Inducible nitric oxide synthase increases secretion from inflamed salivary glands

Abstract

Objective. Salivary gland secretion is dependent on cholinergic stimulation via autonomic nerves and calcium signalling in acinar cells. Secretory dysfunction associated with SS may be partly caused by the damaging effects of increased glandular concentrations of nitric oxide (NO) derived from up-regulation of inducible NO synthase (iNOS) that accompanies glandular inflammation. The present study examines the effects of increased iNOS expression on salivary gland secretory function.Methods. The inflammogen lipopolysaccharide (LPS) was introduced intraductally into rat submandibular glands, and glandular responsiveness to cholinergic stimulation was determined.Results. LPS provoked a rapid, long-lasting inflammation, increasing gland weight (by almost 20%) and inflammatory cell infiltration at 3 and 24 h. Immunoblotting of glandular homogenates indicated that iNOS expression was increased ∼4-fold, and immunohistochemistry of frozen tissue sections showed increased iNOS expression in acinar cells. Salivary secretion from inflamed glands was significantly increased in response to low doses of methacholine and accompanied by increased acinar cell calcium signalling in vitro. Prior administration of the iNOS inhibitors, aminoguanidine or l-NIL [l-N6-(1-iminoethyl)-lysine dihydrochloride] abolished increased secretion and acinar cell calcium signalling.Conclusions. Up-regulation of glandular iNOS expression can increase cholinergically evoked salivary secretion and appears to offset any secretory hypofunction linked with glandular inflammation. It seems unlikely that increased glandular levels of NO are responsible for the secretory hypofunction that accompanies SS.

Epithelial disruptions, but not immune cell invasion, induced secretory dysfunction following innate immune activation in a novel model of acute salivary gland injury

“…These experiments verified that innate immune activation interferes with the secretory ability of the SMGs, independent of the invasive immune cell signal. Findings from the current experiments, combined with other studies which demonstrated the little correlation between secretory hypofunction and immune cellular infiltration, strongly implicate an alternative impairment mechanism by which the SG epithelial cells endogenously respond to injury and cease secretion.…”

Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model

“…The supersensitivity is thought to reflect changes beyond the receptor level rather than at the recognition site (15). It was recently shown that the secretory response to intravenous methacholine is transiently increased in the inflamed rat submandibular gland (at 3 and 24 h, but not at 96 h) after the intraductal injection of the inflammogen lipopolysaccharide (17). This finding is in contrast to the results of other studies on the inflamed rat submandibular gland, which showed decreased secretory responses to secretogogues during a similar period of time after exposure to lipopolysaccharide (18, 19).…”

Impairment of acetylcholine-mediated endothelium-dependent relaxation in isolated parotid artery of the alloxan-induced diabetic rabbit

“…Evidence suggests that iNOS could be the critical determinant in the development of diabetes complications in humans because the vascular deterioration observed in diabetes is proven to be, at least partially, attributed to the pathological production of increased levels of superoxide that stimulates the overgeneration of NO by iNOS (12, 13). Immunohistochemical analysis revealed an up‐regulation of iNOS expression in the rat submandibular gland, associated with Sjögren’s syndrome (14), as well as in the gingival tissues of rat (15) and of humans with periodontitis (16).…”