Document Detail


Secretion of cyclic GMP by cultured epithelial and fibroblast cell lines in response to nitric oxide.
MedLine Citation:
PMID:  7536242     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
LLC-PK1 epithelial cells and RFL-6 fibroblasts secreted both cyclic AMP (cAMP) and cyclic GMP (cGMP) when costimulated with forskolin and 3-morpholinosydnonimine (a chemical nitric oxide generator). Intracellular cAMP levels as high as 1100 and 12,000 pmol/10(6) cells were achieved for the two cell types, respectively. These levels were high enough to reach approximately 50% saturation of the cAMP transporter and inhibited transport of cGMP to an equal extent, suggesting that the two cyclic nucleotides compete for a common transport system. The rates of secretion of cGMP and cAMP from LLC-PK1 cells increased in proportion to their rates of synthesis as concentrations of stimulant were varied, but increased only 25% relative to intracellular concentrations in response to inhibition of phosphodiesterases by 3-isobutylmethylxanthine. It is proposed that secretion of cyclic nucleotides is not simply proportional to the total intracellular pool in these cells, but rather is coupled to synthesis. In support of this model, oxyhemoglobin was used to trap nitric oxide and block activity of guanylate cyclase in cells treated with 3-morpholinosydnonimine. As a result, secretion of cGMP ceased within 1 min, whereas intracellular levels decreased slowly over 60 min. Probenecid [p-(dipropylsulfamoyl)benzoic acid] is a nonselective antagonist of anion transport that inhibited secretion of cAMP in both cell types but, unexpectedly, blocked synthesis of cGMP, and this was reflected in direct inhibition of soluble guanylate cyclase in cell lysates. Two heat-stable, high molecular weight factors that confer sensitivity to probenecid were identified, and these factors increased the sensitivity of guanylate cyclase to nitric acid by an order of magnitude.
Authors:
M J Patel; D M Wypij; D A Rose; T J Rimele; J S Wiseman
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  273     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1995 Apr 
Date Detail:
Created Date:  1995-05-17     Completed Date:  1995-05-17     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  16-25     Citation Subset:  IM    
Affiliation:
Glaxo Research Institute, Research Triangle Park, North Carolina, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-3-isobutylxanthine / pharmacology
Animals
Cell Line
Cyclic AMP / pharmacology
Cyclic GMP / secretion*
Epithelium / metabolism
Fibroblasts / metabolism
Guanylate Cyclase / metabolism
Molsidomine / analogs & derivatives,  pharmacology
Nitric Oxide / physiology*
Oxyhemoglobins / pharmacology
Probenecid / pharmacology
Swine
Chemical
Reg. No./Substance:
0/Oxyhemoglobins; 10102-43-9/Nitric Oxide; 25717-80-0/Molsidomine; 28822-58-4/1-Methyl-3-isobutylxanthine; 33876-97-0/3-morpholino-sydnonimine; 57-66-9/Probenecid; 60-92-4/Cyclic AMP; 7665-99-8/Cyclic GMP; EC 4.6.1.2/Guanylate Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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