Document Detail

Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels.
MedLine Citation:
PMID:  23420659     Owner:  NLM     Status:  MEDLINE    
The role of nitric oxide (NO) in regulating lymphatic contractile function and, consequently, lymph flow has been the subject of intense study. Despite this, the precise effects of NO on lymphatic contractile activity remain unclear. Recent hypotheses posit that basal levels of endogenous NO increase lymphatic contraction strength as a consequence of lowering frequency (i.e. positive lusitropy), whereas higher agonist-evoked concentrations of NO exert purely inhibitory effects on contractile function. We tested both hypotheses directly by isolating and cannulating collecting lymphatic vessels from genetically modified mice for ex vivo study. The effects of basal NO and agonist-evoked NO were evaluated, respectively, by exposing wild-type (WT), endothelial NO synthase (eNOS)(-/-) and inducible NO synthase (iNOS)(-/-) lymphatic vessels to controlled pressure steps followed by ACh doses. To compare with pharmacological inhibition of eNOS, we repeated both tests in the presence of l-NAME. Surprisingly, genetic removal of basal NO enhanced contraction amplitude significantly without increasing contraction frequency. Higher levels of NO production stimulated by ACh evoked dilation, decreased tone, slowed contraction frequency and reduced fractional pump flow. We conclude that basal NO specifically depresses contraction amplitude, and that greater NO production then inhibits all other aspects of contractile function. Further, this work demonstrates definitively that mouse collecting lymphatic vessels exhibit autonomous, large-amplitude contractions that respond to pressure similarly to collecting lymphatics of other mammalian species. At least in the peripheral lymphatic vasculature, NO production depresses contractile function, which influences lymph flow needed for fluid regulation, humoral immunity and cancer metastasis.
Joshua P Scallan; Michael J Davis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-18
Journal Detail:
Title:  The Journal of physiology     Volume:  591     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-16     Completed Date:  2013-10-18     Revised Date:  2014-04-15    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  2139-56     Citation Subset:  IM    
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MeSH Terms
Enzyme Inhibitors / pharmacology
Lymphatic Vessels / physiology*
Mice, Inbred C57BL
Mice, Knockout
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / physiology*
Nitric Oxide Synthase Type II / deficiency,  genetics
Nitric Oxide Synthase Type III / antagonists & inhibitors,  deficiency,  genetics
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 31C4KY9ESH/Nitric Oxide; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, mouse; EC protein, mouse; V55S2QJN2X/NG-Nitroarginine Methyl Ester

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