Am. J. Respir. Crit. Care Med., Volume 165, Number 4, February 2002, 481-488

Nitric Oxide-dependent Modulation of Smooth-Muscle Tone by Airway Parasympathetic Nerves

BRANKO S. KESLER, STUART B. MAZZONE, and BRENDAN J. CANNING

Department of Medicine, The Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland

We addressed the hypothesis that noncholinergic parasympathetic nerves modulate airway smooth-muscle (ASM) tone in guinea pigs. The NO synthase inhibitor L-N^G-nitro-arginine (L-NNA) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) potentiated cholinergic contractions and partly inhibited noncholinergic relaxations of the trachealis evoked by nerve stimulation in vitro or in situ. When delivered selectively to the trachea in situ, L-NNA and ODQ also increased baseline cholinergic tone of the trachealis, and L-NNA potentiated histamine-induced contractions of the trachealis in situ. L-Arginine prevented the effects of L-NNA. Vagotomy or selective nerve blockade with tetrodotoxin (TTX) mimicked the effects of L-NNA on histamine responses. The effects of TTX and L-NNA were not additive, however, suggesting that the two agents have common mechanisms of action, and indicating that other nonadrenergic, noncholinergic relaxant neurotransmitters lack influence under baseline conditions. When reflexly activated by bradykinin, noncholinergic parasympathetic nerves partly reversed histamine-induced contractions of the trachealis. L-NNA failed to inhibit this response, however, and did not potentiate the reflex tracheal cholinergic contractions produced by bradykinin. These results show that noncholinergic parasympathetic nerves modulate ASM tone. The NO-dependent component of this response is most effective at baseline levels of nerve activity.

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