Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs

Masunaga, Hiroaki; Ogawa, Hiromi; Uematsu, Yasuhiro; Tomizuka, Toshie; Yasuda, Hiroshi; Takeshita, Yasuyoshi

doi:10.1016/s0014-2999(97)01338-1

Cited by 43 publications

(23 citation statements)

References 14 publications

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“…It has been reported that BH 4 is a critical factor in producing NO from L-arginine (Kwon et al, 1989), and BH 4 deficiency not only reduces the production of NO but also enhances superoxide generation (Pou et al, 1992;Shinozaki et al, 1999). SNI-2011, a novel muscarinic M 1 agonist (Fisher et al, 1991) that possesses a long-lasting sialogogic action (Masunaga et al, 1997), increased amylase secretion from parotid tissues in rats (Yuan et al, 2003). This effect was inhibited by a cell-permeable Ca 2ϩ chelator or inhibitors of calmodulin kinase II, nNOS, soluble guanylyl cyclase, cyclic GMP-dependent protein kinase, and myosin light chain kinase.…”

Section: Secretion and Neurogenic Nitric Oxidementioning

confidence: 99%

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Toda

Herman

2005

Pharmacol Rev

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Section: Secretion and Neurogenic Nitric Oxidementioning

confidence: 99%

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Toda

Herman

2005

Pharmacol Rev

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“…These findings strongly suggest that intracellular trafficking of AQP5 is regulated in response to agonist-induced stimulation of M 3 mAChRs. In vitro, SNI-2011 (cevimeline) induces long-lasting salivation with a persistent increase in AQP5 levels in the APM of parotid glands (12,17,26). These findings, however, have not been supported by in vivo experiments.…”

mentioning

confidence: 95%

Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M₃ mAChRs in interlobular ducts of rat parotid gland

Ishikawa¹,

Yuan²,

Inoue³

et al. 2005

American Journal of Physiology-Cell Physiology

118

113

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, an apical plasma membrane (APM) water channel in salivary glands, lacrimal glands, and airway epithelium, has an important role in fluid secretion. M 3 muscarinic acetylcholine receptor (mAChR)-induced changes in AQP5 localization in rat parotid glands were investigated with immunofluorescence or immunoelectron microscopy, detergent solubility, and gradient density floatation assays. Confocal microscopy revealed AQP5 localization in intracellular vesicles of interlobular duct cells in rat parotid glands and AQP5 trafficking to the APM 10 min after injection of the mAChR agonist cevimeline. Conversely, 60 min after injection, there was a diffuse pattern of AQP5 staining in the cell cytoplasm. The calcium ionophore A-23187 mimicked the effects of cevimeline. Immunoelectron microscopic studies confirmed that cevimeline induced AQP5 trafficking from intracellular structures to APMs in the interlobular duct cells of rat parotid glands. Lipid raft markers flotillin-2 and GM1 colocalized with AQP5 and moved with AQP5 in response to cevimeline. Under control conditions, the majority of AQP5 localized in the Triton X-100-insoluble fraction and floated to the light-density fraction on discontinuous density gradients. After 10-min incubation of parotid tissue slices with cevimeline or A-23187, AQP5 levels decreased in the Triton X-100-insoluble fraction and increased in the Triton X-100-soluble fraction. Thus AQP5 localizes in the intracellular lipid rafts, and M 3 mAChR activation induces AQP5 trafficking to the APM with lipid rafts via intracellular Ca 2ϩ signaling and induces AQP5 dissociation from lipid rafts to nonrafts on the APM in the interlobular duct cells of rat parotid glands.translocation; aquaporin-5 AQUAPORINS (AQPs) form water channels that selectively transport water across the plasma membrane (19). Thirteen mammalian AQPs, AQP0 -AQP12, have been identified (1, 27). AQP5, initially cloned from rat submandibular glands (32), is an apical membrane water channel that is distributed to epithelial cells in several secretory glands, such as salivary glands (10). Salivary fluid secretion is defective in transgenic mice lacking AQP5, indicating that AQP5 has an important role in fluid secretion (24).The parotid glands are innervated by both sympathetic and parasympathetic nerves (2). The activation of M 3 muscarinic acetylcholine receptors (mAChRs) and ␣ 1 -adrenoceptors increases intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and induces salivary fluid secretion (2). In vitro experiments using rat parotid slices demonstrated that ACh and epinephrine acting at M 3 mAChRs and ␣ 1 -adrenoceptors, respectively, induce a rapid increase in the AQP5 levels in the apical plasma membrane (APM) by increasing [Ca 2ϩ ] i (14, 15). We previously investigated (16) the possible role of Ca 2ϩ -mediated intracellular signal transduction in the M 3 mAChR agonist-induced increase in AQP5 levels in the APM and demonstrated that activation of endogenous nitric oxide synthase and protein kinase G in the cells is coupled with t...

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“…Its effects on salivation depends mainly on the direct stimulation of the M3 receptors of the salivary glands. 17,27,31 It is common knowledge that salivation and lacrimation are regulated by the acetylcholine mediators on the receptors, and muscarinic effects on the M1 and M3 subcategories, with a prevalence of 93% of the M3 subcategory on the parotid glands.…”

Section: Mechanism Of Action Metabolism and Pharmacokinetic Profi Lementioning

confidence: 99%

“…13 The dominant characteristics of this drug compared to Pilocarpine are its longer lasting effect on salivation, from 1.4 to 1.8 times longer in rats, and twice as long in dogs. 17 The studies on rats have also demonstrated that cevimeline is able to induce lacrimal secretions without having to increase the intake of water with the dosage necessary for the induction of salivation. 25 The doses used in experiments on animals provoked the increase of salivation (3-10 mg/Kg) without causing any particular systemic effects when the treatment was administered orally.…”

Section: Mechanism Of Action Metabolism and Pharmacokinetic Profi Lementioning

confidence: 99%

Cevimeline for the treatment of dry mouth in patients with Sjogren's syndrome

Coaccioli

Landucci

2009

Clinical Medicine. Therapeutics

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Sjogren's Syndrome (SS) is a chronic autoimmune disease characterized by the presence of xerostomia and xerophthalmia and by the dysfunction of salivary and lacrimal glands. The disease is frequently associated with other systemic manifestations, including vasculitis, pulmonary interstitial disorders and lymphoma. SS constitutes the primary cause of disability and xerostomia can represent an obstacle to deglutition and to oral hygiene, making it difficult for these patients to talk, eat, and swallow. In addition, it can cause tooth decay and recurring candidosis of the oral cavity, as well as premature teeth loss. The treatment of SS is based on the use of artificial tears, saliva substitutes, and lubricants to control the symptoms, and is usually associated with muscarinic agonist drugs such as pilocarpine, especially in cases of severe dryness. Pilocarpine has been proven to increase the secretion of saliva, but its use in clinical practices is highly limited to the short duration of its action, less than 3 hours, which considerably reduces its compliance. There have recently been studies of a new muscarinic receptor agonist, Cevimeline, which has a longer half-life than Pilocarpine (about 5 hours), and has already been commercialised in some countries. The purpose of this article is to review the published literature regarding the pharmacological and clinical properties of this drug, as well as its efficacy, tolerability, and safety in the treatment of xerostomia in patients suffering from primary and secondary SS.

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Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs

Cited by 43 publications

References 14 publications

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M₃ mAChRs in interlobular ducts of rat parotid gland

Cevimeline for the treatment of dry mouth in patients with Sjogren's syndrome

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Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs

Cited by 43 publications

References 14 publications

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M3 mAChRs in interlobular ducts of rat parotid gland

Cevimeline for the treatment of dry mouth in patients with Sjogren's syndrome

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Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M₃ mAChRs in interlobular ducts of rat parotid gland