Action of neltenexine on anion secretion in human airway epithelia

Division of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kioto, Kyōto, Japan
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 05/2007; 356(4):1050-5. DOI: 10.1016/j.bbrc.2007.03.095
Source: PubMed


Neltenexine has been applied to human lung diseases such as chronic obstructive pulmonary disease (COPD) as a mucolytic agent. However, we have no information on the neltenexine action in bronchial epithelial cells. We studied the neltenexine action on the ion transport in human submucosal serous Calu-3 cells. Under a hyper-secreting condition caused by terbutaline (a beta2-adrenergic agonist), neltenexine diminished anion secretion by inhibiting the Cl- and HCO3- uptake via Na+/K+/2Cl- cotransporter and Na+/HCO3- cotransporter without blockade of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, and also diminished anion secretion via stimulation of Cl-/HCO3- exchanger, which facilitates the extrusion of more CFTR-permeant anion, Cl-, with the uptake of less CFTR-permeant anion, HCO3-. Thus, neltenexine reduced the hyper-secretion to keep an appropriate fluid level in the airway, providing a possibility that neltenexine can be an effective drug in airway obstructive diseases by decreasing the airway resistance under a hyper-secreting condition.

343 Reads
  • Source
    • "Then, solution A was set in the chambers as the apical and basolateral solutions stirred with 21% O 2 /79% N 2 . The transepithelial potential (V t ) was continuously measured by a high-impedance milivoltmeter that could function as a voltage clamp with automatic fluid resistance compensation (VCC-600, Physiologic Instrument, San Diego, CA, USA) [14] [15] [16] [17]. We measured a transepithelial conductance (G) using the previously reported method [18– 20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, we investigated the effect of osmolality on the paracellular ion conductance (Gp) composed of the Na+ conductance (GNa) and the Cl� conductance (GCl). An osmotic gradient generated by NaCl with relatively apical hypertonicity (NaCl-absorption-direction) induced a large increase in the GNa associated with a small increase in the GCl, whereas an osmotic gradient generated by NaCl with relatively basolateral hypertonicity (NaCl-secretion-direction) induced small increases in the GNa and the GCl. These increases in the Gp caused by NaCl-generated osmotic gradients were diminished by the application of sucrose canceling the NaCl-generated osmotic gradient. The osmotic gradient generated by apical application of sucrose without any NaCl gradients had little effects on the Gp. However, this apical application of sucrose produced a precondition drastically quickening the time course of the action of the NaCl-generated osmotic gradient on the Gp. Further, we found that application of the basolateral hypotonicity generated by reduction of NaCl concentration shifted the localization of claudin-1 to the apical from the lateral side. These results indicate that the osmotic gradient regulates the paracellular ion conductive pathway of tight junctions via a mechanism dependent on the direction of NaCl gradients associated with a shift of claudin-1 localization to the apical side in renal A6 epithelial cells.
    Biochemical and Biophysical Research Communications 03/2008; 366(2):464-70. DOI:10.1016/j.bbrc.2007.11.167 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nasal cavity and paranasal sinus have various functions. However, little information is available on ion transport in these upper airway epithelia. In the present study, we measured the anion secretion and the anion channel activity to characterize the ion transport in epithelial cells prepared from human paranasal sinus mucosa (PSM) and nasal polyp (NP). To estimate the anion secretion and the anion channel activity, we measured the short-circuit current (Isc) and the transepithelial conductance (Gt) sensitive to NPPB (a Cl(-) channel blocker). The NPPB-sensitive Isc in PSM was larger than that in NP, correlating to the NPPB-sensitive Gt (Cl(-) channel activity). Forskolin stably elevated the NPPB-sensitive Isc associated with an increase in the NPPB-sensitive Gt in PSM and NP. UTP transiently stimulated the Isc associated with an elevation of Gt in PSM and NP. The stimulatory action of UTP on Isc and Gt was diminished by application of NPPB but not benzamil in PSM and NP, suggesting that UTP induced the NPPB-sensitive Isc (Cl(-) secretion) and Gt (Cl(-) channel activity). These observations suggest that in human PSM and NP, cAMP stably stimulates anion secretion by activating the Cl(-) (anion) channels, and that UTP just transiently elevates anion secretion via activation of some Cl(-) (anion) channels.
    American Journal of Respiratory Cell and Molecular Biology 05/2007; 36(4):466-72. DOI:10.1165/rcmb.2006-0064OC · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of the present study is to characterize the ENaC-mediated Na+ absorption in human upper airway epithelia, nasal cavity, and paranasal sinus. To perform the purpose, we obtained epithelial cells from human nasal polyp (NP) and paranasal sinus mucosa (PSM) by endoscopic surgery. We measured the short-circuit current (I(sc)) sensitive to benzamil (a specific ENaC blocker). The benzamil-sensitive I(sc) (Na+ absorption) in NP was larger than that in PSM. The mRNA expression of three subunits of ENaC was as follows: alpha>beta>gamma in both tissue, NP and MS. The mRNA expression of gamma subunit of ENaC in NP was larger than that in PSM, but no difference of mRNA expression of alpha or beta ENaC subunit between NP and PSM was detected. We found correlation of the Na+ absorption to mRNA expression of gamma ENaC in NP and PSM. Forskolin diminished the Na+ absorption associated with an increase in Cl- secretion. These observations suggest that: (1) human NP absorbs more ENaC-mediated Na+ than PSM, (2) expression of gamma ENaC in plays a key role in the ENaC-mediated Na+ absorption in NP and PSM, and (3) cAMP diminishes the ENaC-mediated Na+ absorption by stimulating Cl- secretion (diminution of driving force for Na+ absorption) in NP and PSM.
    Biochemical and Biophysical Research Communications 11/2007; 362(3):753-8. DOI:10.1016/j.bbrc.2007.08.065 · 2.30 Impact Factor
Show more