title: Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis.
abstract: OBJECTIVE
  Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80.
  
  
  METHODS
  Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen.
  
  
  RESULTS
  The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels.
  
  
  CONCLUSIONS
  Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chiang
authors.forename: P
authors.initials: P
authors.lastname: Patra
authors.forename: R
authors.initials: R
authors.lastname: Letourneau
authors.forename: S
authors.initials: S
authors.lastname: Jeudy
authors.forename: W
authors.initials: W
authors.lastname: Boucher
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.forename: G R
authors.initials: GR
authors.lastname: Sant
authors.forename: T C
authors.initials: TC
authors.lastname: Theoharides
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D018856:Cystitis, Interstitial / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects*; D006651:Histocytochemistry; D007073:Immunoglobulin E / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D010537:Peritoneum / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000494:pharmacology; D001743:Urinary Bladder / Q000166:cytology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013373:Substance P; D010426:Pentosan Sulfuric Polyester; D007073:Immunoglobulin E; D003189:p-Methoxy-N-methylphenethylamine; D002809:Chondroitin Sulfates; D004205:Cromolyn Sodium; D002118:Calcium