This Article Full Text Full Text (PDF) All Versions of this Article: 2006-0389OCv1 37/3/357    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tamada, T. Articles by Hattori, T. Search for Related Content PubMed PubMed Citation Articles by Tamada, T. Articles by Hattori, T.

A Potentiating Effect of Endogenous NO in the Physiologic Secretion from Airway Submucosal Glands

Department of Infectious and Respiratory Diseases, Department of Comprehensive Medicine, and Department of Cardiovascular Medicine, Tohoku University School of Medicine, Sendai, Japan

Correspondence and requests for reprints should be addressed to Tsutomu Tamada, M.D., Ph.D., Department of Infectious and Respiratory Diseases, Tohoku University School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai 980–8574, Japan. E-mail: tamada{at}rid.med.tohoku.ac.jp

It is known that several second messengers, such as Ca²⁺ or cAMP, play important roles in the intracellular pathway of electrolyte secretion in tracheal submucosal gland. However, the participation of cGMP, and therefore nitric oxide (NO), is not well understood. To investigate the physiologic role of NO, we first examined whether tracheal glands can synthesize NO in response to acetylcholine (ACh), and then whether endogenous NO has some effects on the ACh-triggered ionic currents. From the experiments using the NO-specific fluorescent indicator 4,5-diaminofluorescein diacetate salt (DAF-2DA), we found that a physiologically relevant low dose of ACh (100 nM) stimulated the endogenous NO synthesis, and it was almost completely suppressed in the presence of the nonspecific NO synthase (NOS) inhibitor N-Nitro-L-arginine Methyl Ester Hydrochloride (L-NAME) or the neuronal NOS (nNOS)-specific inhibitor 7-Nitroindazole (7-NI). Patch-clamp experiments revealed that both the NOS inhibitors (L-NAME or 7-NI) and cGK inhibitors (KT-5823 or Rp-8-Br-cGMP) partially decreased ionic currents induced by 30 nM of ACh, but not in the case of 300 nM of ACh. Our results indicate that NO can be synthesized through the activation of nNOS endogenously and has potentiating effects on the gland secretion, under a physiologically relevant ACh stimulation. When cells were stimulated by an inadequately potent dose of ACh, which caused an excess elevation in [Ca²⁺]_i, the cells were desensitized. Therefore, due to NO, gland cells become more sensitive to calcium signaling and are able to maintain electrolyte secretion without desensitization.

Key Words: cholinergic receptor • calcium • chloride secretion • Clca • Kca

CLINICAL RELEVANCE Nitric oxide works as one of the second messengers in the physiologic electrolyte secretion from airway submucosal glands. This pathway may become a new therapeutic target for not only hypersecretion of chronic bronchitis or bronchial asthma, but also dehydration of airway mucosa in cystic fibrosis.