Introduction: (E,E)-farnesol is a metabolite of the sesquiterpenoid class present in plant essential oils (Sell, 2009). In addition to being recognized by the US Food and Drug Administration as GRAS (Generally Recognized as Safe) (FDA, 21 CFR 172.515, Lapczynski et al., 2008), previous studies have reported that (E,E)-farnesol has vasorelaxant and hypotensive potential in different experimental models (Roullet et al., 1996, Roullet et al., 1997a, Roullet et al., 1997b, Luft et al., 1999, Silva et al., 2021). In this sense, we explored the relaxing effect of (E,E)-farnesol on human umbilical veins, making it possible to highlight its therapeutic potential for gestational hypertensive and metabolic disorders that directly affect these vessels, and consequently compromise fetal survival (Djokic et al., 2020).
Aims: To characterize the involvement of voltage-operated calcium channels in the relaxing effect of (E,E)-farnesol in human umbilical veins.
Methods: Ethical approval was initially obtained (CEP/URCA, nº 3.832.881) to carry out the experiments. Segments of human umbilical cord were collected from parturients without complications in the prepartum period, with their written informed consent. In the laboratory, these segments were carefully dissected to remove the attached tissues and isolate the human umbilical veins (HUV). Subsequently, these vessels were cut into rings (3 – 5 mm) and mounted in an organ bath coupled to isometric force transducers. To investigate the involvement of voltage-operated calcium channels (VOCC) in the relaxing effect of (E,E)-farnesol (Silva et al., 2020, Borges et al., 2022, Dantas et al., 2022), the HUV rings were pre-contracted with Krebs-Henseleit solution with potassium chloride (60 mM) in its composition. The rings were then pre-incubated (25 min) with (E,E)-farnesol (800 µmol/L or 1 mmol/L) or nifedipine (10 µmol/L) used as a reference control. Venous preparations were cumulatively contracted with CaCl2 or BaCl2 (0.1 – 20 mmol/L) at addition intervals every 5 min, at each new concentration. HUV rings not exposed to (E,E)-farnesol or nifedipine were reserved as controls. The set of experiments was carried out in Krebs-Henseleit solution with and without calcium in the composition.
Results and discussion: In calcium-free medium, CaCl2 induced concentration-dependent contractions with greater amplitude (EMAX 3.80 gf) than BaCl2 (EMAX 2.37), these data revealing the activity of calcium channels in HUV. In a medium with available calcium, no significant changes in HUV contractility were observed in the presence of Ba2+, indicating that these ions permeate L-type VOCC better in the absence of Ca2+ in the medium (Silva et al., 2020, Borges et al., 2022). The nifedipine used as a reference, as expected, inhibited contractions induced by both Ca2+ (EMAX 2.52 gf) and Ba2+ (EMAX 0.80 gf), showing its selectivity for L-type VOCC. In general, (E,E)-farnesol (800 µmol/L or 1 mmol/L) reduced the amplitude of the contraction in response to Ba2+, similar to nifedipine, suggesting a common mechanism, such as inhibition in L-type VOCC, this property having already been observed previously for (E,E)-farnesol (Luft et al., 1999). The concentration of 1 mmol/L of (E,E)-farnesol showed greater efficacy (EMAX 1.16 gf) than nifedipine (EMAX 2.52 gf) in suppressing the response to Ca2+, based on these results it is plausible to suggest that (E,E)-farnesol blocks other types of VOCC (not only L-type) to induce relaxation in HUV, such as T-type VOCC involved in contractile responses in HUV (He et al., 2016).
Conclusion: The data presented support the hypothesis that (E,E)-farnesol inhibits the contractile response of human umbilical veins through a direct blockade of L-type VOCC, although it is likely that this inhibitory action may extend to other types of VOCC.
Acknowledgment: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) e Financiadora de Estudos e Projetos (FINEP).
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Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
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