG has a relaxing, reversible effect, partially dependent on the endothelium [51, 83]. In rat aorta, with endothelium, this phenylpropanoid inhibited PHE-induced contraction in normotensive (EUG at 1–100 μM) and hypertensive animals (EUG at 0.006–6 mM, DOCA-salt model) [48, 75, 84].

The vasorelaxant effect of the EUG was confirmed with flow measurements. In normotensive animals, EUG induced an increase in flow through the vascular mesenteric bed pre-contracted with KCl (IC50 0.31 0.05 mM) or noradrenaline (0.2, 2 or 20 μM) [50, 85].

EUG also has a vasodilatory effect on pressurized cerebral artery of rats (IC50 of 234.2 11.3 <sup>μ</sup>M) or pre-contracted with K<sup>+</sup> (IC50 of 323.3 14.0 <sup>μ</sup>M)[11].

The hypotensive and vasorelaxing effect of the EUG is due to multiple mechanisms, the effect of which on ion channels stands out. In VSM cells, the EUG blocks VDCCs by the channel pore blocking mechanism and by changing the steady state of channel inactivation [11, 51]. Consistent with this effect, in rat heart muscle, it was suggested that the negative inotropic effect of EUG (0.1–0.5 mM) is due to the

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

blocking of Ca2+ channels without, however, altering the activity of the contractile intracellular machinery [85]. Similar results were also observed in canine myocytes, where EUG reduced the amplitude and changed the kinetics of the Ca2+ current of VDCC L-type channel [86].

Studies have also shown that endothelial TRP channels can participate in the vasorelaxant effect of EUG (5 mg/kg, i.v). EUG at low concentrations (100 μM) is able to activate TRPV4 currents in these cells, triggering actions that lead to vasorelaxation [51].

It is known that among the predominant pathological changes in DM are blood vessel alterations. Nangle et al. [87] demonstrated that the EUG (200 mg/kg/day, p.o.) was able to reverse the increase in sensitivity to PHE and the reduction of ACh-induced relaxation in the renal artery of diabetic rats. This mechanism probably occurred through NO and EDHF.

As EUG has low toxicity, affects several vascular beds and has an inhibitory effect on Ca2+ channels, it has therapeutic potential in treatment of DM and Hypertension.

#### **3.4 Aldehydes**

**3.3 Phenylpropanoids**

*Terpenes and Terpenoids-Recent Advances*

Anethole (AN) is a phenylpropanoid with very low toxicity, it has been

AN (5–10 mg/kg, i.v.) induced, in a concentration-dependent manner, in conscious normotensive rats, hypotension and bradycardia (phase 1), followed by pressoric and bradycardic response (phase 2) [47]. In animals with nicotineinduced hypertension associated with immobilization stress, AN (125–250 mg/kg, i. p.) had an anti-hypertensive effect with efficacy similar to physical exercise and

Soares et al. [48] reported, in relation to concentration, a biphasic effect of AN on the aortic artery. Between 10<sup>6</sup> to 10<sup>4</sup> M, AN induced an increase in basal tone and PHE-induced contraction in preparations with endothelium. Between 10<sup>4</sup> and 10<sup>3</sup> the Figure 2b [48] shows this contraction vanishes and full relaxation stablishes (maximum efficacy). It was suggested that the activity on VDCC (activation (10<sup>6</sup> to 10<sup>4</sup> M) and inhibition (10<sup>3</sup> to 10<sup>2</sup> M)) is the probable mechanism of this effect [48]. Another study with AN in aortic rings reported only vasorelaxing effects, with higher potencies (for EMC and PMC, IC50: 50–75 μg/ml (0.34–

Estragole (ES) is an isomer of AN which, at 5–10 mg/kg, i.v., induced effects on blood pressure very similar to those of AN (see above) [47, 81]. In the aorta artery of rats with intact endothelium, the ES also had a similar effect to the AN (predominantly vasorelaxant), except that the amplification effect of the contraction

Eugenol (EUG) is a phenylpropanoid with a long effect half-life and low toxicity [82]. EUG is probably the most investigated monoterpenoid with effects on the cardiovascular system. EUG (1–10 mg/kg, i.v.) caused reduction of SBP and HR, in dose-dependent manner, in normotensive animals (conscious or anesthetized) and in hypertensive animals (DOCA-salt model). It was suggested that the hypotensive

In blood vessels, EUG has a relaxing, reversible effect, partially dependent on the endothelium [51, 83]. In rat aorta, with endothelium, this phenylpropanoid inhibited PHE-induced contraction in normotensive (EUG at 1–100 μM) and hypertensive animals (EUG at 0.006–6 mM, DOCA-salt model) [48, 75, 84].

The vasorelaxant effect of the EUG was confirmed with flow measurements. In normotensive animals, EUG induced an increase in flow through the vascular mesenteric bed pre-contracted with KCl (IC50 0.31 0.05 mM) or noradrenaline (0.2, 2

EUG also has a vasodilatory effect on pressurized cerebral artery of rats (IC50 of

The hypotensive and vasorelaxing effect of the EUG is due to multiple mechanisms, the effect of which on ion channels stands out. In VSM cells, the EUG blocks VDCCs by the channel pore blocking mechanism and by changing the steady state of channel inactivation [11, 51]. Consistent with this effect, in rat heart muscle, it was suggested that the negative inotropic effect of EUG (0.1–0.5 mM) is due to the

234.2 11.3 <sup>μ</sup>M) or pre-contracted with K<sup>+</sup> (IC50 of 323.3 14.0 <sup>μ</sup>M)[11].

effect is due to the direct vasorelaxing activity of the EUG [49, 50].

suggested to have great therapeutic potential [46].

0.51 mM))[80]. This discrepancy was not explained.

was smaller and without statistical significance [48].

*3.3.1 Anethole*

NIF [45].

*3.3.2 Estragol*

*3.3.3 Eugenol*

or 20 μM) [50, 85].

**104**

#### *3.4.1 Cinnamaldehyde*

In rat aorta, cinnamaldehyde has an endothelium-dependent relaxing effect on contraction induced by KCl, prostaglandin F2 (PGF2), and NE [88]. Endothelium dependence, however, has been refuted by Xue et al., since the vasorelaxant effect induced by cinnamaldehyde was not mitigated by pretreatment with L-NAME or ODQ [89]. In addition, these authors reported that COX, K+ channels, and β-adrenergic receptors are not involved in the vasorelaxant effect of Cinnamaldehyde [52, 88, 89].

In the coronary artery, cinnamaldehyde has a concentration-dependent and endothelium-independent relaxing effect of maximum efficacy on contractions induced by U46619 and KCl [90].

The cinnamaldehyde relaxation mechanism is suggested to occur due to alterations of the sensitivity of contractile proteins to Ca2+ and, mainly, by inhibiting VDCCs, as this monoterpenoid inhibited the contraction induced by BayK 8644 in the coronary artery [52, 90]. Additionally, cinnamaldehyde has been shown to reduce L-type Ca2+ currents in VSM cells (IC50 of 0.81 0.02 mM; maximum efficacy) [52].

In the aorta and mesenteric artery of diabetic mice, cinnamaldehyde added to the diet (% 0.02) improved the endothelial response to ACh without changing SBP. Additionally, cinnamaldehyde prevented the production of ROS and depletion of NO, with beneficial effect in DM [91, 92]. In DM, cinnamaldehyde (20 mg/kg/day) also protected against the elevation of diastolic pressure, the increase in responsiveness to contracting agents and the hyporesponsiveness to ACh [93].

#### *3.4.2 Citral*

Citral is a monoterpenoid considered to be non-toxic and of therapeutic relevance [54, 96]. Citral reversibly inhibited contractions induced by PHE (IC50 99.34 μg/mL) and KCl (IC50 110.80 μg/mL) in aorta of healthy rats with maximum efficacy. The authors suggested that this effect occurs due to the blockade of VDCCs, since citral inhibited contractions induced by BaCl2 and BayK 8644 [53, 54].

Relaxing effect of citral was observed in the aortic artery of SHR. This monoterpenoid in concentrations of 0.00624 mM–6.24 mM, induced a relaxing effect partially dependent on the NO pathway. Additionally, citral blocked the contraction induced by reposition of Ca2+ to nutrient solution, and this suggested the hypothesis that this compound inhibits Ca2+ influx through VDCC channel [95].

attenuate the elevation of systolic blood pressure in hypertensive rats induced by

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

In another study, in the aorta of normotensive rats, CIN inhibited PHE-induced contraction (IC50 of 663.2 μg/ml (4.29 mM)). This effect was altered by the presence of L-NAME but was not affected by indomethacin or tetrathylamonium [63].

In hypertensive rats, the linalyl acetate (LA, 10–100 mg/kg, i.p.) attenuated the increase in systolic and diastolic blood pressure. LA also modulates the expression of

It was reported that diabetic animals exposed to chronic stress showed a reduction in endothelial function, changes in SBP and HR. LA (100 mg/kg) was able to

In a rabbit carotid artery, LA induced a relaxing effect on PHE-induced contraction, with partial efficacy (Emax = 88.8%) and IC50 3.6 <sup>10</sup><sup>4</sup> M. According to the authors, the cGMP-NO pathway and phosphorylation of myosin light chain, are involved in the relaxing effect of this monoterpenoid, since it was attenuated by L-NAME and ODQ [67]. It was also observed that the LA (300 μM) showed a relaxing effect of PHE-induced contraction in the aorta of mice exposed to nicotine [101].

Based on these studies, it can be concluded that the vast majority of those monoterpenes and monoterpenoids investigated and here presented have a hypotensive and vasorelaxant effect. Concerning the hypotensive effect, the studies did not include medium or long-term treatments; they were all about acute effects. In terms of results obtained, there was great variation in the repercussion on heart rate: concomitant tachycardia, in most cases, which was generally interpreted as a reflex reaction to a hypotensive effect of primary vascular origin; bradycardia or no change in heart rate in other cases. Concerning the investigation of the hypotensive

effect, in terms of the methodology of administration of monoterpene or

hypertension, the oral route of administration is largely preferable, if not

general, they were restricted to the initial stages of a preclinical study.

monoterpenoid, there was great variation in the route of administration employed, intraperitoneal in some cases, intravenous and oral in others, which makes comparisons more difficult. Additionally, concerning the perspective of therapeutic use, this is a relevant issue, since for long lasting treatment, as is the case with essential

Regarding the vasorelaxant effect, most studies describe a relaxing effect in rat aortic rings on contractions mediated by EMC and PMC and suggested, as participant in mechanism of action, based on indirect evidence, the inhibitory effect of these pharmacological agents on the activation of L type VDCC. Participation of K<sup>+</sup> and TRP ionic channels, as well as intracellular mechanisms on monoterpene and monoterpenoid-induced relaxation of contraction have been little investigated. From the point of view of the possible therapeutic use of monoterpenes and monoterpenoids for the treatment of arterial hypertension, it can be concluded that several studies on the pressure and vascular effects have been carried out. These studies point to a potential therapeutic use for several of these agents. However, in

Endothelial NO Synthase (eNOS), preventing its suppression by ROS. This suggested a possible antihypertensive effect of LA [64, 65]. In rats with hypertension induced by chronic exposure to nicotine and stress, LA (10–100 mg/kg), had a

revert these parameters to close to control values [100].

chronic nicotine exposure [61].

*DOI: http://dx.doi.org/10.5772/intechopen.94194*

*3.5.4 Linalyl acetate*

hypotensive effect [66].

**4. Final considerations**

mandatory.

**107**

#### *3.4.3 Citronellal*

Citronellal is a monoterpenoid composed of a racemic mixture of two enantiomers present in plants [96]. In normotensive animals, citronellal (10–40 mg/kg) induced hypotension, bradycardia, and sinoatrial node block. The bradycardic effect probably involves muscarinic receptors as it has been inhibited by atropine. In hypertensive animals, citronellal (200 mg/kg) induced a hypotensive effect of greater duration than that of NIF (1 h of NIF 3 h in citronellal) [55]. On contractions induced by PHE and KCl in the superior mesenteric artery of normotensive rats, citronellal had a endothelium-independent and concentration-dependent vasorelaxing effect, with maximum efficacy [55].

#### **3.5 Ketone**

#### *3.5.1 Carvone*

Carvone is a monocyclic monoterpenoid. Heuberger and collaborators [97] investigated the effects of ()-carvone and (+)-carvone inhalation on the autonomic nervous system. Inhalation of ()-carvone caused an increase in HR and systolic blood pressure; (+)-carvone inhalation increased systolic and diastolic blood pressure [97]. In rat aorta, carvone had a vasorelaxant effect (Emax = 58.9%) for both enantiomers. The IC50 values for (+)-carvone in contractions induced by PHE was 0.62 mM [57].

#### *3.5.2 Rotundifolone*

Rotundifolone (RT) is a monocyclic monoterpenoid. RT (1–30 mg/kg, i.v.) had a hypotensive (partial efficacy = 51%) and bradycardic (partial efficacy = 87%) effect in non-anesthetized rats. The hypotensive effect of RT was attenuated by atropine and L-NAME, suggesting the participation of muscarinic receptors in this effect [58].

On isolated aorta from rats, RT inhibited contractions induced by KCl (IC50 184 μg/ml (1.1 mM)) and PHE (IC50 185 μg/ml), with maximum efficacy. As a mechanism of this effect, a possible blocking of VDCCs and of the release of Ca2+ from sarcoplasmatic reticulum by RT was suggested [58, 59]. Others also observed the vasorelaxing effect of RT in the mesenteric artery of rats contracted with PHE (pD2 = 4.0, maximum efficacy). As a mechanism for this effect, activity on TRPM8 channels, activation of large conductance Ca2+-activated K+ (BKCa) channels, and inactivation of VDCCs were suggested [60, 98, 99].

#### *3.5.3 1,8-cineol*

1.8 cineole (CIN), also known as eucalyptol, in anesthetized and conscious normotensive animals, CIN (0.3–10 mg/kg, i.v.) induced hypotension, with maximum effect in 20–30 s after administration and duration of 1–5 min. This effect was independent of the autonomic nervous system, and a probable dependence on vascular relaxation was suggested [62]. CIN (0.1 mg/kg, i.p.) has been shown to

#### *Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

attenuate the elevation of systolic blood pressure in hypertensive rats induced by chronic nicotine exposure [61].

In another study, in the aorta of normotensive rats, CIN inhibited PHE-induced contraction (IC50 of 663.2 μg/ml (4.29 mM)). This effect was altered by the presence of L-NAME but was not affected by indomethacin or tetrathylamonium [63].

#### *3.5.4 Linalyl acetate*

Relaxing effect of citral was observed in the aortic artery of SHR. This monoterpenoid in concentrations of 0.00624 mM–6.24 mM, induced a relaxing effect partially dependent on the NO pathway. Additionally, citral blocked the contraction induced by reposition of Ca2+ to nutrient solution, and this suggested the hypothesis that this compound inhibits Ca2+ influx through VDCC channel [95].

Citronellal is a monoterpenoid composed of a racemic mixture of two enantiomers present in plants [96]. In normotensive animals, citronellal (10–40 mg/kg) induced hypotension, bradycardia, and sinoatrial node block. The bradycardic effect probably involves muscarinic receptors as it has been inhibited by atropine. In hypertensive animals, citronellal (200 mg/kg) induced a hypotensive effect of greater duration than that of NIF (1 h of NIF 3 h in citronellal) [55]. On contractions induced by PHE and KCl in the superior mesenteric artery of normotensive rats, citronellal had a endothelium-independent and concentration-dependent

Carvone is a monocyclic monoterpenoid. Heuberger and collaborators [97] investigated the effects of ()-carvone and (+)-carvone inhalation on the autonomic nervous system. Inhalation of ()-carvone caused an increase in HR and systolic blood pressure; (+)-carvone inhalation increased systolic and diastolic blood pressure [97]. In rat aorta, carvone had a vasorelaxant effect (Emax = 58.9%) for both enantiomers. The IC50 values for (+)-carvone in contractions induced by

Rotundifolone (RT) is a monocyclic monoterpenoid. RT (1–30 mg/kg, i.v.) had a hypotensive (partial efficacy = 51%) and bradycardic (partial efficacy = 87%) effect in non-anesthetized rats. The hypotensive effect of RT was attenuated by atropine

On isolated aorta from rats, RT inhibited contractions induced by KCl (IC50 184 μg/ml (1.1 mM)) and PHE (IC50 185 μg/ml), with maximum efficacy. As a mechanism of this effect, a possible blocking of VDCCs and of the release of Ca2+ from sarcoplasmatic reticulum by RT was suggested [58, 59]. Others also observed the vasorelaxing effect of RT in the mesenteric artery of rats contracted with PHE (pD2 = 4.0, maximum efficacy). As a mechanism for this effect, activity on TRPM8 channels, activation of large conductance Ca2+-activated K+ (BKCa) channels, and

1.8 cineole (CIN), also known as eucalyptol, in anesthetized and conscious normotensive animals, CIN (0.3–10 mg/kg, i.v.) induced hypotension, with maximum effect in 20–30 s after administration and duration of 1–5 min. This effect was independent of the autonomic nervous system, and a probable dependence on vascular relaxation was suggested [62]. CIN (0.1 mg/kg, i.p.) has been shown to

and L-NAME, suggesting the participation of muscarinic receptors in this

inactivation of VDCCs were suggested [60, 98, 99].

vasorelaxing effect, with maximum efficacy [55].

*3.4.3 Citronellal*

*Terpenes and Terpenoids-Recent Advances*

**3.5 Ketone**

*3.5.1 Carvone*

PHE was 0.62 mM [57].

*3.5.2 Rotundifolone*

effect [58].

*3.5.3 1,8-cineol*

**106**

In hypertensive rats, the linalyl acetate (LA, 10–100 mg/kg, i.p.) attenuated the increase in systolic and diastolic blood pressure. LA also modulates the expression of Endothelial NO Synthase (eNOS), preventing its suppression by ROS. This suggested a possible antihypertensive effect of LA [64, 65]. In rats with hypertension induced by chronic exposure to nicotine and stress, LA (10–100 mg/kg), had a hypotensive effect [66].

It was reported that diabetic animals exposed to chronic stress showed a reduction in endothelial function, changes in SBP and HR. LA (100 mg/kg) was able to revert these parameters to close to control values [100].

In a rabbit carotid artery, LA induced a relaxing effect on PHE-induced contraction, with partial efficacy (Emax = 88.8%) and IC50 3.6 <sup>10</sup><sup>4</sup> M. According to the authors, the cGMP-NO pathway and phosphorylation of myosin light chain, are involved in the relaxing effect of this monoterpenoid, since it was attenuated by L-NAME and ODQ [67]. It was also observed that the LA (300 μM) showed a relaxing effect of PHE-induced contraction in the aorta of mice exposed to nicotine [101].

#### **4. Final considerations**

Based on these studies, it can be concluded that the vast majority of those monoterpenes and monoterpenoids investigated and here presented have a hypotensive and vasorelaxant effect. Concerning the hypotensive effect, the studies did not include medium or long-term treatments; they were all about acute effects. In terms of results obtained, there was great variation in the repercussion on heart rate: concomitant tachycardia, in most cases, which was generally interpreted as a reflex reaction to a hypotensive effect of primary vascular origin; bradycardia or no change in heart rate in other cases. Concerning the investigation of the hypotensive effect, in terms of the methodology of administration of monoterpene or monoterpenoid, there was great variation in the route of administration employed, intraperitoneal in some cases, intravenous and oral in others, which makes comparisons more difficult. Additionally, concerning the perspective of therapeutic use, this is a relevant issue, since for long lasting treatment, as is the case with essential hypertension, the oral route of administration is largely preferable, if not mandatory.

Regarding the vasorelaxant effect, most studies describe a relaxing effect in rat aortic rings on contractions mediated by EMC and PMC and suggested, as participant in mechanism of action, based on indirect evidence, the inhibitory effect of these pharmacological agents on the activation of L type VDCC. Participation of K<sup>+</sup> and TRP ionic channels, as well as intracellular mechanisms on monoterpene and monoterpenoid-induced relaxation of contraction have been little investigated.

From the point of view of the possible therapeutic use of monoterpenes and monoterpenoids for the treatment of arterial hypertension, it can be concluded that several studies on the pressure and vascular effects have been carried out. These studies point to a potential therapeutic use for several of these agents. However, in general, they were restricted to the initial stages of a preclinical study.

*Terpenes and Terpenoids-Recent Advances*

**References**

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*DOI: http://dx.doi.org/10.5772/intechopen.94194*

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*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth…*

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10.5935/abc.20190173.

**2007**, *12*, 259–264.

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[11] Peixoto-Neves, D.; Leal-Cardoso, J. H.; Jaggar, J.H. Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage-dependent calcium channels. *J. Cardiovasc. Pharmacol.* **2014**, *64*, 401–406, doi:10.1038/

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#### **Author details**

Ana Carolina Cardoso-Teixeira<sup>1</sup> , Klausen Oliveira-Abreu<sup>1</sup> , Levy Gabriel de Freitas Brito<sup>1</sup> , Andrelina Noronha Coelho-de-Souza<sup>2</sup> and José Henrique Leal-Cardoso<sup>1</sup> \*

1 Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Ceará, Brazil

2 Laboratório de Fisiologia Experimental, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Ceará, Brazil

\*Address all correspondence to: lealcard@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Effects of Terpenes and Terpenoids of Natural Occurrence in Essential Oils on Vascular Smooth… DOI: http://dx.doi.org/10.5772/intechopen.94194*

#### **References**

[1] Cox-Georgian, D.; Ramadoss, N.; Dona, C.; Basu, C. Therapeutic and medicinal uses of terpenes. In *Medicinal Plants: From Farm to Pharmacy*; 2019; pp. 333–359 ISBN 9783030312695.

[2] Lahlou, M. Methods to Study the Phytochemistry and Bioactivity of Essential Oils. *Phyther. Res.* **2004**, *18*, 435–448.

[3] Tetali, S.D. Terpenes and isoprenoids: a wealth of compounds for global use. *Planta* **2019**, *249*, doi: 10.1007/s00425-018-3056-x.

[4] Paduch, R.; Kandefer-Szerszeń, M.; Trytek, M.; Fiedurek, J. Terpenes: substances useful in human healthcare. *Arch. Immunol. Ther. Exp. (Warsz).* **2007**, *55*, 315–327, doi:10.1007/ s00005-007-0039-1.

[5] Edris, A. Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: a review. *Phyther. Res.* **2007**, *21*, 308–323, doi:10.1002/ptr.

[6] De Andrade, T.U.; Brasil, G.A.; Endringer, D.C.; Da Nóbrega, F.R.; De Sousa, D.P. Cardiovascular activity of the chemical constituents of essential oils. *Molecules* **2017**, *22*, doi:10.3390/ molecules22091539.

[7] Lahlou, S.; Galindo, C.A.B.; Leal-Cardoso, J.H.; Fonteles, M.C.; Duarte, G.P. Cardiovascular effects of the Essential Oil of *Alpinia zerumbet* leaves and its Main Constituent, Terpinen-4 ol, in rats: Role of the Autonomic Nervous System. *Planta Med.* **2002**, *68*, 1097–1102.

[8] Vasconcelos, C.M.L.; Oliveira, I.S.N.; Santos, J.N.A.; Souza, A.A.; Menezes-Filho, J.E.R.; Silva Neto, J.A.; Lima, T.C.; de Sousa, D.P. Negative inotropism of terpenes on Guinea pig left atrium: Structure-activity relationships. *Nat.*

*Prod. Res.* **2018**, *32*, 1428–1431, doi: 10.1080/14786419.2017.1344658.

[9] Maia-Joca, R.P.M.; Joca, H.C.; Ribeiro, F.J.P.; Nascimento, R.V. Do; Silva-Alves, K.S.; Cruz, J.S.; Coelho-de-Souza, A.N.; Leal-Cardoso, J.H. Investigation of terpinen-4-ol effects on vascular smooth muscle relaxation. *Life Sci.* **2014**, *115*, 52–58, doi:10.1016/j. lfs.2014.08.022.

[10] Cardoso-Teixeira, A.C.; Ferreira-da-Silva, F.W.; Peixoto-Neves, D.; Oliveira-Abreu, K.; Pereira-Gonçalves, Á.; Coelho-de-Souza, A.; Leal-Cardoso, J. Hydroxyl Group and Vasorelaxant Effects of Perillyl Alcohol, Carveol, Limonene on Aorta Smooth Muscle of Rats. *Molecules* **2018**, *23*, 1430, doi: 10.3390/molecules23061430.

[11] Peixoto-Neves, D.; Leal-Cardoso, J. H.; Jaggar, J.H. Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage-dependent calcium channels. *J. Cardiovasc. Pharmacol.* **2014**, *64*, 401–406, doi:10.1038/ jid.2014.371.

[12] Nascimento, G.A. do; Souza, D.S. de; Lima, B.S.; Vasconcelos, C.M.L. de; Araújo, A.A. de S.; Durço, A.O.; Quintans-Junior, L.J.; Almeida, J.R.G. da S.; Oliveira, A.P.; Santana-Filho, V.J. de; et al. Bradycardic and antiarrhythmic effects of the D-limonene in rats. *Arq. Bras. Cardiol.* **2019**, *113*, 925–932, doi: 10.5935/abc.20190173.

[13] Sun, J. D-Limonene: safety and clinical applications. *Altern. Med. Rev.* **2007**, *12*, 259–264.

[14] Menezes, I.A.C.; Barreto, C.M.N.; Antoniolli, Â.R.; Santos, M.R.V.; de Sousa, D.P. Hypotensive activity of terpenes found in essential oils. *Zeitschrift fur Naturforsch. - Sect. C J. Biosci.* **2010**, *65 C*, 562–566, doi:10.1515/ znc-2010-9-1005.

**Author details**

**108**

Ana Carolina Cardoso-Teixeira<sup>1</sup>

*Terpenes and Terpenoids-Recent Advances*

and José Henrique Leal-Cardoso<sup>1</sup>

Universidade Estadual do Ceará, Ceará, Brazil

provided the original work is properly cited.

Levy Gabriel de Freitas Brito<sup>1</sup>

, Klausen Oliveira-Abreu<sup>1</sup>

\*

1 Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Laboratório de Fisiologia Experimental, Instituto Superior de Ciências

Biomédicas, Universidade Estadual do Ceará, Ceará, Brazil

\*Address all correspondence to: lealcard@gmail.com

, Andrelina Noronha Coelho-de-Souza<sup>2</sup>

,

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[101] Kim, J.R.; Kang, P.; Lee, H.S.; Kim, K.Y.; Seol, G.H. Cardiovascular effects of linalyl acetate in acute nicotine exposure. *Environ. Health Prev. Med.* **2017**, *22*, 1–7, doi:10.1186/s12199-017- 0651-6.

**117**

**Chapter 9**

**Abstract**

*Dwi Setyorini*

content in the fruit.

**1. Introduction**

plant interactions with the environment [2].

Terpenoids: Lycopene in Tomatoes

Terpenoids are compounds that only contain carbon and hydrogen, or carbon, hydrogen and oxygen that are aromatic, some terpenoids contain carbon atoms whose number is a multiple of five called isoprene units. There are many terpenoids in tomatoes, one of which is a tretrapenoid. A type of tetrapenoid, the carotenoids. Lycopene is a terpenoid found in tomatoes. Lycopene is the most carotenoid group in tomatoes. Lycopene plays a very important role in maintaining human health, including its role in the risk of chronic diseases such as cancer, heart disease, and others. The lycopene content in tomatoes depends on genetic factors, in this case the tomato variety, the environment where the tomatoes grow and the fruit storage environment, and the age of the tomatoes. The genetic factor of tomato fruit that greatly affects lycopene content in tomatoes is the color of the fruit. Color is generally an accurate indicator of lycopene content, with yellow cultivars containing less lycopene than red cultivars, and two out of three red cultivars contain more than orange cultivars. Shade tomato plants can increase the lycopene content in tomatoes. Aside from the lack of light in the tomato plant environment, the humidity and air temperature around the tomato plants also greatly affect the lycopene

**Keywords:** terpenoids, carotenoids, lycopene, genetics and environment

Terpene is a group of hydrocarbons that are produced by many plants and animals. In plants, terpenes are contained in the sap and vacuoles of cells. Hydrocarbons are commonly known as terpenes and oxygen-containing compounds called terpenoids are the most important constituents of essential oils. In plants, terpene compounds and their modification, terpenoids, are secondary metabolites. These tarpenes exist in large numbers and in a variety of molecular frameworks, but can be easily recognized by the regularity of the monomers formed from isoprene [1, 2]. Apart from being a secondary metabolite, terpenes are the building blocks of a number of important compounds for living things. Humanity has used terpenes extracted from plants for various purposes, namely as fragrances and flavorings, as pharmaceutical agents and as insecticides. Despite their great commercial value, terpene products have important biological functions in plants. The terpene metabolites are not only important for plant growth and development (eg gibberellin phytochromes) but also an important tool in various

Terpenoids are plant components that have an odor and can be isolated from plant material by distillation, known as essential oils. Essential oils derived from flowers were initially known from a simple structure determination with the ratio

#### **Chapter 9**

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[101] Kim, J.R.; Kang, P.; Lee, H.S.; Kim, K.Y.; Seol, G.H. Cardiovascular effects of linalyl acetate in acute nicotine exposure. *Environ. Health Prev. Med.* **2017**, *22*, 1–7, doi:10.1186/s12199-017-

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**116**

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