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Am. J. Respir. Crit. Care Med., Volume 160, Number 6, December 1999, 2072-2078

Cholinergic Contraction Is Altered in nNOS Knockouts
Cooperative Modulation of Neural Bronchoconstriction by nNOS and COX

MASAHIRO KAKUYAMA, AMRITA AHLUWALIA, JOSE RODRIGO, and PATRICK VALLANCE

Centre for Clinical Pharmacology, The Rayne Institute, University College London, London, United Kingdom; and Instituto Cajal, Madrid, Spain

Endogenous nitric oxide (NO) is a bronchodilator but its physiologic role in small airways is not clear. In this study, we investigated the role of endogenous NO in the regulation of bronchiolar tone in the small airways of wild type and NO synthase (NOS) isoform (eNOS and nNOS)-knockout mice. Pretreatment with the cyclooxygenase inhibitor indomethacin significantly enhanced electrical field stimulation (EFS)-induced contraction in the airways from all types of mice by approximately 60 to 170% (n = 8 in each case), whereas pretreatment with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) did not (n = 8). Combined pretreatment with L-NAME and indomethacin enhanced airway contraction of wild-type and eNOS-knockout mice to a significantly 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 knockout mice (n = 8). Neither indomethacin nor L-NAME alone affected carbachol (CCh) potency or maximal efficacy in the airways of wild-type mice, whereas the combined pretreatment slightly enhanced the maximal response without altering the potency of CCh (n = 6). Our results show that both NO and prostaglandins modulate neuronal contraction of murine small airways. NO is produced by nNOS, which may be located in nerves, and its overall effects are tonically inhibited by cyclooxygenase products. Kakuyama M, Ahluwalia A, Rodrigo J, Vallance P. Cholinergic contraction is altered in nNOS knockouts: cooperative modulation of neural bronchoconstriction by nNOS and COX.




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