Abnormal Modulation of Cholinergic Neurotransmission by Endogenous Nitric Oxide in the Bronchus of Rats with Hyperresponsiveness Induced by Allergen Challenge.

Abstract

ABSTRACT-The involvement of endogenous nitric oxide (NO) in bronchial cholinergic neurotransmission was compared between normal rats and airway hyperresponsive (AHR) rats. Male Wistar rats were sensi tized and repeatedly challenged with dinitrophenylated (DNP)-Ascaris antigen. Twenty-four hours after the last antigenic challenge, enhancements of both the electrical field stimulation (EFS)-induced bronchocon striction and acetylcholine (ACh) release were observed. NG-Monomethyl-L-arginine (L-NMMA; NO syn thase inhibitor, 0.1 mM) augmented the EFS-induced bronchoconstriction and ACh release without affect ing exogenously applied ACh-induced bronchoconstriction in normal rats. Interestingly, the augmentative effects of L-NMMA seen in normal rats were not manifested in AHR rats. Sodium nitroprusside inhibited the EFS-induced bronchoconstriction in a concentration-dependent manner; the inhibition was much larger than that of exogenously applied ACh-induced constriction in both normal and AHR rats. Furthermore, dibutyryl cGMP (3 mM) inhibited the EFS-induced bronchoconstriction with no effect on the ACh-induced bronchoconstriction in both normal and AHR rats. These findings suggest that endogenous NO may have a modulatory role in bronchial cholinergic neurotransmission in normal rats and that the augmented ACh release in the AHR rats may result from the defect of endogenous NO-induced modulation of cholinergic nerve transmission.Keywords: Airway hyperresponsiveness, Nitric oxide, Cholinergic neurotransmission, Nitrergic dysfunction, Dinitrophenylated (DNP)-AscarisNitric oxide (NO) may play an important regulatory role in airway functions as an inhibitory non-adrenergic non-cholinergic (NANC) neurotransmitter in many spe cies including humans (1-3). It has been demonstrated that neurally released NO not only relaxes tracheal smooth muscle but also inhibits acetylcholine (ACh) re lease from tracheal cholinergic nerves in rats and cats (4, 5). Furthermore, excessively produced NO from macro phages, leuckocytes and epithelium of airways may take part in airway diseases (6).Increased ACh release from cholinergic nerves may be an important mechanism that contributes to airway hyperresponsiveness in bronchial asthma (7). The ACh overrelease might be related to dysfunction of the modulatory NO pathway in cholinergic neurotransmis sion; however, the role of endogenous NO in accelerated cholinergic neurotransmission in airway hyperresponsive ness has not been confirmed.The purpose of the present study was to determine whether NO has a modulatory effect on bronchial cholinergic neurotransmission in normal rats and whether any alteration of the modulatory effect of NO takes place in airway hyperresponsiveness. We therefore investigated the effects of an NO synthase (NOS) inhibitor, NG monomethyl-L-arginine (L-NMMA), on both the choliner gic bronchoconstriction and amount of released ACh from bronchial tissue evoked by electrical field stimula tion (EFS) in normal rats and dinitrophenylated (DNP) Ascaris antigen-induced airway hyp...

Endogenous nitric oxide modulates responses of tissue and airway resistance to vagal stimulation in piglets

“…However, when NOS was blocked with L-NAME, bronchial responsiveness to histamine was enhanced only in normal animals, suggesting that the NO inhibitory pathway becomes weaker after antigen sensitization. Impairment in the iNANC-NO pathway has been also observed in the airway hyperresponsiveness of allergen-sensitized rabbits and rats exposed to hyperoxia or ferrets infected with respiratory syncytial virus (2,3,16,26), although the relevance of these observations to the developing human respiratory system remain uncertain.…”