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Journal of Dental Research
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Biological

Responses of the Human Submandibular Artery to ACh and VIP

D. Stojic1,*, S. Pesic2, M. Radenkovic3, J. Popovic-Roganovic1, Z. Pesic4 and L. Grbovic3

1 Department of Pharmacology, Faculty of Stomatology, University of Belgrade, Dr. Subotica br. 8, 11 000 Belgrade;
2 Department of Pharmacology, Medical Faculty, University of Nis;
3 Department of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade; and
4 Department of Maxillofacial Surgery, Medical Faculty, University of Nis, Serbia and Montenegro

Correspondence: * corresponding author, miona-25{at}beotel.yu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Endothelial vasodilatory substances may play a central role in the local regulation of vascular tone. We hypothesized that these substances can mediate endothelium-dependent vasodilatory responses to acetylcholine (ACh) and vasoactive intestinal peptide (VIP) in the human submandibular artery. We evaluated the contributions of endothelial vasodilatory substances to vessel relaxation in response to ACh and VIP, using different inhibitors of endothelial vasodilation, the nitric oxide synthase inhibitor, the cyclo-oxygenase inhibitor, indomethacin, the potassium channel blocker, and 4-aminopyridine. ACh and VIP caused an endothelium- and concentration-dependent relaxation in this artery. ACh relaxation was completely blocked after the concomitant addition of NG-nitro-L-arginine and indomethacin. The vasorelaxant effect of ACh was not influenced by 4-aminopyridine. VIP relaxation was almost completely abolished by 4-aminopyridine, and was partly inhibited by NG-nitro-L-arginine, but was not affected by indomethacin. Thus, in the human submandibular artery, ACh and VIP produced endothelium-dependent vasodilation with different underlying mechanisms: release of nitric oxide (NO) and cyclo-oxygenase products for ACh, and release of NO and endothelium-derived hyperpolarizing factor for VIP.

Key Words: ACh • VIP • human submandibular artery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Parasympathetic stimulation of salivary glands promotes salivation, to which the accompanying vasodilation significantly contributes to the overall fluid secreted volume. Thus, vasodilation within the gland is controlled not only in an autocrine fashion, locally by the parenchymal gland cells, but also by neurotransmitters released by parasympathetic neurons (Edwards, 1998). However, little is known regarding the extraglandular regulation of vasodilation for the main artery that provides the blood supply to each gland. A case in point is the parasympathetic control of the human submandibular artery, the main vessel supplying the submandibular gland.

The human submandibular gland is richly innervated with numerous acetylcholinesterase-positive terminals present around acini and glandular blood vessels (Garrett, 1967). To this, parasympathetic innervation, mediated by acetylcholine (ACh), further contributes a non-cholinergic mechanism of control involving release of co-transmitters, such as vasoactive intestinal peptide (VIP) (Ekström, 1999). The human submandibular gland shows a lesser presence of VIP-reactive nerve fibers around blood vessels, but a denser distribution of these nerve fibers around mucous acini (Kusakabe et al., 1997), while data are lacking for the extraglandular distribution of parasympathetic fibers around the main supply artery. Functional studies have also shown the presence of VIP in resting, as well as in stimulated, saliva in healthy individuals (Dawidson et al., 1997). Moreover, animal studies have demonstrated that VIP itself stimulates salivary flow and increases protein secretion, as well as potentiating the salivary volume response to ACh, and that neuronal VIP significantly increases the blood flow in the salivary glands (Lundberg et al., 1981; Ekström, 1999).

In addition, vascular endothelium contributes to the local regulation of vascular smooth-muscle tone by releasing various vasoactive products. Endothelial cells of many blood vessels induce vasodilation when stimulated by ACh and the ACh-released dilatory mediators, such as nitric oxide (NO), cyclo-oxygenase products, and endothelium-derived hyperpolarizing factor (EDHF) (Ignarro et al., 1987a; Palmer et al., 1987). VIP can cause endothelium-dependent (through release of NO) or endothelium-independent vasodilation (through elevation of cAMP levels in vascular smooth-muscle cells) (Fiscus, 1988).

To understand the extraglandular parasympathetic control of vascular tone of the human submandibular artery, the present study aimed to determine the vasorelaxant responses to ACh and VIP in the presence and absence of endothelium, and to establish whether mediators produced by endothelial or non-endothelial cells contribute to the control of vascular responses.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Fourteen patients (ages 30–45 yrs; eight females and six males) undergoing surgery for salivary duct calculus excision were enrolled in this study. Before the administration of anesthesia, initiated with propofol (1.5 mg/kg), and maintained with halothane (0.5 %) and NO2 (65%), the patients were administered diazepam (0.1 mg/kg), fentanyl (1 µg/kg), and succinylcholine (1 mg/kg) intravenously. During surgery, submandibular arteries were ligated and dissected into segments (2 segments from each patient). Segments were immediately immersed in ice-cold Krebs-Ringer-bicarbonate solution and transported to the in vitro experimental set-up within 20 min.

Prior to the study, the experimental design was approved by the Ethical Committee at the Faculty of Medicine, University of Nis, and written informed patient consent was obtained.

Vascular Preparations
Segments of the human submandibular arteries (diameter, 1–3 mm) were carefully dissected free from surrounding connective tissue and cut into 3-mm-long circular rings. All vessel segments were immediately placed in Krebs-Ringer-bicarbonate solution (composition, in mmol/L: NaCl, 118.3; KCl, 4.7; CaCl2, 2.5; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 25.0; glucose, 11.1). In some rings, we removed the endothelial layer mechanically by gently rubbing the surface with a stainless-steel wire. The rings were then suspended in organ chambers filled with 10 mL Krebs-Ringer-bicarbonate solution (37°C), aerated with 95% O2 and 5% CO2, which produced a solution pH of 7.4. The rings were then connected to a displacement transducer (Hugo Sachs K30, Freiburg, Germany), and changes in isometric force were recorded (Hugo Sachs model MC 6621 recorder, Freiburg, Germany).

The vascular preparations were equilibrated for 1 hr, after which the segments were gradually given a final pre-load of 0.5 g (Larsson et al., 1986). Once at their optimal length, the rings were allowed to equilibrate for a further 30 min before experimentation.

Experimental Procedure
The presence of functional endothelium was confirmed by the apparent relaxation of artery rings in response to ACh (1 µM) pre-contracted with phenylephrine (1 µM).

We obtained concentration-response curves for acetylcholine (10–10 – 3 x 10–4 mol/L) and VIP (3 x 10–9 – 3 x 10–7 mol/L) by adding increasing concentrations of those agonists to rings pre-contracted with phenylephrine. It could be hypothesized that, during eating, the blood vessels being investigated have a "sympathetic" tone, since, according to Bartsch et al.(1996), sympathetic vasoconstrictor neurons within the submandibular gland of the rat appeared to exercise a continuous tonic effect. Since separate experiments with preparations of submandibular arteries showed that the first and second concentration-response curves (obtained after 60 min) for tested agonists were not significantly different, a multiple-curve experimental design was applied.

Therefore, the following protocol was used: (1) pre-contraction with phenylephrine (1–3 x 10–6 mol/L), and a concentration-response curve with ACh, followed by 3 washes, the addition of specific inhibitor, and a 30-minute equilibration period; and (2) pre-contraction with phenylephrine (1–3 x 10–6 mol/L) and a concentration-response curve with ACh. The same procedure was applied for VIP, except that, in some experiments, specimens were incubated with forskolin. Phenylephrine-elicited pre-contractions for the first and the second concentration-response curves were not significantly different, regardless of the absence or the presence of incubated antagonists.

Treatment of Data and Statistics
The relaxation induced by each concentration of ACh or VIP was expressed as a percent relaxation of the pre-contraction, including maximal relaxant effect. The concentration of ACh or VIP eliciting 50% of its own maximum response (EC50) was determined graphically for each curve by linear interpolation. EC50 values are presented as pEC50 (pEC50 = –logEC50). The results are expressed as means ± SEM; n refers to the number of experiments. The data were analyzed statistically by Student’s t test for paired observations. Differences between means were considered to be significant when P < 0.05.

Drugs Used
The following drugs were used: phenylephrine hydrochloride, indomethacin (a cyclo-oxygenase inhibitor), forskolin (an adenylate cyclase stimulator) (all from Sigma, St. Louis, MO, USA), NG-nitro-L-arginine (L-NOARG; a non-selective NO synthase inhibitor; RBI, Natick, MA, USA), 4-aminopyridine (4-AP; potassium channel blocker; Tocris, Bristol, UK), acetylcholine iodide (Serva, Heidelberg, Germany); and vasoactive intestinal peptide (Calbiochem, La Jolla, CA, USA). Indomethacin was dissolved in equimolar Na2CO3 solution, and forskolin and 4-AP were dissolved in DMSO. All other agents were dissolved in distilled water. All drugs were added directly to the bath in volumes of 150 mL, and the concentrations given are the calculated final concentrations in the bath solution.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
ACh-induced Relaxation
In phenylephrine-pre-contracted intact human submandibular arterial rings, ACh (10–10 – 3 x 10–4 mol/L) induced concentration-dependent relaxation, with an pEC50 = 6.35 ± 0.02 and maximal relaxation of 89.5 ± 2.6% (n = 4). Acetylcholine-induced vasodilation was not observed in rings where the endothelium had been removed (n = 4, Fig. 1AGo).


Figure 1
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  		Figure 1. The effects of endothelial denudation (A) and L-NOARG, 10–5 mol/L (B), on ACh-produced relaxant action in the human submandibular artery. Each point represents mean ± SEM (n = 4). Responses are expressed as percentages of the phenylephrine pre-contraction.

 
Treatment with L-NOARG (10–5 mol/L), a non-selective inhibitor of NOS, resulted in significant reduction of the ACh-evoked relaxation. In the presence and absence of L-NOARG, the response to ACh, expressed as pEC50, was 6.48 ± 0.05 and 6.31 ± 0.01, and maximal relaxation was 92.0 ± 2.9% and 62.2 ± 4.6%, n = 4 (P < 0.05), respectively (Fig. 1BGo).

Moreover, in the presence of indomethacin (10–5 mol/L), a cyclo-oxygenase inhibitor, the relaxant effect of ACh was also reduced. Indeed, the pEC50 of ACh was 6.62 ± 0.01 and 6.13 ± 0.02, and maximal relaxation 82.9 ± 3.0% and 68.4 ± 2.1%, n = 4 (P < 0.05), with and without indomethacin, respectively (Fig. 2AGo).


Figure 2
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  		Figure 2. The effects of indomethacin, 10–5 mol/L (A), concomitant incubation of indomethacin, 10–5 mol/L, and L-NOARG, 10–5 mol/L (B), and 4-aminopyridine, 10–5 mol/L (C), on ACh-produced relaxant action in the human submandibular artery. Each point represents mean ± SEM (n = 4). Responses are expressed as percentages of the phenylephrine pre-contraction.

 
In fact, the concomitant addition of L-NOARG and indomethacin had an additive effect and strongly inhibited ACh-induced relaxation (pEC50 = 6.21 ± 0.02 vs. 6.33 ± 0.08; maximal relaxation = 91.6 ± 3.0% vs. 38.5 ± 2.1%, n = 4, P < 0.01) (Fig. 2BGo). The obtained reduction was significantly higher compared with those observed after separate incubation with L-NOARG or indomethacin.

In contrast to the effects of L-NOARG and indomethacin, treatment with 4-AP (10–5 mol/L), a broad-spectrum potassium channel blocker, had no effect on ACh-induced relaxation (pEC50 = 6.50 ± 0.01 vs. 6.47 ± 0.06; maximal relaxation = 80.0 ± 3.0% vs. 88.0 ± 3.5%, n = 4, P > 0.05) (Fig. 2CGo).

VIP-induced Relaxation
Similarly to ACh, VIP (3 x 10–9 – 3 x 10–7 mol/L) induced a concentration-dependent relaxation in endothelium-containing (pEC50 = 7.62 ± 0.01; maximal relaxation = 80.4 ± 4.2%, n = 7), but not in endothelium-denuded, rings of the human submandibular artery (n = 7, Fig. 3AGo).


Figure 3
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  		Figure 3. The effects of endothelial denudation (A) and L-NOARG, 10–5 mol/L (B), on VIP-produced relaxant action in the human submandibular artery. Each point represents mean ± SEM (A, n = 7; B, n = 5). Responses are expressed as percentages of the phenylephrine pre-contraction.

 
However, in contrast to ACh, the VIP vasorelaxant effect, although responsive to NOS inhibition, was not responsive to cyclo-oxygenase inhibition. Specifically, when the artery segments were pre-treated with 10–5 mol/L L-NOARG, the relaxant response to VIP was significantly reduced (pEC50 = 7.50 ± 0.10 vs. 7.30 ± 0.09; maximal relaxation = 79.3 ± 6.1% vs. 39.3 ± 3.8%, n = 5, P < 0.05; Fig. 3BGo), whereas indomethacin (10–5 mol/L) was without effect (pEC50 = 7.56 ± 0.14 vs. 7.66 ± 0.05; maximal relaxation = 78.0 ± 3.1% vs. 85.5 ± 2.6%, n = 4, P > 0.05; Fig. 4AGo).


Figure 4
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  		Figure 4. The effects of indomethacin, 10–5 mol/L (A), 4-aminopyridine, 10–5 mol/L (B), and forskolin, 10–5 mol/L (C), on VIP-produced relaxant action in the human submandibular artery. Each point represents mean ± SEM (A and C, n = 4; B, n = 5). Responses are expressed as percentages of the phenylephrine pre-contraction.

 
Furthermore, pre-treatment with 4-AP (10–5 mol/L) almost completely inhibited VIP-induced relaxation (maximal relaxation = 84.5 ± 1.5% vs. 18.0 ± 2.7%, n = 5, P < 0.01; Fig. 4BGo).

Since VIP vascular effects are mediated through cAMP signaling, the effect of VIP was tested in the presence of adenylate cyclase inhibitor, forskolin. In the presence of forskolin (10–5 mol/L), the relaxant effect of VIP was not significantly changed (pEC50 = 7.67 ± 0.03 vs. 7.58 ± 0.13; maximal relaxation = 79.8 ± 3.8% vs. 79.9 ± 2.6%, n = 4, P > 0.05) (Fig. 4CGo).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Analysis of the present data demonstrates that ACh and VIP induced endothelium-dependent vasorelaxation of the human submandibular artery. While ACh acted through the release of NO and cyclo-oxygenase products, VIP acted via the release of NO and EDHF. This would suggest the existence of distinct pathways in the parasympathetic neurotransmitter and co-transmitter regulation of vascular activity of the main artery supplying the human submandibular gland.

This is supported by the following findings. ACh-induced relaxation in the human submandibular artery rings was completely abolished by removal of the endothelium, and was only partly reduced by treatment with either L-NOARG, an inhibitor of NO synthase, or indomethacin, an inhibitor of cyclo-oxygenase. Thus, the relaxation induced by ACh in endothelium-intact submandibular artery rings appeared to involve endothelial NO, as well as endothelial-derived cyclo-oxygenase vasodilatory products. It is interesting to note that, since non-steroidal anti-inflammatory analgesics, acting as cyclo-oxygenase inhibitors, cause dry mouth (Gage and Pickett, 2003), it is feasible that their anti-sialogogue effects could be partly attributed to the inhibition of parasympathetic-induced vasodilation of the main artery supplying the gland, and, consequently, to a decrease of blood supply, at least in submandibular glands, as suggested by analysis of the present data. The simultaneous involvement and synergistic action of NO and cyclo-oxygenase products in mediating ACh action were further suggested by separate experiments, in which the concomitant addition of L-NOARG and indomethacin almost completely abolished the relaxant effect of ACh. In contrast, the fact that 4-AP, a potassium channel blocker, did not influence the relaxation of submandibular artery rings to ACh indicates that endothelium-derived hyperpolarizing factor seems not to be involved. In this respect, the human submandibular artery differs from many other smaller arteries, since it has been reported that responses to ACh are more dependent on endothelial NO in large conduit arteries, such as the aorta, and less dependent on endothelial NO in smaller resistance arteries, where endothelium-derived hyperpolarizing factor is thought to be more important (Corriu et al., 1996; Mombouli et al., 1996; Chan and Fiscus, 2003).

We have recently reported that the relaxant effect of ACh on the glandular branch of the rabbit facial artery (the artery supplying the submandibular gland) is mediated through release of endothelium-derived NO and cyclo-oxygenase products, but not by endothelium-derived hyperpolarizing factor (Stojic et al., 2003). In light of the present results, it seems reasonable that the rabbit facial artery (glandular branch) could be a useful experimental model for analysis of the vascular effects of ACh in healthy and, especially, in impaired endothelium-dependent dilation in glandular vessels in systemic diseases, such as hypertension, atherosclerosis, and diabetes. In particular, atherosclerotic signs have already been detected by panoramic radiography in the human facial (a branch of which is the submandibular artery), maxillary, and lingual arteries (Suarez-Cunqueiro et al., 2002).

The results show that the vasorelaxant response to VIP in the human submandibular artery is dependent on the presence of endothelium, because denuding the endothelium abolishes the response to VIP. The obtained data extend the findings of Larsson et al.(1986), who previously demonstrated a concentration-dependent VIP vasorelaxant effect in the human submandibular artery. It is known that VIP can cause either endothelium-dependent or endothelium-independent vasorelaxation, depending on both the species and the blood vessel studied. For example, VIP induces endothelium-dependent relaxation in the rat aorta (Davies and Williams, 1984; Sata et al., 1988) and the bovine intrapulmonary artery (Ignarro et al., 1987b), whereas the relaxation in response to this peptide is not influenced by the presence of endothelial cells in cat cerebral (Lee et al., 1984), canine carotid (D’Orleans-Juste et al., 1985), and rabbit hepatic arteries (Brizzolara and Burnstock, 1991). The endothelium-dependent vasorelaxation caused by VIP is thought to involve release of endothelium-derived mediators, whereas the endothelium-independent vasorelaxation caused by VIP is thought to involve elevation of cAMP levels in vascular smooth-muscle cells (Fiscus, 1988). The additional evidence presented here, that the VIP-induced vasorelaxation is not potentiated in the presence of forskolin, an adenylate cyclase stimulator, supports the above-mentioned findings.

To analyze which of the endothelium-derived mediators is involved in VIP-induced vasorelaxation in human submandibular artery rings, we tested the effects of L-NOARG, indomethacin, and 4-AP. The obtained results show that 4-AP completely, and L-NOARG significantly, reduced the vasodilatory effect of VIP, while indomethacin was without effect. Thus, the relaxation induced by VIP in endothelium-intact human submandibular artery rings appears to be produced by endothelium-derived hyperpolarizing factor and NO.

The responsiveness of the human submandibular artery to ACh and VIP cannot be regarded as a reliable indicator of vascular innervation, and uncertainty as to whether this artery is supplied with cholinergic and/or VIP-ergic nerve fibers still exists.

This study provides an initial characterization of the vasorelaxant responses of the human submandibular artery. ACh and VIP were found to operate through apparently separate mechanisms, albeit in an endothelium-dependent manner. This is of significance, since endothelial dysfunction associated with various disease conditions could differentially impair the release and effectiveness of individual endothelium-derived vasorelaxant factors (Vanhoutte, 1997; Kojda and Harrison, 1999). Since it has been shown that, in an animal model, diabetes has an adverse impact on the parasympathetic regulation of the rat submandibular gland blood flow (Anderson and Garrett, 2004), the present results are important as a basis for understanding the cellular mechanisms involved in the development of endothelial dysfunction in diabetic patients.


   ACKNOWLEDGMENTS
 
This investigation was supported by the Ministry of Science and Environmental Protection, Serbia (Research Grant No. 1975).

Received for publication May 23, 2005. Revision received June 26, 2006. Accepted for publication October 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Journal of Dental Research, Vol. 86, No. 6, 565-570 (2007)
DOI: 10.1177/154405910708600615
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