A role for nitric oxide-mediated glandular hypofunction in a non-apoptotic model for Sjogren's syndrome.
OBJECTIVE
To investigate a role for the inflammatory mediator, nitric oxide (NO) in SS, an autoimmune condition characterized by salivary and lacrimal gland hypofunction resulting from failure of acinar cells to secrete.


METHODS
FURA-2 microfluorimetry was used to measure agonist-evoked changes of [Ca(2+)](i) in isolated mouse and human salivary acinar cells following exposure to NO donors.


RESULTS
NO had a biphasic effect on salivary acinar function. Acute exposure to NO (2 min) caused a cyclic guanosine monophosphate (GMP)-dependent, 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-sensitive increase in the Ca(2+) signal elicited in response to acetylcholine (ACh) stimulation, consistent with stimulation of ryanodine receptors by cyclic adenosine diphosphate ribose. Prolonged exposure to NO (>40 min) significantly reduced the ACh-evoked Ca(2+) signal by a mechanism independent of cyclic GMP. We found no differences between the responses of human and mouse acinar cells.


CONCLUSIONS
Our data show that chronic exposure to NO, which is known to be elevated in SS, could have a role in salivary gland hypofunction. We note a similarity in the response to stimulation of salivary acinar exposed to NO and that which we have previously reported in salivary acinar cells isolated from patients with SS. We speculate that NO-mediated nitrosylation of one or more elements of the signal transduction pathway could underlie down-regulation of salivary function in SS.
Caulfield
Vicky L
VL
School of Dental Sciences, University of Liverpool, Liverpool, UK.
Balmer
Colette
C
Dawson
Luke J
LJ
Smith
Peter M
PM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005470:Fluorometry / Q000379:methods; D016257:Fura-2; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012859:Sjogren's Syndrome / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism*
C118603:NOC 12; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D000109:Acetylcholine; D002118:Calcium; D016257:Fura-2