title: Role of endogenous NO in modulating airway contraction mediated by muscarinic receptors during development.
abstract: We sought to characterize the role of endogenous nitric oxide (NO) released from airway epithelium in attenuating tracheal smooth muscle (TSM) contraction induced by exposure to acetylcholine (ACh). Organ bath experiments were performed on TSM from young pigs of three ages (3-7 days, 2-3 wk, and 3 mo). Concentration-response curves to cumulative doses of ACh (10(-8) to 10(-4) M) were generated before and after addition of the NO synthase blocker N omega-nitro-L-arginine methyl ester (L-NAME). L-NAME caused a significant increase in cholinergic sensitivity (decrease in 50% effective dose) at 3-7 days and 2-3 wk but not 3 mo. Maximum responses to ACh increased after L-NAME at all three ages. Removal of tracheal epithelium caused a significant increase in sensitivity to ACh at all ages, which progressively declined with advancing age. In the absence of epithelium, L-NAME no longer influenced contractile responses to ACh. Density of M3 muscarinic receptors in tracheal epithelium was upregulated in the youngest piglets. We conclude that, under in vitro conditions, release of endogenous NO opposes cholinergically induced contraction of piglet TSM. This phenomenon diminishes with advancing postnatal age, requires an intact airway epithelium, and correlates with upregulation of M3 muscarinic receptors in airway epithelium. We speculate that NO may play a useful role in attenuating cholinergically mediated airway smooth muscle contraction in early life when pulmonary function is characterized by high airway resistance.
authors.affiliation: Department of Pediatrics, Rainbow Babies and Childrens Hospital, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-6010, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jakupaj
authors.forename: R J
authors.initials: RJ
authors.lastname: Martin
authors.forename: I A
authors.initials: IA
authors.lastname: Dreshaj
authors.forename: C F
authors.initials: CF
authors.lastname: Potter
authors.forename: M A
authors.initials: MA
authors.lastname: Haxhiu
authors.forename: P
authors.initials: P
authors.lastname: Ernsberger
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000375:Aging / Q000502:physiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009092:Mucous Membrane / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D024510:Muscle Development; D009130:Muscle, Smooth / Q000254:growth & development / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D014132:Trachea / Q000254:growth & development / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester