Cholinergic contraction is altered in nNOS knockouts - Cooperative modulation of neural bronchoconstriction by nNOS and COX

Endogenous nitric oxide (NO) is a bronchodilator but its physiologic role i n small airways is not clear. In this study, we investigated the role of en dogenous NO in the regulation of bronchiolar tone in the small airways of w ild type and NO synthase (NOS) isoform (eNOS and nNOS)-knockout mice. Pretr eatment with the cyclooxygenase inhibitor indomethacin significantly enhanc ed electrical field stimulation (EFS)-induced contraction in the airways fr om all types of mice by approximately 60 to 170% (n = 8 in each case), wher eas pretreatment with the NOS inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME) did not (n = 8). Combined pretreatment with L-NAME and indomethaci n enhanced airway contraction of wild-type and eNOS-knockout mice to a sign ificantly greater extent (i.e., by 140 to 290%) than did indomethacin alone (n = 8 for each). This potentiation by L-NAME was not seen in nNOS knockou t mice (n = 8). Neither indomethacin nor L-NAME alone affected carbachol (C Ch) potency or maximal efficacy in the airways of wild-type mice, whereas t he combined pretreatment slightly enhanced the maximal response without alt ering the potency of CCh (n = 6). Our results show that both NO and prostag landins modulate neuronal contraction of murine small airways. NO is produc ed by nNOS, which may be located in nerves, and its overall effects are ton ically inhibited by cyclooxygenase products.