cyclic-gmp and Sjogren-s-Syndrome

Nitric oxide (NO) plays multiple roles in both intracellular and extracellular signalling mechanisms with implications for health and disease. This review focuses on the role of NO signalling in salivary secretion. Attention will be paid primarily to endogenous NO production in acinar cells resulting from specific receptor stimulation and to NO-regulated Ca2+ homeostasis. Due to the fact that NO readily crosses membranes by simple diffusion, endogenous NO may play a physiological role in processes as diverse as modifying the secretory output, controlling blood supply to the gland, modulating transmitter output from nerve endings, participating in the host defence barrier, and affecting growth and differentiation of surrounding tissue. Furthermore, the role of NO in the pathogenesis of human oral diseases will be considered.

Topics: Animals; Calcium; Calcium Signaling; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Homeostasis; Humans; Nitric Oxide; Nitric Oxide Synthase; Saliva; Salivary Glands; Signal Transduction; Sjogren's Syndrome

Isolated congenital heart block may be associated with primary Sjögren syndrome. In this work we describe circulating antibodies in the sera of primary Sjögren syndrome patients that are able to interact with neonatal myocardium by activating muscarinic acetylcholine receptors of M1 subtype. We report on the presence of autoantibodies against the second extracellular loop of human M1 muscarinic acetylcholine receptors in primary Sjögren syndrome mothers whose children have congenital heart block using a synthetic peptide in indirect immunofluorescence technique. Autoantibodies from primary Sjögren syndrome patients gave positive image on neonatal atria but not on adult atria slices. The synthetic M1 peptide selectively abrogated indirect immunofluorescence recognition. The primary Sjögren syndrome-immunoglobulin G also displayed an 'agonist like' activity modifying the intracellular events associated with muscarinic acetylcholine receptor activation. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This, in turn, triggers cascade reactions involving calcium/calmodulin and leads to activation of nitric oxide synthase and soluble guanylate cyclase. All of these effects were selectively blunted by pirenzepine and neutralized by M1 synthetic peptide. These biological effects were not obtained using adult instead of neonatal rat atria and neither occurred with the sera of normal healthy women of childbearing age. It could be concluded that antibodies against neonatal M1 muscarinic acetylcholine receptor may be another serum factor to be considered in the pathophysiology of the development of congenital heart block associated with primary Sjögren syndrome mothers.

Topics: Adult; Animals; Animals, Newborn; Autoantibodies; Cyclic GMP; Female; Fluorescent Antibody Technique, Indirect; Heart Atria; Heart Block; Humans; Immunoglobulin G; Infant, Newborn; Inositol Phosphates; Nitric Oxide Synthase; Pregnancy; Pregnancy Complications; Rats; Receptors, Muscarinic; Sjogren's Syndrome

IgG obtained from sera of primary Sjögren's syndrome (pSS-IgG) patients and its interaction with M3 muscarinic cholinoceptors of rat exorbital lacrimal glands were studied by indirect immunofluorescence (IFI) and binding assay. Primary Sjögren's syndrome IgG stained epithelial cells with a continuous fluorescence pattern. The IFI imagen was attenuated by incubating the pSS-IgG with a synthetic peptide corresponding to the second extracellular loop of M3 muscarinic cholinoceptor. Primary SS-IgG was also able to bound irreversibly to muscarinic acetylcholine receptors (mAChRs) displacing the specific cholinergic antagonist QNB. Moreover, these antibodies triggered intracellular signals coupled to M3 muscaric cholinoceptors such as nitric oxide synthase (NOS) activation and cGMP production. Both primary Sjögren's syndrome IgG effects mimicked carbachol action and were abrogated by specific muscarinic antagonist 4-DAMP. The nitric oxide pathway through muscarinic cholinoceptors activation by pSS-IgG on rat exorbital lacrimal gland is also described. We proposed that chronic interaction of these autoantibodies on lacrimal gland muscarinic acetylcholine receptors could lead to tissue damage through nitric oxide release after immunological stimulation.

Topics: Adult; Animals; Autoantibodies; Cyclic GMP; Dose-Response Relationship, Drug; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoglobulin G; Lacrimal Apparatus; Middle Aged; Muscarinic Agonists; Muscarinic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Radioligand Assay; Rats; Rats, Wistar; Receptor, Muscarinic M3; Receptors, Muscarinic; Sjogren's Syndrome

In this study we demonstrate that IgG present in the sera of patients with primary Sjögren's syndrome (PSS) could bind and activate muscarinic acetylcholine receptors (mAChRs) of rat parotid gland. These antibodies were able to inhibit in a non-competitive manner the binding of 3H-quinuclidinyl benzilate (QNB) to mAChRs of purified rat parotid gland membranes. Moreover, IgG from PSS could modify biological effects mediated by mAChR activation; i.e. decrease cAMP, increase phosphoinositide turnover without affecting cGMP. Atropine and 4-DAMP blocked all of these effects, and carbachol mimicked them, confirming the M3 subtype mAChRs mediated PSS IgG action. Neither binding nor biological effect were obtained with IgG from sera of normal women. The prevalence of cholinergic antibody was 100% in PSS, and was independent of Ro/SS-A and La/SS-B antibodies. It could be concluded that antibody against mAChRs may be another serum factor to be considered in the pathophysiology of the development of PSS.

Topics: Adolescent; Adrenergic beta-Agonists; Adult; Animals; Antibodies, Blocking; Atropine; Carbachol; Carbamates; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Immunoglobulin G; Isoproterenol; Muscarinic Antagonists; Parasympatholytics; Parotid Gland; Phenylcarbamates; Phosphatidylinositols; Piperidines; Pirenzepine; Protease Inhibitors; Quinuclidinyl Benzilate; Rats; Rats, Wistar; Receptors, Muscarinic; Sjogren's Syndrome

Human parotid saliva was revealed to contain considerable amounts of cAMP and cGMP. On sour lemon drop stimulation, the salivary cyclic nucleotides concentration decreased and the cyclic nucleotides secretory rate increased in close relationship with the salivary flow rate in control subjects. On feeding, both cAMP concentration and secretory rate increased significantly in control subjects. Parotid saliva from a patient of Sjögren's syndrom was revealed to have a significantly higher of cGMP concentration than those from control subjects. Saliva derived from the malignant tumor of the parotid gland was revealed to have a higher cGMP concentration and a lower cAMP concentration than the healthy site. From these findings, the possibilities of the clinical usefulness of studying salivary cyclic nucleotides were discussed.

Topics: Adult; Cyclic AMP; Cyclic GMP; Eating; Humans; Middle Aged; Parotid Gland; Parotid Neoplasms; Saliva; Salivation; Sjogren's Syndrome; Taste