Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis.
OBJECTIVE
Interstitial cystitis (IC) is a painful, sterile bladder disorder that occurs primarily in women, many of whom also experience allergies with symptoms that worsen perimenstrually. Increased numbers of activated bladder mast cells have recently been implicated in the pathophysiology of IC. These mast cells express high-affinity estrogen receptors and are located close to increased bladder nerves, many of which contain the neuropeptide substance P (SP). We therefore investigated whether the neurotransmitter acetylcholine (ACh) and SP could activate bladder mast cells and whether estradiol could influence this effect.


METHODS
Bladder pieces from male Sprague-Dawley rats were perfused with carbachol (the stable analogue of ACh), SP, or the mast cell secretagogue compound 48/80 (C48/80) with or without preincubation with beta-estradiol. The effect of carbachol was also investigated after pretreatment with the muscarinic antagonist atropine. Mast cell activation was assessed by release of 3H-serotonin and morphologic evidence of secretion by light and electron microscopy.


RESULTS
Carbachol triggered rat bladder mast cell serotonin release in a dose-dependent manner, an effect increased by tissue pretreatment with estradiol and blocked by atropine. The effect of carbachol was accompanied by ultrastructural evidence of mast cell activation and was stronger than that obtained by either C48/ 80 or SP.


CONCLUSIONS
Bladder mast cell activation is neurogenically mediated and augmented by estradiol, findings that could possibly explain the painful symptoms of IC and its prevalence in women, as well as the worsening of symptoms perimenstrually.
Department of Pharmacology, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111, USA.
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C
Spanos
M
M
el-Mansoury
R
R
Letourneau
P
P
Minogiannis
J
J
Greenwood
P
P
Siri
G R
GR
Sant
T C
TC
Theoharides
D000109:Acetylcholine / Q000031:analogs & derivatives; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D018856:Cystitis, Interstitial / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D012701:Serotonin; D003189:p-Methoxy-N-methylphenethylamine; D004958:Estradiol; D002217:Carbachol; D000109:Acetylcholine