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Asthma is a chronic inflammatory disease that targeting lower airways, being characterized by bronchial smooth muscle hyper responsiveness and mucus hypersecretion. Asthma is considered the most common respiratory disease in the world, affecting approximately 235 million individuals. The main therapy sometimes fails to establish clinical improvement in patients, which leads to a constant search for new alternatives. Camphor is a transparent solid monoterpene with a strong aroma, which due to its high lipophilicity is insoluble in water. Nanostructured carrier systems have shown promise as a delivery system for lipophilic compounds such as monoterpenes. Therefore, the objective of this work was to evaluate the relaxant effect of nanoemulsified camphor (NEC), as well as the mechanism of action of that monoterpene, in isolated rat trachea. The results obtained demonstrated that NEC promote relaxation of the isolated rat trachea when smooth muscle contraction was induced by both carbachol (CCh) and KCl, presenting a pCE 50 of 2.25 ± 0.27 and 3.30 ± 0.07, respectively. In the presence of dexamethasone (DEXA), tetraethylammonium (TEA), glibenclamide (GLIB), 1H-[1,2,4]-oxadiazole-[4,3,-a]-quinoxaline-1-one (ODQ) and ruthenium red (RR) there was a significant difference in at least one of the evaluated pharmacological parameters, such as concentration-response curves shape, E max or pCE 50 . As conclusion, NEC may be involved with β-adrenergic receptors, channels for K + sensitive to ATP (K ATP ) or Channels for K+ opened by Ca 2+ (K Ca ), increase in prostanoids and with receptor channel with transient potential (TRPv). In conclusion, β-adrenergic receptors, prostanoids, nitric oxide (NO), ATP-sensitive K + channels (K ATP ), Ca 2+ -opened K + channels (K Ca ), and transient receptor potential cation channel subfamily V (TRPV) are involved in the relaxing effect of NEC. In addition, the mechanism of action of NEC may be involved with the signal transduction pathway Nitric Oxide/soluble guanylyl cyclase/cGMP/cGMP-activated protein kinase. NEC, therefore, demonstrates spasmolytic activity when presenting tracheal relaxation compared to CCh and KCl contracturants., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the field of experimental pharmacology, researchers continuously investigate new relaxant agents of the airway smooth muscle cells (ASMCs), since the pathophysiology of respiratory illnesses, such as asthma, involves hyperresponsiveness and changes in ASMC homeostasis. In this scenario, labdane-type diterpenes, like forskolin (FSK), are a class of compounds known for their relaxing action on smooth muscle cells (SMCs), being this phenomenon related to the direct activation of AC-cAMP-PKA pathway. Considering the continuous effort of our group to study the mechanism of action and prospecting for compounds isolated from natural sources, in this paper, we presented how the diterpene 8(17),12E,14-labdatrien-18-oic acid (LBD) promotes relaxant effect on ASMC, performing in vitro experiments using isolated guinea pig trachea and in silico molecular docking/dynamics simulations. In vitro experiments showed that in the presence of aminophylline, FSK and LBD had their relaxant effect potentiated (EC 50 from 1.4 ± 0.2 × 10 -5 M to 1.5 ± 0.3 × 10 -6 M for LBD and from 2.0 ± 0.2 × 10 -7 M to 6.4 ± 0.4 × 10 -8 M for FSK) while in the presence of Rp-cAMPS this effect was attenuated (EC 50 from 1.4 ± 0.2 × 10 -5 M to 3 × 10 -4 M for LBD and from 2.0 ± 0.2 × 10 -7 to 3.1 ± 1.0 × 10 -6 M for FSK). Additionally, in silico simulations evidenced that the lipophilic character of LBD is probably responsible for its stability on AC binding site. LBD presented two preferential orientations, where the double bonds of the isoprene moiety as well as the unique polar group (carboxylic acid) in this compound form important anchoring points. In this sense, we consider that the LBD can interact stabilizing the catalytic dimmer of AC as the FSK, although less efficiently.

Ethnopharmacological Relevance: Lippia alnifolia Mart. & Schauer, known as "alecrim-do-mato", "alecrim-de-vaqueiro" and "pedrécio", is used in folk medicine as antiseptic and to treat diseases that affect respiratory system, like bronchitis and asthma., Aim of the Study: The aim of this work was to investigate the spasmolytic activity and relaxant mechanism of the Lippia alnifolia essential oil (EOLA) on isolated guinea-pig trachea and to correlate with its use in folk medicine., Materials and Methods: Leaves from L. alnifolia were collected in Pico das Almas, Chapada Diamantina, situated in the city of Rio de Contas, Bahia, Brazil. EOLA was extracted by hydrodistillation, analyzed by GC/FID and GC/MS and the volatile constituents were identified. Spasmolytic activity was assayed in isolated guinea-pig trachea pre-contracted with carbachol 1 μM or histamine 10 μM. Relaxant mechanism of EOLA was determined comparing concentration-response curves in the presence or absence of different blockers., Results: Chemical analysis revealed the presence of carvone (60 ± 0.8%) as major constituent. EOLA (1-243 μg/mL) relaxed isolated guinea-pig trachea pre-contracted with carbachol 1 μM [EC 50  = 53.36 (44.75-63.51) μg/mL] or histamine 10 μM [EC 50  = 5.42 (4.42-6.65) μg/mL]. The pre-incubation of 4-aminopyridine in histamine-induced contractions did not alter significantly the relaxant effect of EOLA. However, the presence of cesium chloride, glibenclamide, tetraethylammonium, propranolol, indomethacin, dexamethasone, hexamethonium, atropine, L-NAME, methylene blue or ODQ reduced EOLA relaxant effect. EOLA 18 μg/mL pre-incubation in calcium-free medium reduced histamine-evoked contractions, but did not alter histamine contractions in the presence of nifedipine., Conclusions: Lippia alnifolia essential oil has spasmolytic activity on isolated guinea-pig trachea and its mechanism of action possibly involves the activation of multiple signal transduction pathways, which culminate in potassium channels activation and cytosolic calcium reduction., (Copyright © 2019 Elsevier B.V. All rights reserved.)