Introduction: (E,E)-farnesol is a sesquiterpene alcohol found in essential oils (Jäger and Höferl, 2020) and has a variety of applications in the food, cosmetics and perfumery industries (Delmondes et al., 2019), showing hypotensive and vasorelaxant properties in in vivo, in vitroand ex vivo models (Roullet et al., 1996, Roullet et al., 1997a, Roullet et al., 1997b, Luft et al., 1999, Silva et al., 2021), involving calcium signaling, a critical ion for the contractile process of vascular smooth muscle cells. We hypothesize that this effect could also occur in human umbilical arteries and have important implications for the treatment of gestational hypertensive disorders.
Aims: To evaluate the influence of voltage-operated calcium channels on the myorelaxant effect of (E,E)-farnesol in human umbilical arteries.
Methods: After ethical approval (CEP/URCA, nº 3.832.881), human umbilical cord fragments from healthy women were obtained by donation. The human umbilical arteries (HUA) were then isolated and sectioned into rings (3 – 5 mm) to be suspended in an organ bath to record isometric tension. To investigate the participation of voltage-operated calcium channels (VOCC) in the myorelaxant effect of (E,E)-farnesol (Silva et al., 2020, Borges et al., 2022, Dantas et al., 2022), the HUA rings were depolarized with high potassium solution (60 mM), and then pre-incubated for 25 minutes with (E,E)-farnesol (800 µmol/L or 1 mmol/L) or nifedipine (10 µmol/L) as a positive control. Cumulative contractions were induced in the arterial preparations by CaCl2 or BaCl2 (0.1 – 20 mmol/L) at 5-minute intervals. HUA rings not exposed to (E,E)-farnesol or nifedipine were used as controls. The experimental section was conducted in calcium-free Krebs-Henseleit solution and with available calcium.
Results and discussion: In calcium-free Krebs-Henseleit solution, control rings contracted in a concentration-dependent manner with CaCl2 showed greater contractile activity (EMAX 2.16 gf) compared to control rings contracted with BaCl2 (EMAX 1.84 gf). Considering that barium ions are selective for L-type calcium channels, this shows the contribution of these channels to the contractility of HUA (Silva et al., 2020, Borges et al., 2022, Dantas et al., 2022). In Krebs-Henseleit solution with available calcium, no concentration-dependent contractile changes were observed for either ion (Ca2+ or Ba2+). (E,E)-farnesol at both concentrations tested (800 µmol/L or 1 mmol/L) inhibited contractile activity induced by Ca2+ or Ba2+, with the 800 µmol/L concentration being more effective (EMAX of Ca2+ 0.99 gf and EMAX of Ba2+ 0.95 gf), even in comparison with nifedipine (EMAX of Ca2+ 1.35 gf and EMAX of Ba2+ 1.02 gf), suggesting an inhibition of VOCC, especially of the L type to promote the myorelaxant effect in HUA. These data corroborate a previous study proposing an inhibition of L-type VOCC by (E,E)-farnesol (Luft et al., 1999). In addition, it is possible that (E,E)-farnesol has an inhibitory action on other classes of calcium channels such as the P-/Q and T-types expressed in HUA (Salemme et al., 2007).
Conclusion: Our pharmacological findings show that (E,E)-farnesol promotes a myorelaxant effect in human umbilical arteries, possibly by directly inhibiting L-type VOCC, but the inhibition of other types of VOCC (P-/Q and T) cannot be ruled out.
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).
Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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