Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.
Sensory nerves play an important role in airway disease by mediating central reflexes such as cough, and local axon reflexes resulting in the peripheral release of neuropeptides. We have tested whether the benzimidazolone compound, NS1619, an opener of large conductance calcium-activated potassium (BK Ca) channels, inhibits the activity of sensory fibers, and central and local airway reflexes in guinea pig airways. In in vitro single fiber recording experiments, NS1619 applied to identified receptive fields in the trachea inhibited the firing of A(delta)-fibers evoked by hypertonic saline and distilled water, and bradykinin-evoked firing of C-fibers. Electrically evoked nonadrenergic noncholinergic contractions of isolated bronchi mediated by the release of neurokinin A (NKA) from C-fibers, but not those elicited by exogenous NKA, were inhibited by NS1619. These effects of NS1619 were prevented by iberiotoxin, a selective blocker of BK Ca channels. In conscious guinea pigs, cough evoked by aerosolized citric acid was also inhibited by NS1619. These data show that BK Ca channel activation inhibits sensory nerve activity, resulting in a reduction of both afferent and efferent function. BK Ca channel openers may therefore be of potential benefit in reducing neurogenic inflammation and central reflexes seen during inflammatory conditions of the airways, and may represent a new class of antitussive drug.
Fox
A J
AJ
Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
Barnes
P J
PJ
Venkatesan
P
P
Belvisi
M G
MG
D000344:Afferent Pathways / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D001980:Bronchi / Q000294:innervation; D001985:Bronchial Provocation Tests; D019343:Citric Acid / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced; D004525:Efferent Pathways / Q000187:drug effects; D017950:Ganglia, Sensory / Q000187:drug effects* / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D014132:Trachea / Q000294:innervation
D001562:Benzimidazoles; D010455:Peptides; D015221:Potassium Channels; C086491:NS 1619; D019343:Citric Acid; C064719:iberiotoxin; D015288:Neurokinin A; D001920:Bradykinin