Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation

Background

Since salivary fluid is created from blood plasma, hemodynamics in the salivary glands play an important role in the production of saliva. Trigeminal sensory input induces both salivary secretion and reflex parasympathetic vasodilation in salivary glands. This glandular vasodilation is thought to be important for the regulation of glandular hemodynamics due to the rapidity with which blood flow is increased. This review article summarizes recent research on the involvement of parasympathetic vasodilation in regulating hemodynamics in the salivary gland.

A tentative model for d-glucose turnover in human saliva

Objective

The aim of the present study is to propose a tentative model for d-glucose turnover in human saliva. The whole saliva and the saliva from parotid and submandibular/sublingual glands were collected by use of the Salivette™.

Results

The saliva glucose concentration was measured by the hexokinase method, saliva bacteria glycolysis by use of d-[5-³H] glucose, and the saliva ATP content by the luciferase method. The concentration of glucose amounted to 43.9 ± 6.3 (n = 29), 197.5 ± 17.3 (n = 29), 104.0 ± 12.4 (n = 27) μM in whole saliva, parotid saliva and submandibular/sublingual saliva, respectively. The rate of d-glucose utilization by oral bacteria at a physiological concentration of d-glucose in saliva (50 μM) was estimated at 0.047 ± 0.003 (n = 11) nmol/min per 10⁶ bacteria. Unstimulated salivary d-glucose turnover rate, as calculated from the amount of glucose secreted in saliva which comes from parotid and submandibular and sublingual glands represented 214.6 ± 19.1%/min. In order for salivary d-glucose production to match bacterial utilization of the hexose, the total number of oral bacteria was estimated at about 2.0 × 10⁹ bacteria, in fair agreement with previously published data.

Conclusion

This study thus provides support for a tentative model for d-glucose turnover in human saliva.     

Salivary glands: applied anatomy and clinical correlates.

The major salivary glands include the paired parotid, submandibular and sublingual glands. Salivary glands act as accessory digestive glands and produce a secretion referred to as saliva. Saliva has lubricating, cleansing, digestive and antimicrobial properties. The parotid is the largest salivary gland and saliva is secreted into the mouth via the parotid duct (Stensen's duct). The submandibular gland lies inferior to the body of the mandible and is susceptible to sialolithiases. Drainage is via the duct of the submandibular gland (Wharton's duct) into the floor of the mouth on either side of the lingual frenulum. The sublingual glands are situated under the mucosa in the floor of the mouth, on the sides of the tongue. These glands are in relationship to important nerves in the surrounding tissue. Disease processes such as chronic intraparenchymal sialolithiasis and neoplastic changes frequently mandate surgical removal of the underlying salivary gland. Detailed, applied knowledge of anatomy on a regional basis is required to avoid inadvertent nerve damage during surgery and resulting litigation.     

The host defense peptide LL‐37 is detected in human parotid and submandibular/sublingual saliva and expressed in glandular neutrophils

The human host defense peptide, LL‐37, is an important player in the first line of defense against invading microorganisms. LL‐37 and its precursor, hCAP18, have been detected in unstimulated whole saliva but no reports showing hCAP18/LL‐37 in isolated, parotid, and/or submandibular/sublingual saliva have been presented. Here, we measured the levels of hCAP18/LL‐37 in human parotid and submandibular/sublingual saliva and investigated the expression of hCAP18/LL‐37 in parotid and submandibular gland tissue. Parotid and submandibular/sublingual saliva was collected from healthy volunteers, and the levels of hCAP18/LL‐37 in saliva were analyzed by dot blot, ELISA, and western blotting. Cellular expression of hCAP18/LL‐37 in human parotid and submandibular glands was investigated by immunohistochemistry. Immunoreactivity for hCAP18/LL‐37 was detected in both parotid and submandibular/sublingual saliva of all individuals. The concentration of hCAP18/LL‐37 was similar in parotid and submandibular/sublingual saliva, and was determined by densitometric scanning of each dot and normalization to the total protein concentration of each sample, and by ELISA. Double immunohistochemistry revealed that intravascular neutrophils of both parotid and submandibular glands express hCAP18/LL‐37. For the first time, we demonstrate hCAP18/LL‐37 in isolated human parotid and submandibular/sublingual saliva and expression of hCAP18/LL‐37 in glandular intravascular neutrophils, indicating that neutrophils of the major salivary glands contribute to the LL‐37 content of whole saliva.     

The effect of X-ray irradiation on the function and saliva composition of rat parotid and submandibular/ sublingual glands

Radiation therapy to the head and neck area frequently causes severe salivary gland dysfunction and xerostomia. Morphological studies of irradiated salivary glands have suggested that the submandibular/sublingual gland may be less radiosensitive than the parotid gland. The purpose of this study was to evaluate the effect of radiation on major salivary gland functions in rats with radiation-induced xerostomia. The effect of salivary gland irradiation on salivary function was examined in specific pathogen-free Sprague-Dawley rats. The animals were irradiated with a single exposure of either 22 Gy or 32 Gy. Stimulated saliva excretion time was measured for the parotid and submandibular/ sublingual glands, and the total protein in saliva was analysed. Our results showed that the saliva flow rate and protein concentration of parotid saliva were significantly reduced in the 32 Gy-irradiated rats.     

Structural characterization of endogenous peroxidase activity in human,rat, hamster,and Suncus murinus salivary glands

Background

3,3’-diaminobenzidine tetrazolium (DAB)-based methods have been developed to detect the localization of peroxidase (PO) activity. Histochemically, endogenous PO activity has been localized to acini of human and rodent salivary glands. This suggests that the enzyme may be used as a convenient marker of differentiated acinar cells to study factors that influence the development of the rat submandibular gland. We also investigated endogenous PO localization differences between rodent and insectivora (Suncus murinus) major salivary glands by light and electron microscopy. Moreover, ectopic sublingual gland-like tissue was found in the resin-embedded semi-thin sections of DAB-reacted hamster submandibular gland by confocal laser scanning microscopy.

Characterization of cGMP-related phosphodiesterase isoenzymes in rat salivary glands

 Isolation and characterization of the cGMP-related phosphodiesterase (PDE) isoenzymes in rat salivary glands were investigated. Both cGMP- and cAMP-PDE activities were mainly present in the 100 000 g supernatant fractions from the parotid, submandibular, and sublingual glands. The results of inhibition studies and ion-exchange chromatography suggest that Ca²⁺/calmodulin markedly stimulates PDE1 in the parotid and sublingual glands, and slightly in the submandibular gland. PDE2 was detected only in the parotid gland. PDE3 was identified in the parotid and submandibular glands. PDE5 was detected in the submandibular and sublingual glands by using inhibition studies, ion-exchange chromatography, and Western blotting. Received: August 21, 2001 / Accepted: May 28, 2002     

The contribution of oral minor mucous gland secretions to the volume of whole saliva in man

To determine the contribution of minor mucous gland secretions to total saliva by a direct method, flow rates of both unstimulated and sour lemon drop (SLD)-stimulated saliva were initially determined in 15 subjects. The right and left lingual nerves were then anaesthetized to halt submandibular and sublingual secretion, and both parotid ducts were cannulated. The only remaining saliva in the mouth was that secreted by minor salivary glands. Unstimulated and SLD-stimulated minor mucous gland secretions were then collected and the median percentage contributions to whole saliva were calculated to be 8 and 7 per cent, respectively. Comparable results were obtained on 3 subjects using an indirect method similar to that of Schneyer (1956). With the left parotid duct cannulated, subjects maintained a constant, SLD-stimulated, left parotid flow rate of 1 ml/min and the remaining mixed saliva was collected to determine its flow rate. The right parotid and the submandibular and sublingual glands were then also cannulated and the flow rate from these glands determined whilst that from the left parotid was maintained at 1 ml/min. The contribution from minor mucous glands was the difference between the flow rate of mixed saliva and the combined flow rate from the right parotid, submandibular and sublingual glands.     

Quantitative changes in amylase activity in the salivary glands, pancreas, saliva, and serum after administration of isoproterenol, pilocarpine, and acetylcholine

Amylase activity in various tissues--i.e., submandibular/sublingual and parotid glands, the pancreas, saliva, and serum--in rats was measured after injection of isoproterenol, pilocarpine, and acetylcholine. All agents reduced amylase activity in the parotid gland and increased the enzyme activity in the submandibular/sublingual glands, in saliva and serum.     

Physostigmine-induced salivary secretion in the rat

The purpose of this study was to see if physostigmine, a reversible cholinesterase inhibitor, affects the secretion and composition of saliva of the major salivary glands of the rat. Low doses of physostigmine did not elicit secretion. At higher doses there was significant flow from the parotid and submandibular glands within 5 min; however, no sublingual secretion was observed. The submandibular flow rate was highest for the first 5 min, then declined rapidly. The parotid flow rate initially was one-fifth of the maximum submandibular rate and then gradually decreased. The concentrations of Ca, Na and K of physostigmine-induced parotid saliva, and the Na of submandibular saliva, were similar to those with carbachol stimulation. The Ca and K concentrations of submandibular saliva were significantly higher than with carbachol or parasympathetic stimulation, and resembled those of alpha-adrenergic stimulation. The protein concentrations of physostigmine-evoked saliva from both glands were similar. The amylase activity of physostigmine-evoked parotid saliva was much higher than that of carbachol or parasympathetic stimulation. Physostigmine-evoked secretion was completely blocked by atropine, a cholinergic antagonist, and by reserpine, partially blocked by phentolamine, an alpha-adrenergic antagonist and not affected by surgical sympathectomy. Morphologically, physostigmine resulted in a moderate decrease in the number of acinar, but not ductal, secretory granules of both the parotid and submandibular glands, while the sublingual gland was unaffected. Numerous patches of parotid acini also developed vacuoles or vesicles. These results suggest that physostigmine-induced salivary secretion is mediated primarily by direct effects on cholinergic and alpha-adrenergic receptors.     

Simultaneous pleomorphic adenoma of the left parotid gland and adenoid cystic carcinoma of the contralateral sublingual salivary gland: a case report

Introduction

Sublingual salivary gland neoplasms are extremely rare, accounting for only 0.3–1% of all epithelial salivary gland tumors. Most of the sublingual tumors are malignant, adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC) being the most common histological types. The coexistence of two salivary gland tumors located in different major salivary glands is uncommon.

Case report

A rare case of two simultaneous tumors of the major salivary glands, one in the sublingual and the other in the contralateral parotid gland in a female patient is reported.

Discussion

The diagnostic procedure followed, and the management of the patient, is outlined in the paper.     

Human glandular salivas: their separate collection and analysis

Human saliva is secreted by the three pairs of major salivary glands (parotid, submandibular, and sublingual), and numerous minor ones, e.g. labial, buccal and (glosso)palatine glands. Using individually adapted collection devices, sublingual. submandibular, parotid and palatine secretions of five individuals were collected and analyzed. Electrophoretic analysis revealed that each type of saliva possesses characteristic features, despite interindividual variations. Parotid salivas are characterized by intensely staining amylase and proline-rich protein bands, but contain minute amounts of cystatins. lysozyme and the extra-parotid glycoprotein. Sublingual salivas are characterized by high concentrations of both types of salivary mucins. MG1 and MG2, and contain relatively high levels of lysozyme. Submandibular salivas contain highest concentration of salivary cystatin S. Palatine secretions contain high molecular weight mucins and a relatively high amylase concentration.     

Expression of adrenomedullin and its receptors in human salivary tissue

Adrenomedullin is a multifunctional peptide produced by a wide range of different cells and tissues. This study was designed to investigate whether adrenomedullin is present in human saliva and in salivary glands. It was expected that saliva may contain high concentrations of adrenomedullin, which has antimicrobial activity in vitro, which may have functional implications in the oral cavity. Saliva from the submandibular and parotid glands contained higher concentrations of adrenomedullin than did the circulation, but lower concentrations than in whole saliva. This suggests that oral epithelium may contribute the majority of the adrenomedullin peptide found in saliva. Specific adrenomedullin receptors were found in cell lines from the submandibular (HSG) and parotid (HSY) salivary glands. These findings suggest a paracrine/autocrine role for adrenomedullin in these tissues; however, the concentration of adrenomedullin in saliva was insufficient to suggest a significant antimicrobial action in the healthy oral cavity.     

Epithelial-stromal interactions in salivary glands of rats exposed to chronic passive smoking

Objectives

Cigarette smoke leads to precancerous and cancerous lesions in the mouth even when the exposure is passive. The salivary glands are amongst the tissues exposed to the smoke but it is unclear whether or not passive cigarette exposure is related to detectable changes in these tissues. The objective of this study was to observe the tissue architecture of the parotid and submandibular glands in rats after passive cigarette exposure and to measure any changes that occurred.

Design

Twenty Wistar rats were divided into 10 non-smoking animals and 10 animals exposed to cigarette smoke. After 6 months of smoke exposure samples were collected from both exposed and unexposed salivary glands for histological examination under both transmitted and polarized light microscopy.

Results

Changes in the glands of exposed animals included involution of the cytoplasm and nucleus of the acinar cells and the presence of an inflammatory infiltrate. There was an abnormal accumulation of type I collagen in the stroma and an enlarged interacinar space filled with extracellular matrix.

Conclusion

Passive smoking led to substantial structural changes in the salivary glands which could significantly affect function.     

Morphological and biochemical changes in the rat parotid gland after compensatory and isoproterenol-induced enlargement

Enlargement of parotid glands can be induced in rats by treatment with isoproterenol (ISP) or by removal of the submandibular and sublingual glands. In this study, morphological changes in the enlarged parotid glands and qualitative changes in secreted proteins were examined in rats that had been treated with ISP for 10 days or that had been partially sialoadenectomized by removal of the submandibular/sublingual glands 2 weeks prior to killing. After ISP treatment or salivary gland ablation, secretory cells were enlarged and contained enlarged secretory granules that stained differently from granules in normal glands. Isoproterenol treatment induced the greatest enlargement of cells and granules. Even though gland structure was altered in both experimental groups, electrophoresis of saliva showed that submandibular/sublingual gland ablation did not lead to significant qualitative changes in secreted proteins, while ISP treatment induced major changes in the pattern of secreted protein. The results suggest that compensatory enlargement of the parotid glands and changes after ISP treatment are induced by stimulation of different regulatory pathways.     

Bacterial agglutinins in rat salivary glands: effect of glandular stimulation and calcium dependency

The secretory pattern of salivary, bacterial agglutinins was studied in the rat. The three major salivary glands were cannulated bilaterally and their secretions collected separately after parasympathomimetic and sympathetic stimulation. The bacterial aggregating activity of the secretions was tested against four strains of bacteria indigenous to the rat. Agglutinin activity was demonstrated in both parasympathomimetic and sympathetic secretions. The parotid glands tended to show the highest total output of agglutinins, with the highest titers found in parotid saliva on sympathetic stimulation. In submandibular and, particularly, parotid saliva, titers tended to increase when stimulation with pilocarpine was followed by sympathetic stimulation. In contrast, titer in sublingual saliva tended to decrease on sympathetic stimulation. When expressed as titer output per minute, sympathetic parotid secretion showed the highest agglutinin activity. Agglutinin activity appeared unrelated to total protein or to duct-derived amidolytic activity. Titers of parotid or submandibular saliva were increased 5- to 10-fold by the presence of 3.3 mM CaCl2 in the reaction mixture. By contrast, the agglutinating activity of sublingual saliva on parasympathomimetic stimulation was unaffected by extraneous CaCl2. Measurements of Ca concentration in similarly obtained rat salivary secretions did not show patterns of Ca concentration that could be related to the varying sensitivity of the agglutinating activity to Ca.     

Expression of podoplanin in the mouse salivary glands

OBJECTIVE: Podoplanin is one of the most highly expressed lymphatic-specific genes. Here, we report the distribution of cells expressing podoplanin in mouse salivary glands. DESIGN: We immunohistochemically investigated the distribution of cells expressing podoplanin in mouse major salivary glands by laser-scanning microscopy. The expression of endothelial cell marker PECAM-1 was tested to discriminate lymphatic endothelium from salivary gland cells, and myoepithelial cells were identified by an antibody for P-cadherin. RESULTS: The podoplanin expression was rarely found in acini of the parotid gland but clearly found at the basal portion of acini in the submandibular and sublingual glands. The number of portion reacted with anti-podoplanin is greater in the sublingual gland than in the submandibular gland. The expression was also found at the basal portion of ducts in all major salivary glands. The P-cadherin expression was rarely found in acini of the parotid gland but found in acini of the sublingual gland and on ducts in parotid and sublingual glands, corresponding to the area of podoplanin expression. CONCLUSIONS: It was suggested that the acinar and myoepithelial cells in the salivary glands have the ability to express podoplanin, and that the expression may be concerned with the mucous saliva excretion.     

The physiology of salivary secretion

Saliva in the mouth is a biofluid produced mainly by three pairs of major salivary glands – the submandibular, parotid and sublingual glands – along with secretions from many minor submucosal salivary glands. Salivary gland secretion is a nerve‐mediated reflex and the volume of saliva secreted is dependent on the intensity and type of taste and on chemosensory, masticatory or tactile stimulation. Long periods of low (resting or unstimulated) flow are broken by short periods of high flow, which is stimulated by taste and mastication. The nerve‐mediated salivary reflex is modulated by nerve signals from other centers in the central nervous system, which is most obvious as hyposalivation at times of anxiety. An example of other neurohormonal influences on the salivary reflex is the circadian rhythm, which affects salivary flow and ionic composition. Cholinergic parasympathetic and adrenergic sympathetic autonomic nerves evoke salivary secretion, signaling through muscarinic M3 and adrenoceptors on salivary acinar cells and leading to secretion of fluid and salivary proteins. Saliva gland acinar cells are chloride and sodium secreting, and the isotonic fluid produced is rendered hypotonic by salivary gland duct cells as it flows to the mouth. The major proteins present in saliva are secreted by salivary glands, creating viscoelasticity and enabling the coating of oral surfaces with saliva. Salivary films are essential for maintaining oral health and regulating the oral microbiome. Saliva in the mouth contains a range of validated and potential disease biomarkers derived from epithelial cells, neutrophils, the microbiome, gingival crevicular fluid and serum. For example, cortisol levels are used in the assessment of stress, matrix metalloproteinases‐8 and ‐9 appear to be promising markers of caries and periodontal disease, and a panel of mRNA and proteins has been proposed as a marker of oral squamous cell carcinoma. Understanding the mechanisms by which components enter saliva is an important aspect of validating their use as biomarkers of health and disease.     

The relationship between salivary histatin levels and oral yeast carriage

Candida species are common commensal inhabitants of the oral cavity. Human saliva contains antifungal proteins called histatins. We tested the hypothesis that oral yeast status is related to salivary histatin levels. Thirty subjects were divided into two groups based on the presence (n = 15) or absence (n = 15) of yeast on oral mucosa surfaces. Unstimulated and stimulated submandibular and sublingual and parotid saliva was collected from each subject. Salivary flow rates were measured and histatin concentrations were determined in the stimulated saliva samples. The yeast colony positive group showed lower median unstimulated parotid saliva flow rates as well as lower median concentrations of total histatins in submandibular and sublingual saliva. There was a negative correlation between yeast colony-forming units and unstimulated parotid saliva flow rates and between yeast colony-forming units and submandibular and sublingual saliva histatin concentration and secretion. The results suggest that oral yeast status may be influenced by unstimulated parotid saliva flow rates and by submandibular and sublingual histatin concentration and secretion.