Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: An alternative explanation of its beneficial effect in interstitial cystitis

Purpose: Mast cells are ubiquitous cells derived from the bone marrow and a re 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 nu mber of peptides, such as bradykinin and substance P, and may also be invol ved in the development of inflammatory responses. An example is interstitia l cystitis, which is a sterile painful bladder disorder that has been assoc iated with a defective glycosaminoglycan bladder mucosal layer and an incre ased number of activated mast cells. Pentosanpolysulfate is a synthetic, su lfated polysaccharide that has been approved for the treatment of interstit ial cystitis on the premise that it may replenish the defective glycosamino glycan layer. We hypothesize that pentosanpolysulfate may also have an addi tional or alternate action on bladder mast cells. We report that pentosanpo lysulfate has a powerful dose dependent inhibitory effect on mast cell rele ase of histamine induced by the mast cell secretagogue compound 48/80. Materials and 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 in hibition by pentosanpolysulfate was apparent within 1 minute, was unaffecte d by the length of pre-incubation and persisted after the drug was washed o ff. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leu kemia cells, pentosanpolysulfate inhibited histamine secretion from both. C onfocal microscopy using a calcium indicator dye showed that pentosanpolysu lfate decreased intracellular calcium ion levels. Conclusions: Pentosanpolysulfate appears to be a potent inhibitor of allerg ic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.