Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease

doi:10.1016/S0024-3205(01)01487-4

Life Sciences

Volume 70, Issue 9, 18 January 2002, Pages 977-990

https://doi.org/10.1016/S0024-3205(01)01487-4 Get rights and content

Abstract

Airway smooth muscle (ASM) cells express various types of potassium (K⁺) channels which play a key role in determining the resting membrane potential, a relative electrical stability and the responsiveness to both contractile and relaxant agents. In addition, K⁺ channels are also involved in modulation of neurotransmitter release from airway nerves. The most important K⁺ channels identified in airways include large and small Ca²⁺-activated, delayed-rectifier, and ATP-sensitive channels. These K⁺ channels are structurally and functionally different, thus playing distinct roles in airway electrophysiology and pharmacology. Many in vitro and in vivo studies, performed in both animals and humans, have shown that K⁺ channel openers are able to induce hyperpolarization of ASM cells, bronchodilation, suppression of airway hyperresponsiveness (AHR), and inhibition of neural reflexes. Therefore, airway K⁺ channels represent a suitable pharmacological target for the development of new effective therapeutic options in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

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Cited by (63)

Supplemental treatment to atropine improves the efficacy to reverse nerve agent induced bronchoconstriction
2022, Chemico-Biological Interactions
Exposure to highly toxic organophosphorus compounds causes inhibition of the enzyme acetylcholinesterase resulting in a cholinergic toxidrome and innervation of receptors in the neuromuscular junction may cause life-threatening respiratory effects. The involvement of several receptor systems was therefore examined for their impact on bronchoconstriction using an ex vivo rat precision-cut lung slice (PCLS) model. The ability to recover airways with therapeutics following nerve agent exposure was determined by quantitative analyses of muscle contraction.
PCLS exposed to nicotine resulted in a dose-dependent bronchoconstriction. The neuromuscular nicotinic antagonist tubocurarine counteracted the nicotine-induced bronchoconstriction but not the ganglion blocker mecamylamine or the common muscarinic antagonist atropine. Correspondingly, atropine demonstrated a significant airway relaxation following ACh-exposure while tubocurarine did not. Atropine, the M3 muscarinic receptor antagonist 4-DAMP, tubocurarine, the β₂-adrenergic receptor agonist formoterol, the Na⁺-channel blocker tetrodotoxin and the K⁺_ATP-channel opener cromakalim all significantly decreased airway contractions induced by electric field stimulation. Following VX-exposure, treatment with atropine and the Ca²⁺-channel blocker magnesium sulfate resulted in significant airway relaxation. Formoterol, cromakalim and magnesium sulfate administered in combinations with atropine demonstrated an additive effect.
In conclusion, the present study demonstrated improved airway function following nerve agent exposure by adjunct treatment to the standard therapy of atropine.
Pharmacological evaluation of Euphorbia hirta, Fagonia indica and Capparis decidua in hypertension through in-vivo and in vitro-assays
2021, Heliyon
Citation Excerpt :
K+ (Kdr) channels are blocked by 4-aminopyridine and participate significantly in the initiation of resting membrane potential. The inward rectifier K+ (Kir) channels are inhibited by Ba++ (50 μM for Kir channel), whereas TEA (30 μM) is considered as non-specific blocker [41, 42]. To attest the existence of any vasoconstrictor constituent within the tested material(s), assays were accomplished over the resting baseline tension of aortae.
This study determines the efficacy and probable underlying mode of action to the folk usage of Euphorbia hirta, Fagonia indica and Capparis decidua in hypertension.
The aqueous-methanol extracts of E. hirta (EH.Cr), F. indica (FI.Cr) and C. decidua (CD.Cr) were tested for antihypertensive effects in rats using non-invasive and in-vasive blood pressure measuring apparatus. In-vitro assays were carried out using isolated rat aortae using PowerLab station.
EH.Cr, FI.Cr and CD.Cr at 500 mg/kg (orally) caused a fall in the mean systolic blood pressure in arsenic-induced hypertensive and normotensive rats, similar to nifedipine. In rat aortae, EH.Cr, CD.Cr and FI.Cr reversed low (20 mM), high (80 mM) K⁺ and phenylephrine (P.E)-driven contractions, while F. indica partially inhibited high K⁺ contractions. In the presence of TEA, F. indica remained unable to relax low K⁺ contractions. EH.Cr and CD.Cr moved Ca⁺⁺ concentrations response curves to the right, like nifedipine. All fractions of EH.Cr and CD.Cr except aqueous, pet-ether and chloroform fractions of FI.Cr displayed Ca⁺⁺ antagonistic activity. FI.Cr, its ethyl acetate and aqueous fraction exhibited TEA-sensitive potassium channel activation. On baseline tension, test materials also produced phentolamine-sensitive vasospasm.
E. hirta, F. indica and C. decidua possess antihypertensive activity in arsenic-induced hypertensive rats possibly mediated via endothelium-dependent vasorelaxation. In normotensive rats, E. hirta and C. decidua showed antihypertensive activities through endothelium-dependent and Ca⁺⁺ antagonistic pathways, while F. indica exhibited potassium channel activation and Ca⁺⁺ antagonistic like effects in its vasorelaxation. Additional weaker vasospastic effects were derived through α-adrenergic like pathways.
Investigation of the relaxing effect of a camphor nanoemulsion on rat isolated trachea
2021, Chemico-Biological Interactions
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 pCE₅₀ 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 pCE₅₀.
As conclusion, NEC may be involved with β-adrenergic receptors, channels for K⁺ sensitive to ATP (K_ATP) or Channels for K+ opened by Ca²⁺ (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), Ca²⁺-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.
Relaxant effect of Lippia origanoides essential oil in guinea-pig trachea smooth muscle involves potassium channels and soluble guanylyl cyclase
2018, Journal of Ethnopharmacology
Citation Excerpt :
It is known that the control of membrane voltage by K+ channels serves as a negative feedback to oppose voltage-dependent calcium influx pathways that contribute to airway smooth muscle (ASM) contraction. K+ channel openers may be useful as bronchodilators for asthma since ASM hyperpolarization by K+ efflux can partly induce relaxation (Pelaia et al., 2002). K+ channels expressed in ASM include Ca2+- and voltage-activated K+ (KCa) channels; a number of low conductance, voltage-dependent K+ channels belonging to a large and diverse gene family and functionally resembling classical delayed rectifier (Kdr channels); ATP-sensitive K+ (KATP) channels, whose activity is increased when the concentration of ATP falls at the cytosolic channel surface; and inwardly rectifying K+ channels (KIR) and voltage-gated (Kv) channels (Brueggemann et al., 2011; Kotlikoff and Kamm, 1996).
Lippia origanoides H.B.K. is an aromatic species used in folk medicine to treat respiratory diseases, including asthma.
The aim of this work was to evaluate the relaxing potential and mechanism of action of the L. origanoides (LOO) essential oil in isolated guinea-pig trachea.
Leaves from L. origanoides were collected at experimental fields under organic cultivation, at the Forest Garden of Universidade Estadual de Feira de Santana. Essential oil was extracted by hydrodistillation, analyzed by GC/FID and GC/MS and the volatile constituents were identified. Spasmolytic activity and relaxant mechanism of LOO were assayed in isolated guinea-pig trachea contracted with histamine, carbachol or hyperpolarizing KCl.
Chemical analysis revealed the presence of carvacrol (53.89%) as major constituent. LOO relaxed isolated guinea-pig trachea pre-contracted with KCl 60 mM [EC₅₀ = 30.02 μg/mL], histamine 1 µM [EC₅₀ = 9.28 μg/mL] or carbachol 1 µM [EC₅₀ = 51.80 μg/mL]. The pre-incubation of glibenclamide, CsCl, propranolol, indomethacin, hexamethonium, aminophylline or L-NAME in histamine-induced contractions did not alter significantly the relaxant effect of LOO. However, the presence of 4-aminopyridine, tetraethylammonium or methylene blue reduced LOO effect, while the presence of dexamethasone or atropine potentialized the LOO relaxant effect. LOO pre-incubation inhibited carbachol-evoked contractions, with this effect potentialized in the presence of sodium nitroprusside and blocked in the presence of ODQ.
The relaxant mechanism of LOO on the tracheal smooth muscle possibly involves stimulating of soluble guanylyl cyclase with consequent activation of the voltage-gated and Ca²⁺-activated K⁺ channels.
The vasorelaxant effect of 8(17),12E,14-labdatrien-18-oic acid involves stimulation of adenylyl cyclase and cAMP/PKA pathway: Evidences by pharmacological and molecular docking studies
2015, European Journal of Pharmacology
The relaxant effect of 8(17),12E,14-labdatrien-18-oic acid (LBD) was investigated on isolated aortic rings and compared with forskolin (FSK), a standard and potent activator of adenylyl cyclase (AC) with relaxing effect. The presence of potassium channel blockers, such as glibenclamide (ATP-blocker), apamin (SK_Ca-blocker), charybdotoxin (BK_Ca-blocker) did not significantly affect either the LBD or FSK concentration-response curves. However, in the presence of 4-aminopyridine (K_V-blocker), the relaxant effect for both diterpenes was significantly attenuated, with reduction of its relative potencies. Moreover, the relaxation induced by 8-Br-cAMP, an analog of cAMP, was also significantly attenuated in the same conditions, i.e., in the presence of 4-aminopyridine. The presence of aminophylline, a nonselective phosphodiesterase inhibitor, caused a significant increasing in the potency for both LBD and FSK. On the other hand, the presence of Rp-cAMPS, a selective PKA-inhibitor, significantly attenuated the relaxant effect of LBD. In this work, in the same experimental conditions, both labdane-type diterpenes presented remarkably similar results; FSK, however, presented a higher potency (100-fold) than LBD. Thus, the hypothesis that LBD could be a novel AC-activator emerged. To assess that hypothesis, computational molecular docking studies were performed. Crystallographic structure of adenylyl cyclase/forskolin complex (1AB8) was obtained from RSCB Protein Data Bank and used to compare the modes of interaction of the native ligand and LBD. The computational data shows many similarities between LBD and FSK concerning the interaction with the regulatory site of AC. Taken together, the results presented here pointed to LBD as a novel AC-activator.
Ion channels in asthma
2011, Journal of Biological Chemistry
Citation Excerpt :
ASM plays a central role in BHR and remodeling (58) and has being the subject of intense research to identify the molecular mechanisms participating in its contraction, proliferation, and migration. Ion channels facilitating ASM contraction aim to increase overall intracellular Ca2+ concentration (e.g. VGCCs (59)), whereas those favoring bronchodilatation generally produce the opposite effect (e.g. potassium channels (60)). The role of ion channels in ASM contraction and asthma pathophysiology has been critically reviewed (61, 62), and the initial emphasis on VGCC blockers and potassium channel openers has not been warranted by their success in clinical trials (Refs. 14 and 63 and references within).
Ion channels are specialized transmembrane proteins that permit the passive flow of ions following their electrochemical gradients. In the airways, ion channels participate in the production of epithelium-based hydroelectrolytic secretions and in the control of intracellular Ca²⁺ levels that will ultimately activate almost all lung cells, either resident or circulating. Thus, ion channels have been the center of many studies aiming to understand asthma pathophysiological mechanisms or to identify therapeutic targets for better control of the disease. In this minireview, we focus on molecular, genetic, and animal model studies associating ion channels with asthma.

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Original articlesPotential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease

Abstract

Original articles
Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease