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Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation
Journal of Oral Biosciences 59 (2017) 80–86
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Review
Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation Toshiya Sato, Hisayoshi Ishii n Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 16 January 2017 Received in revised form 22 February 2017 Accepted 27 February 2017 Available online 28 March 2017
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. Highlight: Electrical stimulation of the lingual nerve, a branch of the trigeminal nerve, elicits parasympathetic vasodilation in the salivary glands. Parasympathetic vasodilation is mainly evoked by cholinergic fibers in the submandibular and parotid glands and by cholinergic and vasoactive intestinal peptide (VIP)-ergic fibers in the sublingual gland. The vasodilator mechanism changes from cholinergic to VIP-ergic when muscarinic receptors are deactivated. Conclusion: Glandular hemodynamics in the submandibular, parotid, and sublingual glands are regulated by different parasympathetic vasodilator mechanisms, which may functionally contribute to the differences in secretion among the major salivary glands. & 2017 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
Keywords: Parasympathetic vasodilation Cholinergic vasodilator fibers Non-cholinergic vasodilator fibers Vasoactive intestinal polypeptide
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nerve-mediated vasodilation in the orofacial area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Parasympathetic vasodilation evoked by electrical stimulation of the trigeminal afferent nerve in the rat major salivary gland. 4. Interaction between acetylcholine and vasoactive intestinal peptide on the control of hemodynamics in salivary glands . . . . . . 5. Physiological role of parasympathetic vasodilation in the salivary glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Hemodynamics in the salivary gland are largely regulated by
Abbreviations: Ach, acetylcholine; SABP, systemic arterial blood pressure; VC, vascular conductance; VIP, vasoactive intestinal peptide; Vsp, spinal trigeminal nucleus n Correspondence to: Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail address: [email protected] (H. Ishii).
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both the sympathetic and parasympathetic nervous systems [1]. The importance of the autonomic nervous system in the regulation of glandular hemodynamics was established by Bernard in 1858 [2], who observed that stimulation of the sympathetic nerve caused vasoconstriction, whereas stimulation of the parasympathetic nerve led to marked vasodilation. The parasympathetic vasodilator response is due to both cholinergic and non-cholinergic neurotransmitters, such as vasoactive intestinal peptide (VIP) [3–15]. Conversely, the sympathetic
http://dx.doi.org/10.1016/j.job.2017.03.002 1349-0079/& 2017 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
T. Sato, H. Ishii / Journal of Oral Biosciences 59 (2017) 80–86
vasoconstrictor response is mainly due to α-adrenoceptor activation and neuropeptide Y, and only a small portion of the vasodilator response is attributable to β-adrenoceptor activation [16]. Taken together, these studies demonstrated that the autonomic nervous system is involved in regulating the secretion and hemodynamics of the salivary gland. In addition to salivary secretion, trigeminal sensory input induces cholinergic as well as non-cholinergic parasympathetic reflex vasodilation in the salivary glands [3–5]. The sympathetic vasoconstrictive nerve fibers to the salivary glands, however, remain in a state of tonic control. Therefore, parasympathetic vasoactive nerve fibers predominantly contribute to vasodilation under reflex conditions, such as during feeding [1]. This glandular vasodilation is thought to be important in the regulation of glandular hemodynamics due to the rapidity with which blood flow increases. Parasympathetic reflex vasodilation in salivary glands, especially in the submandibular gland, has been previously examined [3–5]. It is thought that the mechanisms underlying glandular parasympathetic vasodilation differ among the major salivary glands, because of differences in the composition of serous and mucous acini and the type of secretion. In this review, we focus on the differences in parasympathetic vasodilation among the major salivary glands, the interaction between cholinergic and non-cholinergic vasodilator mechanisms, and the physiological role of parasympathetic vasodilation in salivary glands.
2. Nerve-mediated vasodilation in the orofacial area Until quite recently, it was believed that the regulation of blood flow in the orofacial area depended on vasoconstrictor fibers from the cervical sympathetic trunk, that is, an increase in sympathetic nerve activation induced vasoconstriction, while vasodilation was elicited by a decrease in sympathetic nerve activation. However, as we previously reported, parasympathetic vasodilator fibers exist in
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the orofacial area, and trigeminal sensory input elicits vasodilation mediated via trigeminal-parasympathetic reflex mechanisms in the lower lip [17–24], tongue [25], palate [22,24], masseter muscle [26–34], and submandibular gland [3–5]. Furthermore, recent research on blood vessels in cerebral, pulmonary, renal, mesenteric, hepatic, ocular, uterine, nasal, skeletal muscle, and cutaneous arteries provides evidence of the existence of parasympathetic vasodilator fibers [35]. These studies indicate the importance of parasympathetic vasodilator fibers in regulating hemodynamics. The neural pathways mediating parasympathetic vasodilation, evoked by trigeminal nerve stimulation in salivary glands, are thought to be composed of the trigeminal afferent, spinal trigeminal nucleus (Vsp), superior and inferior salivary nucleus, submandibular, and otic postganglionic neurons (Fig. 1). The activation of neurons in the Vsp, elicited by trigeminal sensory input, has been previously observed in association with the immunohistochemical detection of c-Fos expression [36]. Parasympathetic preganglionic neurons in the salivary nucleus receive projections from the Vsp [37]; however, central neural connections between the salivary nucleus and other nuclei are still not well understood. The glossopharyngeal nerve contains efferent fibers from the inferior salivary nucleus, and connects with the parotid gland via the otic ganglion. Meanwhile, the facial nerve contains efferent fibers from the superior salivary nucleus, and connects with the submandibular and sublingual gland via the submandibular ganglion [38]. There are two different mechanisms that elicit parasympathetic vasodilation in the orofacial area; these are the reflex mechanism and direct stimulation of the parasympathetic efferent vasodilator fibers [17]. Electrical stimulation of the central cut end of the lingual nerve (Fig. 1), a branch of the trigeminal nerve, elicits reflex vasodilation, not only in the submandibular gland [3–5] but also in the lower lip [17–24], tongue [25], palate [22,24], and masseter muscle [26–34]. Conversely, direct electrical stimulation of the peripheral cut end of the parasympathetic vasodilator fibers, such as the chorda-lingual nerve innervation of the submandibular
Fig. 1. Schematic representation of neural pathways mediating the parasympathetic vasodilation evoked by trigeminal nerve stimulation and blood flow measurements in salivary glands. Solid lines indicate trigeminal sensory inputs to the brain stem (A) and sympathetic vasoconstrictor fibers to the salivary glands from the cervical sympathetic trunk, which were cut on both sides of the neck before the experiments (B). Broken lines indicate the possible pathways by which nerve excitation may evoke vasodilation in the salivary glands in response to lingual nerve stimulation. The stimulation site was the central cut end of the lingual nerve. Blood flow was measured in the three major salivary glands by using a laser speckle imaging flow meter. V, trigeminal nerve root; VII, facial nerve root; IX, glossopharyngeal nerve root.
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gland, elicits a non-reflex parasympathetic vasodilation in the submandibular gland [4,5]. The technique used to cause reflex vasodilation selectively activates the parasympathetic nerve in the orofacial area of animals who have undergone cervical sympathectomy, and simultaneously elicits vasodilation in major salivary glands. Thus, this technique enables us to understand the mechanisms underlying parasympathetic vasodilation and the physiological role of vasodilation in the orofacial region.
3. Parasympathetic vasodilation evoked by electrical stimulation of the trigeminal afferent nerve in the rat major salivary gland Lingual nerve stimulation-elicited intensity- and frequencydependent blood flow increases in the parotid, submandibular, and sublingual glands in rats, who have been anesthetized with urethane and artificially ventilated (Figs. 2 and 3). Although there was a significant increase in the systemic arterial blood pressure (SABP) during lingual nerve stimulation (from 95.2 73.3 mmHg before lingual nerve stimulation to 134.4 75.9 mmHg during lingual nerve stimulation), the changes in glandular vascular conductance (VC) obtained by dividing the blood flow by the mean SABP were significantly larger on the ipsilateral side than on the contralateral side (Fig. 2). This indicates that the increase in glandular blood flow was not secondary to changes in the SABP.
Additionally, there were no significant differences in the heart rate before and during lingual nerve stimulation [32]. These results suggest that the increases in glandular blood flow, which was caused by lingual nerve stimulation, was not a passive result of any evoked blood pressure change, and thus, can be justifiably referred to as ‘vasodilation’. The magnitude of the changes in VC was greater in the submandibular gland than in the parotid and sublingual glands, when the lingual nerve was stimulated by low intensities or frequencies (Fig. 3). The parasympathetic vasodilator fibers in the submandibular gland seem to be activated at high sensitivity in response to trigeminal sensory input. Vasodilation in the major salivary glands was significantly inhibited by intravenous administration of the autonomic cholinergic ganglion blocker hexamethonium, which indicates that this vasodilation was mainly mediated via parasympathetic nerves, since the cervical sympathetic trunks were cut in the neck bilaterally (Figs. 1 and 4). The antimuscarinic agent atropine markedly inhibited vasodilation in the parotid and submandibular glands, and partly inhibited vasodilation in the sublingual gland (Fig. 4). Atropine-resistant vasodilation in rat sublingual glands was significantly inhibited by infusion of a VIP receptor antagonist in the presence of atropine, although administration of a VIP receptor antagonist alone had no effect (Fig. 5). This suggests that non-cholinergic vasodilation in the sublingual gland is evoked via VIP receptors, when muscarinic receptors are blocked. Namely, vasodilation in the rat parotid and
Fig. 2. The effect of electrical stimulation of the central cut end of the left lingual nerve (LN) on blood flow in the submandibular gland (SMG) and the sublingual gland (SLG) on both sides. A: A photograph showing real images and the results of laser speckle imaging (LSI; at rest and during LN stimulation) of the SMG and SLG on both sides. Regions of interest (ROIs) are shown as open squares on both sides of the SMG and SLG. B: Typical examples of changes of blood flow (a.u., arbitrary units) and vascular conductance (VC) of the SMG and SLG on both sides, and systemic arterial blood pressure (SABP). VC was obtained by dividing the averaged signals from the ROI by the mean SABP. LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses (LN stim.). C: The change in the mean ( 7 standard of error) VC in the SLG (closed bars) and SMG (open bars) on both sides. *P o 0.01. (Modified from Ref. [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
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Fig. 3. The effect of electrical stimulation of the central cut end of the left lingual nerve (LN) on blood flow in the submandibular gland (SMG), parotid gland (PG), and the sublingual gland (SLG). A: Real images and the results of laser speckle imaging (LSI; at rest and during LN stimulation) of the three glands. Regions of interest (ROIs) are shown as open squares on the three glands. B: Typical examples of the changes in the vascular conductance (VC) of the three glands and the systemic arterial blood pressure (SABP). LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses (LN stim.). C: Stimulus intensity and frequency response relationships for changes in vascular conductance (VC) of the three glands on the left side, which was evoked by electrical stimulation of the central cut end of the left LN. The intensity and frequency response curves for VC in the SMG (filled circles), PG (filled squares), and SLG (filled triangles) were generated using LN stimulation at various intensities (1–30 V) and frequencies (1–30 Hz) for 20 s, using 2-ms pulses. The intensity response curves were generated using stimulus trains at 20 Hz, whereas frequency response curves were generated using stimulus trains at 20 V. The maximal value of the SMG in response to LN stimulation was taken as 100% and presented as mean 7 standard error. *P o 0.01, vs basal value (at intensity of 1 V and frequency of 1 Hz). ✝P o 0.01, significant differences between changes in the VC in SMG and SLG evoked by LN stimulation. ΦP o 0.01, significant differences between changes in VC in the SMG and PG evoked by LN stimulation. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
Fig. 4. The effect of intravenous administration of atropine and hexamethonium (C6) on blood flow increases in the submandibular gland (SMG), parotid gland (PG), and sublingual gland (SLG), which were evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). Changes in the mean ( 7 standard error) VC of the SLG (closed bars), SMG (open bars), and PG (gray bars) are shown. Changes in the VC of the three glands evoked by LN stimulation (control) were taken as 100%. *P o 0.05, vs control, **,✝,ΦP o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309: R1432–38).
submandibular glands is mainly evoked by cholinergic fibers, while vasodilation in the rat sublingual gland is evoked by cholinergic and non-cholinergic (i.e., VIP-ergic) fibers. Our results indicate that vasodilation, which occurs via the trigeminal-parasympathetic reflex in the major salivary glands, is regulated by
Fig. 5. Effect of intravenous administration of atropine and vasoactive intestinal peptide (VIP) antagonist on blood flow increase in the sublingual gland (SLG) evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). The graph shows the change in the mean ( 7 standard error) VC of the SLG. The changes in the VC of the SLG evoked by LN stimulation (control) were taken as 100%. *P o 0.05, vs control; **P o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
different neural mechanisms. These differences in the magnitude of activation of the parasympathetic vasodilator nerves, and the mechanisms underlying the regulation of hemodynamics may be responsible for the differences in secretory types among the major salivary glands.
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4. Interaction between acetylcholine and vasoactive intestinal peptide on the control of hemodynamics in salivary glands Acetylcholine (Ach) and VIP, two of the main neurotransmitters that are secreted by parasympathetic nerves innervating the salivary glands, are important in regulating glandular blood flow and salivation. The capillaries surrounding the acini receive blood from terminal arterioles, which run along the intralobular duct (intercalated and striated ducts) [39]. The dilation of terminal arterioles increases tissue blood flow. Although little has been reported on determining VIP-containing nerve fibers innervating glandular terminal arterioles by using histological methods, these fibers were richly distributed around striated ducts. Further, VIP-receptor mRNA was strongly expressed in striated ducts in both the submandibular and sublingual glands [40]. Thus, it may be assumed that glandular terminal arterioles are innervated by VIP-ergic vasodilator nerve fibers near the striated ducts. VIP-containing fibers
around the acini are richly observed in the submandibular gland, but not in the sublingual gland, which may play role in salivation [40]. Further, although there has been no description of its co-localization in the sublingual gland, VIP is co-localized with Ach in postganglionic parasympathetic nerve terminals in the submandibular gland [15,39,40]. These observations indicate the existence of interactions between Ach and VIP on the functions of the salivary gland. In our recent research, in order to examine the interaction between Ach and VIP on the regulation of glandular hemodynamics, we analyzed the effect of the time taken from peak to basal blood flow level (recovery time) on the parasympathetic vasodilation in rat sublingual gland (Fig. 6). The recovery time to basal blood flow level was longer for VIP (338.3743.3 s) than for acetylcholine (69.4 77.5 s), which could be attributed to differences in the mechanisms underlying vasodilation between those evoked by Ach and VIP (Fig. 6). Moreover, the recovery time after
Fig. 6. Time course analysis of blood flow increase in the sublingual gland (SLG) evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). A: Typical examples of changes in the blood flow in the sublingual gland (SLGBF; a.u., arbitrary units), vascular conductance (VC), and systemic arterial blood pressure (SABP) after LN stimulation, with and without intravenous administration of atropine (Atr; 1–100 μg/kg), and intravenous administration of acetylcholine (Ach; 100 ng/kg) or vasoactive intestinal peptide (VIP; 10 ng/kg). The LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses. B: Recovery time of blood flow increase in salivary glands. The time taken from peak to basal blood flow level was analyzed. C: The mean ( 7 standard error) recovery time with LN stimulation (closed bar), Ach administration (open bar), LN stimulation with atropine treatment (hatched bar), and VIP administration (shaded bar). *P o 0.05; **P o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
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lingual nerve stimulation was significantly delayed by administration of atropine in a dose-dependent manner, to the same level as that of the vasodilation observed in the sublingual gland, which was evoked following the administration of VIP (Fig. 6). Thus, our data suggest that the cholinergic mechanism of vasodilation in the sublingual gland evoked by lingual nerve stimulation becomes VIP-ergic, and is dependent on the activation of muscarinic receptors. Lundberg et al. (1981) proposed the existence of muscarinic autoreceptors that negatively regulate VIP release from the nerve endings of postganglionic parasympathetic nerves in the submandibular glands [6,41]. Furthermore, Duner-Engstrom et al. (1992) observed that atropine administration increased VIP release from the postganglionic parasympathetic nerves [42]. These investigations support our previous findings that muscarinic receptors negatively regulate VIP release in the parasympathetic vasodilator fibers in salivary glands.
5. Physiological role of parasympathetic vasodilation in the salivary glands The physiological relation between hemodynamics and secretory function in salivary glands is important, and has been the focus of research interest because salivary fluid is a mixture of water and ions created from blood plasma [1]. Thus, both salivary secretion and blood flow have been measured simultaneously to analyze the precise relationship between them. Salivary secretion in response to electrical stimulation of sensory nerves in the orofacial area is accompanied by an immediate blood flow increase to the salivary glands [5]. Lung (1990, 1998) was the first to address the question regarding the relationship between blood flow and salivary secretion directly, with controlled arterial blood flow to the submandibular gland in anesthetized dogs [43,44]. Longer periods (e.g., 5 min) of cessation or reduction in arterial blood flow resulted in reduced salivary secretion, which was highly dependent on blood flow during parasympathetic stimulation. Hanna et al. (1999) demonstrated that salivary secretion induced by electrical stimulation of parasympathetic nerve was significantly decreased when the glandular blood flow was reduced during the period of hypotension in the submandibular glands [45]. Furthermore, a reduction in glandular blood flow induced by endothelin1, a potent vasoconstrictor peptide, causes significant reduction in salivary secretion during stimulation of the chorda-lingual nerve [46–48]. These findings suggest that a reduction in glandular resting blood flow and parasympathetic vasodilation affects salivary flow during parasympathetic salivation. Therefore, although there is limited evidence to suggest this, it is likely that salivary fluid secretion depends on the regulation of glandular blood flow. Reduction in salivary secretion that results in xerostomia, which is widely known as dry mouth, is a common problem among older adults, people who are administered drugs that elicit the symptom, and patients suffering from diseases such as diabetes mellitus and Sjögren's syndrome. In diabetes, dry mouth is caused the decreased salivary flow due to damage to the gland parenchyma, alterations in the microcirculation to the salivary glands, dehydration, and disturbances in glycemic control [49]. Impaired parasympathetic vasodilation in the submandibular gland was demonstrated in streptozotocin-diabetic rats [50,51]. Further, we recently demonstrated that type 2 diabetes impairs parasympathetic vasodilation in the parotid gland, which may be caused by a disturbance in the cholinergic vasodilator pathway [52]. These observations suggest that disturbances in parasympathetic vasodilation may play an important role in the etiology of salivary secretory disorders.
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6. Conclusions Trigeminal sensory input elicits parasympathetic vasodilation in salivary glands, which is mainly evoked by cholinergic fibers in the submandibular and parotid glands, and by cholinergic and VIPergic fibers in the sublingual gland. The differences in the mechanisms underlying parasympathetic vasodilation may be functionally related to differences in secretory types among the major salivary glands.
Ethical approval This review cites papers that have already been published. Each had received its own ethical approval and was documented in the original publications.
Conflicts of interest The authors have declared no conflicts of interest.
Acknowledgments This work was supported in part by MEXT KAKENHI (Grant 26861557 and 16K20425 to T. Sato and Grant 25462896 to H. Ishii).
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Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job
Review
Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation Toshiya Sato, Hisayoshi Ishii n Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 16 January 2017 Received in revised form 22 February 2017 Accepted 27 February 2017 Available online 28 March 2017
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. Highlight: Electrical stimulation of the lingual nerve, a branch of the trigeminal nerve, elicits parasympathetic vasodilation in the salivary glands. Parasympathetic vasodilation is mainly evoked by cholinergic fibers in the submandibular and parotid glands and by cholinergic and vasoactive intestinal peptide (VIP)-ergic fibers in the sublingual gland. The vasodilator mechanism changes from cholinergic to VIP-ergic when muscarinic receptors are deactivated. Conclusion: Glandular hemodynamics in the submandibular, parotid, and sublingual glands are regulated by different parasympathetic vasodilator mechanisms, which may functionally contribute to the differences in secretion among the major salivary glands. & 2017 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
Keywords: Parasympathetic vasodilation Cholinergic vasodilator fibers Non-cholinergic vasodilator fibers Vasoactive intestinal polypeptide
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nerve-mediated vasodilation in the orofacial area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Parasympathetic vasodilation evoked by electrical stimulation of the trigeminal afferent nerve in the rat major salivary gland. 4. Interaction between acetylcholine and vasoactive intestinal peptide on the control of hemodynamics in salivary glands . . . . . . 5. Physiological role of parasympathetic vasodilation in the salivary glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Hemodynamics in the salivary gland are largely regulated by
Abbreviations: Ach, acetylcholine; SABP, systemic arterial blood pressure; VC, vascular conductance; VIP, vasoactive intestinal peptide; Vsp, spinal trigeminal nucleus n Correspondence to: Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail address: [email protected] (H. Ishii).
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both the sympathetic and parasympathetic nervous systems [1]. The importance of the autonomic nervous system in the regulation of glandular hemodynamics was established by Bernard in 1858 [2], who observed that stimulation of the sympathetic nerve caused vasoconstriction, whereas stimulation of the parasympathetic nerve led to marked vasodilation. The parasympathetic vasodilator response is due to both cholinergic and non-cholinergic neurotransmitters, such as vasoactive intestinal peptide (VIP) [3–15]. Conversely, the sympathetic
http://dx.doi.org/10.1016/j.job.2017.03.002 1349-0079/& 2017 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
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vasoconstrictor response is mainly due to α-adrenoceptor activation and neuropeptide Y, and only a small portion of the vasodilator response is attributable to β-adrenoceptor activation [16]. Taken together, these studies demonstrated that the autonomic nervous system is involved in regulating the secretion and hemodynamics of the salivary gland. In addition to salivary secretion, trigeminal sensory input induces cholinergic as well as non-cholinergic parasympathetic reflex vasodilation in the salivary glands [3–5]. The sympathetic vasoconstrictive nerve fibers to the salivary glands, however, remain in a state of tonic control. Therefore, parasympathetic vasoactive nerve fibers predominantly contribute to vasodilation under reflex conditions, such as during feeding [1]. This glandular vasodilation is thought to be important in the regulation of glandular hemodynamics due to the rapidity with which blood flow increases. Parasympathetic reflex vasodilation in salivary glands, especially in the submandibular gland, has been previously examined [3–5]. It is thought that the mechanisms underlying glandular parasympathetic vasodilation differ among the major salivary glands, because of differences in the composition of serous and mucous acini and the type of secretion. In this review, we focus on the differences in parasympathetic vasodilation among the major salivary glands, the interaction between cholinergic and non-cholinergic vasodilator mechanisms, and the physiological role of parasympathetic vasodilation in salivary glands.
2. Nerve-mediated vasodilation in the orofacial area Until quite recently, it was believed that the regulation of blood flow in the orofacial area depended on vasoconstrictor fibers from the cervical sympathetic trunk, that is, an increase in sympathetic nerve activation induced vasoconstriction, while vasodilation was elicited by a decrease in sympathetic nerve activation. However, as we previously reported, parasympathetic vasodilator fibers exist in
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the orofacial area, and trigeminal sensory input elicits vasodilation mediated via trigeminal-parasympathetic reflex mechanisms in the lower lip [17–24], tongue [25], palate [22,24], masseter muscle [26–34], and submandibular gland [3–5]. Furthermore, recent research on blood vessels in cerebral, pulmonary, renal, mesenteric, hepatic, ocular, uterine, nasal, skeletal muscle, and cutaneous arteries provides evidence of the existence of parasympathetic vasodilator fibers [35]. These studies indicate the importance of parasympathetic vasodilator fibers in regulating hemodynamics. The neural pathways mediating parasympathetic vasodilation, evoked by trigeminal nerve stimulation in salivary glands, are thought to be composed of the trigeminal afferent, spinal trigeminal nucleus (Vsp), superior and inferior salivary nucleus, submandibular, and otic postganglionic neurons (Fig. 1). The activation of neurons in the Vsp, elicited by trigeminal sensory input, has been previously observed in association with the immunohistochemical detection of c-Fos expression [36]. Parasympathetic preganglionic neurons in the salivary nucleus receive projections from the Vsp [37]; however, central neural connections between the salivary nucleus and other nuclei are still not well understood. The glossopharyngeal nerve contains efferent fibers from the inferior salivary nucleus, and connects with the parotid gland via the otic ganglion. Meanwhile, the facial nerve contains efferent fibers from the superior salivary nucleus, and connects with the submandibular and sublingual gland via the submandibular ganglion [38]. There are two different mechanisms that elicit parasympathetic vasodilation in the orofacial area; these are the reflex mechanism and direct stimulation of the parasympathetic efferent vasodilator fibers [17]. Electrical stimulation of the central cut end of the lingual nerve (Fig. 1), a branch of the trigeminal nerve, elicits reflex vasodilation, not only in the submandibular gland [3–5] but also in the lower lip [17–24], tongue [25], palate [22,24], and masseter muscle [26–34]. Conversely, direct electrical stimulation of the peripheral cut end of the parasympathetic vasodilator fibers, such as the chorda-lingual nerve innervation of the submandibular
Fig. 1. Schematic representation of neural pathways mediating the parasympathetic vasodilation evoked by trigeminal nerve stimulation and blood flow measurements in salivary glands. Solid lines indicate trigeminal sensory inputs to the brain stem (A) and sympathetic vasoconstrictor fibers to the salivary glands from the cervical sympathetic trunk, which were cut on both sides of the neck before the experiments (B). Broken lines indicate the possible pathways by which nerve excitation may evoke vasodilation in the salivary glands in response to lingual nerve stimulation. The stimulation site was the central cut end of the lingual nerve. Blood flow was measured in the three major salivary glands by using a laser speckle imaging flow meter. V, trigeminal nerve root; VII, facial nerve root; IX, glossopharyngeal nerve root.
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gland, elicits a non-reflex parasympathetic vasodilation in the submandibular gland [4,5]. The technique used to cause reflex vasodilation selectively activates the parasympathetic nerve in the orofacial area of animals who have undergone cervical sympathectomy, and simultaneously elicits vasodilation in major salivary glands. Thus, this technique enables us to understand the mechanisms underlying parasympathetic vasodilation and the physiological role of vasodilation in the orofacial region.
3. Parasympathetic vasodilation evoked by electrical stimulation of the trigeminal afferent nerve in the rat major salivary gland Lingual nerve stimulation-elicited intensity- and frequencydependent blood flow increases in the parotid, submandibular, and sublingual glands in rats, who have been anesthetized with urethane and artificially ventilated (Figs. 2 and 3). Although there was a significant increase in the systemic arterial blood pressure (SABP) during lingual nerve stimulation (from 95.2 73.3 mmHg before lingual nerve stimulation to 134.4 75.9 mmHg during lingual nerve stimulation), the changes in glandular vascular conductance (VC) obtained by dividing the blood flow by the mean SABP were significantly larger on the ipsilateral side than on the contralateral side (Fig. 2). This indicates that the increase in glandular blood flow was not secondary to changes in the SABP.
Additionally, there were no significant differences in the heart rate before and during lingual nerve stimulation [32]. These results suggest that the increases in glandular blood flow, which was caused by lingual nerve stimulation, was not a passive result of any evoked blood pressure change, and thus, can be justifiably referred to as ‘vasodilation’. The magnitude of the changes in VC was greater in the submandibular gland than in the parotid and sublingual glands, when the lingual nerve was stimulated by low intensities or frequencies (Fig. 3). The parasympathetic vasodilator fibers in the submandibular gland seem to be activated at high sensitivity in response to trigeminal sensory input. Vasodilation in the major salivary glands was significantly inhibited by intravenous administration of the autonomic cholinergic ganglion blocker hexamethonium, which indicates that this vasodilation was mainly mediated via parasympathetic nerves, since the cervical sympathetic trunks were cut in the neck bilaterally (Figs. 1 and 4). The antimuscarinic agent atropine markedly inhibited vasodilation in the parotid and submandibular glands, and partly inhibited vasodilation in the sublingual gland (Fig. 4). Atropine-resistant vasodilation in rat sublingual glands was significantly inhibited by infusion of a VIP receptor antagonist in the presence of atropine, although administration of a VIP receptor antagonist alone had no effect (Fig. 5). This suggests that non-cholinergic vasodilation in the sublingual gland is evoked via VIP receptors, when muscarinic receptors are blocked. Namely, vasodilation in the rat parotid and
Fig. 2. The effect of electrical stimulation of the central cut end of the left lingual nerve (LN) on blood flow in the submandibular gland (SMG) and the sublingual gland (SLG) on both sides. A: A photograph showing real images and the results of laser speckle imaging (LSI; at rest and during LN stimulation) of the SMG and SLG on both sides. Regions of interest (ROIs) are shown as open squares on both sides of the SMG and SLG. B: Typical examples of changes of blood flow (a.u., arbitrary units) and vascular conductance (VC) of the SMG and SLG on both sides, and systemic arterial blood pressure (SABP). VC was obtained by dividing the averaged signals from the ROI by the mean SABP. LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses (LN stim.). C: The change in the mean ( 7 standard of error) VC in the SLG (closed bars) and SMG (open bars) on both sides. *P o 0.01. (Modified from Ref. [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
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Fig. 3. The effect of electrical stimulation of the central cut end of the left lingual nerve (LN) on blood flow in the submandibular gland (SMG), parotid gland (PG), and the sublingual gland (SLG). A: Real images and the results of laser speckle imaging (LSI; at rest and during LN stimulation) of the three glands. Regions of interest (ROIs) are shown as open squares on the three glands. B: Typical examples of the changes in the vascular conductance (VC) of the three glands and the systemic arterial blood pressure (SABP). LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses (LN stim.). C: Stimulus intensity and frequency response relationships for changes in vascular conductance (VC) of the three glands on the left side, which was evoked by electrical stimulation of the central cut end of the left LN. The intensity and frequency response curves for VC in the SMG (filled circles), PG (filled squares), and SLG (filled triangles) were generated using LN stimulation at various intensities (1–30 V) and frequencies (1–30 Hz) for 20 s, using 2-ms pulses. The intensity response curves were generated using stimulus trains at 20 Hz, whereas frequency response curves were generated using stimulus trains at 20 V. The maximal value of the SMG in response to LN stimulation was taken as 100% and presented as mean 7 standard error. *P o 0.01, vs basal value (at intensity of 1 V and frequency of 1 Hz). ✝P o 0.01, significant differences between changes in the VC in SMG and SLG evoked by LN stimulation. ΦP o 0.01, significant differences between changes in VC in the SMG and PG evoked by LN stimulation. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
Fig. 4. The effect of intravenous administration of atropine and hexamethonium (C6) on blood flow increases in the submandibular gland (SMG), parotid gland (PG), and sublingual gland (SLG), which were evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). Changes in the mean ( 7 standard error) VC of the SLG (closed bars), SMG (open bars), and PG (gray bars) are shown. Changes in the VC of the three glands evoked by LN stimulation (control) were taken as 100%. *P o 0.05, vs control, **,✝,ΦP o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309: R1432–38).
submandibular glands is mainly evoked by cholinergic fibers, while vasodilation in the rat sublingual gland is evoked by cholinergic and non-cholinergic (i.e., VIP-ergic) fibers. Our results indicate that vasodilation, which occurs via the trigeminal-parasympathetic reflex in the major salivary glands, is regulated by
Fig. 5. Effect of intravenous administration of atropine and vasoactive intestinal peptide (VIP) antagonist on blood flow increase in the sublingual gland (SLG) evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). The graph shows the change in the mean ( 7 standard error) VC of the SLG. The changes in the VC of the SLG evoked by LN stimulation (control) were taken as 100%. *P o 0.05, vs control; **P o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
different neural mechanisms. These differences in the magnitude of activation of the parasympathetic vasodilator nerves, and the mechanisms underlying the regulation of hemodynamics may be responsible for the differences in secretory types among the major salivary glands.
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4. Interaction between acetylcholine and vasoactive intestinal peptide on the control of hemodynamics in salivary glands Acetylcholine (Ach) and VIP, two of the main neurotransmitters that are secreted by parasympathetic nerves innervating the salivary glands, are important in regulating glandular blood flow and salivation. The capillaries surrounding the acini receive blood from terminal arterioles, which run along the intralobular duct (intercalated and striated ducts) [39]. The dilation of terminal arterioles increases tissue blood flow. Although little has been reported on determining VIP-containing nerve fibers innervating glandular terminal arterioles by using histological methods, these fibers were richly distributed around striated ducts. Further, VIP-receptor mRNA was strongly expressed in striated ducts in both the submandibular and sublingual glands [40]. Thus, it may be assumed that glandular terminal arterioles are innervated by VIP-ergic vasodilator nerve fibers near the striated ducts. VIP-containing fibers
around the acini are richly observed in the submandibular gland, but not in the sublingual gland, which may play role in salivation [40]. Further, although there has been no description of its co-localization in the sublingual gland, VIP is co-localized with Ach in postganglionic parasympathetic nerve terminals in the submandibular gland [15,39,40]. These observations indicate the existence of interactions between Ach and VIP on the functions of the salivary gland. In our recent research, in order to examine the interaction between Ach and VIP on the regulation of glandular hemodynamics, we analyzed the effect of the time taken from peak to basal blood flow level (recovery time) on the parasympathetic vasodilation in rat sublingual gland (Fig. 6). The recovery time to basal blood flow level was longer for VIP (338.3743.3 s) than for acetylcholine (69.4 77.5 s), which could be attributed to differences in the mechanisms underlying vasodilation between those evoked by Ach and VIP (Fig. 6). Moreover, the recovery time after
Fig. 6. Time course analysis of blood flow increase in the sublingual gland (SLG) evoked by electrical stimulation of the central cut end of the left lingual nerve (LN). A: Typical examples of changes in the blood flow in the sublingual gland (SLGBF; a.u., arbitrary units), vascular conductance (VC), and systemic arterial blood pressure (SABP) after LN stimulation, with and without intravenous administration of atropine (Atr; 1–100 μg/kg), and intravenous administration of acetylcholine (Ach; 100 ng/kg) or vasoactive intestinal peptide (VIP; 10 ng/kg). The LN was stimulated for 20 s with a supramaximal voltage of 20 V at 20 Hz, using 2-ms pulses. B: Recovery time of blood flow increase in salivary glands. The time taken from peak to basal blood flow level was analyzed. C: The mean ( 7 standard error) recovery time with LN stimulation (closed bar), Ach administration (open bar), LN stimulation with atropine treatment (hatched bar), and VIP administration (shaded bar). *P o 0.05; **P o 0.01, vs control. (Modified from reference [5]: Sato T, Ishii H. Am J Physiol Regul Integr Comp Physiol 2015;309:R1432–38).
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lingual nerve stimulation was significantly delayed by administration of atropine in a dose-dependent manner, to the same level as that of the vasodilation observed in the sublingual gland, which was evoked following the administration of VIP (Fig. 6). Thus, our data suggest that the cholinergic mechanism of vasodilation in the sublingual gland evoked by lingual nerve stimulation becomes VIP-ergic, and is dependent on the activation of muscarinic receptors. Lundberg et al. (1981) proposed the existence of muscarinic autoreceptors that negatively regulate VIP release from the nerve endings of postganglionic parasympathetic nerves in the submandibular glands [6,41]. Furthermore, Duner-Engstrom et al. (1992) observed that atropine administration increased VIP release from the postganglionic parasympathetic nerves [42]. These investigations support our previous findings that muscarinic receptors negatively regulate VIP release in the parasympathetic vasodilator fibers in salivary glands.
5. Physiological role of parasympathetic vasodilation in the salivary glands The physiological relation between hemodynamics and secretory function in salivary glands is important, and has been the focus of research interest because salivary fluid is a mixture of water and ions created from blood plasma [1]. Thus, both salivary secretion and blood flow have been measured simultaneously to analyze the precise relationship between them. Salivary secretion in response to electrical stimulation of sensory nerves in the orofacial area is accompanied by an immediate blood flow increase to the salivary glands [5]. Lung (1990, 1998) was the first to address the question regarding the relationship between blood flow and salivary secretion directly, with controlled arterial blood flow to the submandibular gland in anesthetized dogs [43,44]. Longer periods (e.g., 5 min) of cessation or reduction in arterial blood flow resulted in reduced salivary secretion, which was highly dependent on blood flow during parasympathetic stimulation. Hanna et al. (1999) demonstrated that salivary secretion induced by electrical stimulation of parasympathetic nerve was significantly decreased when the glandular blood flow was reduced during the period of hypotension in the submandibular glands [45]. Furthermore, a reduction in glandular blood flow induced by endothelin1, a potent vasoconstrictor peptide, causes significant reduction in salivary secretion during stimulation of the chorda-lingual nerve [46–48]. These findings suggest that a reduction in glandular resting blood flow and parasympathetic vasodilation affects salivary flow during parasympathetic salivation. Therefore, although there is limited evidence to suggest this, it is likely that salivary fluid secretion depends on the regulation of glandular blood flow. Reduction in salivary secretion that results in xerostomia, which is widely known as dry mouth, is a common problem among older adults, people who are administered drugs that elicit the symptom, and patients suffering from diseases such as diabetes mellitus and Sjögren's syndrome. In diabetes, dry mouth is caused the decreased salivary flow due to damage to the gland parenchyma, alterations in the microcirculation to the salivary glands, dehydration, and disturbances in glycemic control [49]. Impaired parasympathetic vasodilation in the submandibular gland was demonstrated in streptozotocin-diabetic rats [50,51]. Further, we recently demonstrated that type 2 diabetes impairs parasympathetic vasodilation in the parotid gland, which may be caused by a disturbance in the cholinergic vasodilator pathway [52]. These observations suggest that disturbances in parasympathetic vasodilation may play an important role in the etiology of salivary secretory disorders.
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6. Conclusions Trigeminal sensory input elicits parasympathetic vasodilation in salivary glands, which is mainly evoked by cholinergic fibers in the submandibular and parotid glands, and by cholinergic and VIPergic fibers in the sublingual gland. The differences in the mechanisms underlying parasympathetic vasodilation may be functionally related to differences in secretory types among the major salivary glands.
Ethical approval This review cites papers that have already been published. Each had received its own ethical approval and was documented in the original publications.
Conflicts of interest The authors have declared no conflicts of interest.
Acknowledgments This work was supported in part by MEXT KAKENHI (Grant 26861557 and 16K20425 to T. Sato and Grant 25462896 to H. Ishii).
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