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1 Department of Anatomical Sciences2 Dental Program, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, CA 94115, USA3 Department of Physiology and Pharmacology, T. J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA
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Abstract |
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-nitro-L-arginine methyl ester (L-NAME) and indomethacin partly blocked parasympathetic vasodilatation at all frequencies tested (P < 0.05). In female rats significant reductions in nerve-stimulated perfusion were observed only at 2 and 5 Hz, but the effects of L-NAME were greater than in males (–64 compared with –45% at 2 Hz and –45 compared with –33% at 5 Hz, P < 0.05). Indomethacin by itself had no apparent effect in females. The combined effects of L-NAME and indomethacin were dependent on the order of administration and on gender. Following L-NAME, indomethacin had no further effect in males or females. L-NAME reduced indomethacin-resistant vasodilatation in males and females, but the added effect of indomethacin was more pronounced in males. Finally, atropine-resistant vasodilatation was partly blocked by L-NAME, and the remaining vasodilatation was abolished by spantide I (substance P receptor antagonist). We conclude that NO, products of cyclo-oxygenase activity and EDHF all play a role in parasympathetic vasodilatation, but that NO and EDHF are the major endothelium-derived vasodilators in the rat submandibular gland. In addition, when other pathways are blocked EDHF makes a greater contribution in females. Lastly, both vasoactive intestinal peptide and substance P contribute to the atropine-resistant vasodilatation.
(Received 8 November 2005;
accepted after revision 9 December 2005; first published online 19 December 2005)
Corresponding author L. C. Anderson: Department of Anatomical Sciences, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, CA 94115, USA. Email: landerso{at}pacific.edu
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Introduction |
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The increase in glandular blood flow during parasympathetic stimulation is partly attributable to the release of acetylcholine (Anderson & Garrett, 1998), whose vasodilatory actions are entirely dependent on the synthesis and release of several endothelium-derived relaxing factors (EDRF). Although acetylcholine is the main neurotransmitter released from parasympathetic nerves in the submandibular gland, an atropine-resistant parasympathetic vasodilatation has been observed in the cat (Lundberg et al. 1981; Edwards & Garrett, 1993), ferret (Tobin et al. 1991, 1997), pig (Modin et al. 1994), rat (Darke & Smaje, 1972; Thulin, 1976; Templeton & Thulin, 1978; Anderson & Garrett, 1998) and sheep (Edwards et al. 2003). This atropine-resistant vasodilatation is due to the corelease of neuropeptides, such as vasoactive intestinal peptide (VIP) and substance P (Ekström, 1999), and in the rat submandibular gland both substances appear to play a role in this phenomenon (Anderson & Garrett, 1998). Like the actions of acetylcholine, those of VIP and substance P are largely, if not exclusively, endothelium dependent (Furchgott & Vanhoutte, 1989).
Nitric oxide (NO) was the first EDRF to be identified and is therefore the most completely characterized (Furchgott & Vanhoutte, 1989). However, other relaxing factors, such as prostacyclin (PGI2) derived via the metabolism of arachidonic acid (cyclo-oxygenase pathway) and endothelium-derived hyperpolarizing factor (EDHF), have been demonstrated to play a significant physiological role in the regulation of vascular tone (Mombouli & Vanhoutte, 1999; Stankevicius et al. 2003; Félétou & Vanhoutte, 2004). EDHF is itself unlikely to be a single factor, and it has been variously identified as H2O2, or one of several products of the epoxygenase pathway of arachidonic acid metabolism, or potassium ions or myoendothelial gap junction communication (Bryan et al. 2005). Endothelial cells also metabolize arachidonic acid through the lipoxygenase pathway, and some of these metabolites are vasoactive (Miller et al. 2003).
The relative importance of each factor to the regulation of vascular reactivity depends on the particular vascular bed under study. In general, NO is the predominant endothelium-derived vasodilator in large conductance vessels, such as the aorta, whereas EDHF becomes increasingly important as vessel size decreases (Mombouli & Vanhoutte, 1999; Stankevicius et al. 2003; Félétou & Vanhoutte, 2004). In a previous communication we demonstrated that both NO-dependent and -independent mechanisms contribute to parasympathetic vasodilatation in the rat submandibular gland (Anderson & Garrett, 1998). However, the relative contributions of NO, cyclo-oxygenase metabolism of arachidonic acid and EDHF in this gland were not determined.
Finally, vascular tone and reactivity are influenced by gender. Oestrogen, progesterone and testosterone all have cardiovascular effects, and oestrogen is thought to provide numerous cardiovascular benefits due, in part, to its genomic and non-genomic effects on the synthesis and release of EDRF. For example, we reported that oestrogen upregulates endothelial nitric oxide synthase (eNOS) gene expression (Rahimian et al. 2002) and it enhances eNOS activity, possibly through increases in intracellular Ca2+ (Rahimian et al. 1998). Other studies demonstrated that oestrogen can upregulate eNOS by promoting phosphorylation of the enzyme (Haynes et al. 2000) or by a reduction in superoxide (O2–) production (Florian et al. 2004). In addition to its effects on NO, oestrogen also affects arachidonic acid metabolism via the cyclo-oxygenase pathway, as well as affecting the production of EDHF (Wu et al. 2001)
Thus, the purposes of this study were: (1) to determine the relative contributions of NO, arachidonic metabolism (cyclo-oxygenase pathway) and EDHF to parasympathetic vasodilatation in the rat submandibular gland; and (2) to investigate whether gender influences vascular reactivity in this tissue.
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Methods |
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A total of 27 male and 28 female Sprague–Dawley rats (Simonsen Laboratories, Gilroy, CA, USA) were used during these studies. All animals were maintained on a 12 h–12 h light–dark cycle and allowed free access to food and water. Housing conditions and experimental protocols were approved by the Animal Use Committee of the University of the Pacific. At the end of each experiment the anaesthetized rats were killed by intracardiac administration of sodium pentobarbitone (25 mg kg–1).
Parasympathetic nerve stimulation
Anaesthesia was induced with sodium pentobarbitone (35 mg kg–1, I.P.) followed by chloralose (80 mg kg–1, I.V.). Systemic mean arterial blood pressure (MABP) was monitored continuously via a blood pressure transducer placed in the femoral artery. The trachea was cannulated, but the animal was not artificially ventilated. Body temperature was maintained between 37 and 38°C using a heated surgical table.
For parasympathetic nerve stimulation, the chorda-lingual nerve was exposed and carefully reflected onto the submandibular duct. Both the duct and the nerve were then placed on a bipolar electrode, and parasympathetic impulses were delivered at consecutively higher frequencies of 2, 5 and 10 Hz (5–6 V, 2 ms duration).
Laser Doppler flowmetry
The posterior, lateral quadrant of the right submandibular gland was exposed by creating a small window through the skin and overlying subcutaneous tissue. A laser Doppler stainless-steel probe (MP3a, Moor Instruments, Wilmington, DE, USA) was placed at right angles to the gland without applying pressure to the tissue. Preliminary experiments demonstrated that placement of the probe over several different areas within the same quadrant resulted in comparable perfusion recordings. At the end of each stimulation period, blood flow was allowed to return to resting levels before the next stimulus was applied. After the administration of each inhibitor, a 10 min waiting period was observed before the series of parasympathetic stimulations was repeated.
Laser Doppler flowmetry measures blood flow in arbitrary perfusion units (p.u.) and it should be noted that actual blood flow cannot be directly quantified by laser Dopper flowmetry. Nevertheless, laser Doppler flowmetry has proven valuable, because the strength of the technique lies in its ability to record relative changes in perfusion under varying experimental conditions within the same animal. For statistical purposes blood flow was expressed as an integral (see Fig. 1): the sum of the data points multiplied by the duration (total perfusion) or the sum of the data points minus the value at the start of stimulation multiplied by the duration (parasympathetic vasodilatation). All data were captured, stored and analysed using PowerLab© acquisition software (ADInstruments, Colorado Springs, CO, USA).
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Nitric oxide production was blocked by the continuous infusion of N-nitro-L-arginine methyl ester (L-NAME) at a rate of 1.5 mg kg–1 min–1, I.V. Cyclo-oxygenase activity was then inhibited by the administration of indomethacin (1 mg kg–1, I.P.) while continuing the infusion of L-NAME. In a second series of experiments the order of L-NAME and indomethacin administration was reversed. Preliminary studies demonstrated that an infusion of L-NAME for 10 min at a rate of 1.5 mg kg–1 min–1 achieved the maximal effect on both blood pressure and vasodilatation. In preliminary experiments, the effect of indomethacin was found to be no greater at 2 or 5 mg kg–1 than at 1 mg kg–1.
Atropine-resistant vasodilatation
Atropine (1 mg kg–1, I.P.) was administered to block the actions of acetylcholine. The relative contribution of VIP to the atropine-resistant parasympathetic vasodilatation was estimated by measuring blood flow before and after L-NAME. Finally, the competitive tachykinin receptor antagonist, spantide I (D-Arg1,D-Trp7,9,Leu11-substance P), was administered by close arterial infusion (10–45 pmol min–1) via a polythene catheter (PE 10) inserted into the right brachial artery. The tip of the catheter was advanced to the branch point of the subclavian and common carotid arteries.
Statistical analysis
Data were expressed as means ±S.E.M. and analysed for statistical significance using a repeated analysis of variance with the 
level set at 0.05. Differences between individual means (e.g. treatment versus control) were then tested using one of two different post hoc tests: Bonferroni (for normally distributed data) and Dunnett's (when the data were not normally distributed). Differences between male and female rats were analysed using Student's unpaired t test.
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Results |
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Age-matched male and female rats between 14 and 18 weeks of age were used for all blood flow experiments. Final body and submandibular gland weights are given in Table 1. Both body weight and gland weight were significantly smaller in female than in male rats, but the gland to body weight ratios (mg g–1) were similar (0.80 and 0.75, respectively).
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MABP in anaesthetized animals was 103 ± 22 mmHg. There was no difference in MABP between males and females, and parasympathetic stimulation had no effect on MABP. The administration of L-NAME (1.5 mg kg–1 min–1, I.V.) led to an increase in MABP (of 35 ± 7 mmHg in males and 21 ± 12 mmHg in females, P < 0.01). Indomethacin alone had no effect on systemic blood pressure, nor did it affect the increase in MABP seen in the presence of L-NAME.
For any given animal, basal perfusion remained stable over the course of an experiment, and repeated parasympathetic stimulations had no effect on this resting perfusion. After each stimulation period blood flow returned to the values recorded prior to stimulation (see Fig. 1). However, the mean basal perfusion rate (integrated perfusion) was greater in female than in male rats (10984 ± 1771 and 8462 ± 2653 p.u., respectively, P < 0.01). Despite its effect on MABP, L-NAME did not significantly affect basal perfusion in either female or male rats (9422 ± 1973 and 7717 ± 1560 p.u., respectively). Indomethacin also had no effect on basal perfusion (9993 ± 1998 and 8339 ± 1283 p.u., respectively).
Parasympathetic vasodilatation
In the absence of inhibitors, parasympathetic stimulation elicited frequency-dependent increases in submandibular gland perfusion. When calculated as the integrated perfusion above resting levels, no differences between male and female rats were observed at 2, 5 or 10 Hz (Fig. 2A). However, when expressed as a percentage increase above resting (basal) perfusion (Fig. 2B), parasympathetic vasodilatation was significantly greater in male than in female rats at all stimulation frequencies (P < 0.01).
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Atropine-resistant parasympathetic vasodilatation
To determine the effects of cholinergic blockade on parasympathetic vasodilatation, blood flow was measured in the presence of L-NAME, followed by the addition of indomethacin and then atropine. Atropine significantly reduced (P < 0.05), but did not completely abolish, L-NAME- and indomethacin-resistant parasympathetic vasodilatation at all stimulation frequencies in both male and female rats (Fig. 4). However, the remaining atropine-resistant vasodilatation was significantly less in female than in male rats (P < 0.01). In males, atropine-resistant vasodilatation following the application of L-NAME and indomethacin was 33% of that seen without any inhibitors at 2 Hz, and the values at 5 and 10 Hz were 42 and 46% of control values, respectively. In females, atropine-resistant vasodilatation, as a percentage of control values, was only 5% at 2 Hz, 15% at 5 Hz and 33% at 10 Hz.
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Discussion |
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Mean resting perfusion levels in the submandibular gland were 30% greater in female than in male rats, and the basis for this gender difference cannot be determined from our results. Nevertheless, this observation would be consistent with the known effects of gender on EDRF synthesis, as shown by our group (Rahimian et al. 1997, 2002) and others (see review by Orshal & Khalil, 2004). That the greater resting perfusion in females was not due simply to chance placement of the laser Doppler probe was demonstrated by our ability to record very similar blood flow measurements over several different areas in the same gland. Alternatively, the difference in basal perfusion could be related to a sexual dimorphism in rodent submandibular glands. In mice and rats a specialized section of the intralobular duct system, the granular ducts, is considerably more prominent in males than in females (Rins de David et al. 1991). As a consequence, the proportional volume of the granular ducts is reduced in the submandibular glands of female rats and the proportional volume assigned to vascular elements is increased. This relative increase in vascularity could also account for the difference in basal perfusion, but determining which of these two explanations is correct must await further study.
The effects of L-NAME and indomethacin on parasympathetic vasodilatation were dependent on stimulation frequency, gender and the order of their administration. The inhibition of NO synthesis by L-NAME partly blocked parasympathetic vasodilatation in both male and female submandibular glands. However, the estimated percentage contribution of NO to the observed vasodilatation was dependent on both the rate of stimulation and gender. At 2 and 5 Hz L-NAME had a greater effect in females than in males, but at 10 Hz the opposite was true (see Fig. 3). The addition of indomethacin had no further effect in either males or females. When indomethacin was administered and then followed by L-NAME, the gender differences were even more striking. In males, indomethacin partly blocked vasodilatation at 2 and 5 Hz, and L-NAME then led to a further significant reduction in vasodilatation (see Fig. 3B), suggesting that in males both NO and prostacyclin serve as vasodilators under physiological conditions.
In contrast, inhibition of cyclo-oxygenase activity by itself had no apparent effect on vasodilatation in females, and the addition of L-NAME produced only marginal reductions in blood flow during parasympathetic stimulation (see Fig. 3B and D). Because the P values were marginal (P < 0.07), a two-way repeated ANOVA was carried out to test for possible interactions between stimulation frequency and treatment effect, but again no significant effects of either indomethacin alone or indomethacin followed by L-NAME on parasympathetic vasodilatation were found in females. Thus, there appears to be a significant gender difference with respect to the ability of EDHF to compensate for the loss of NO and prostacyclin production under these circumstances.
The complex responses following the inhibition of eNOS and cyclo-oxygenase make it difficult to define the precise physiological role of cyclo-oxygenase-mediated metabolism of arachidonic acid in the rat submandibular gland. In male rats indomethacin reduced vasodilatation when administered alone, which suggested that the prostacyclins or other arachidonic acid metabolites contribute to parasympathetic vasodilatation. However, indomethacin by itself had no apparent effect on glandular perfusion in females. This supports the hypothesis that there is a significant gender effect on the contribution of prostacyclin to vascular reactivity in this gland. Lastly, we observed that indomethacin had no additional effect on vasodilatation when administered after L-NAME in either male or female rats (Fig. 3A and C), which implies that the cyclo-oxygenase pathway plays little or no role in parasympathetic vasodilatation under conditions in which there is an altered bioavailability of NO.
Despite their complexity, our observations are generally in agreement with those of previous studies that demonstrate interactions between pathways leading to the production of endothelium-derived vasodilators. The direction and magnitude of some of these interactions remain controversial, particularly those between eNOS and cyclo-oxygenase. For example, Vassalle et al. (2003) reported that the inhibition of cyclo-oxygenase results in a compensatory increase in NO production and that, conversely, NO stimulates cyclo-oxygenase activity. Osanai et al. (2000) observed exactly the opposite response. While NO and prostaglandin interactions are still being debated, there is an established negative regulatory effect of NO on EDHF synthesis (Bauersachs et al. 1996), and the loss of NO-mediated vascular responses may be compensated for by an increase in EDHF-related mechanisms (de Wit et al. 2000; Félétou & Vanhoutte, 2004).
Irrespective of gender, a substantial L-NAME- and indomethacin-resistant vasodilatation was observed at all stimulation frequencies and, taken as a whole, the data strongly suggest that NO and EDHF are the main contributors to parasympathetic vasodilatation in the rat submandibular gland under physiological conditions. Numerous studies have shown that NO acts as a vasodilator in salivary glands (see Edwards, 1998), but the prominent role of EDHF in salivary glands has not previously been described. However, the conclusion that EDHF makes a significant contribution to parasympathetic vasodilatation in this gland is entirely consistent with the observation that EDHF becomes more important as vessel size decreases (Félétou & Vanhoutte, 2004). In addition, our data support the hypothesis that EDHF serves as the major back-up vasodilator in females when other vasodilatory mechanisms are lost.
Gender differences in the relative contribution of endothelium-derived vasodilators have been extensively studied (see Orshal & Khalil, 2004). For example, we previously reported that oestrogen regulates eNOS expression (Rahimian et al. 2002, 2004), and an increased contribution of EDHF to vascular reactivity in female arteries and arterioles has been observed (Golding & Kepler, 2001; Wu et al. 2001; Pak et al. 2002; Wangensteen et al. 2004). It should be noted that the present study was designed to investigate gender differences rather than the effects of the oestrous cycle on endothelial function. We used female Sprague–Dawley rats (14–18 weeks of age), which is approximately 8–12 weeks after adult oestrogen levels are attained in the rat. According to our previous report on the plasma 17ß-oestradiol (E2) levels in 16-week-old adult female rats (Rahimian et al. 1997) and a recent report by Moien-Afshari et al. (2003) who investigated the plasma concentrations of E2 in rats aged 3–21 months, the E2 levels are stable over time and remain elevated when compared with male rats. In neither study were plasma E2 levels reported at fixed phases of the oestrus cycle, but both showed that age-matched female rats have an improved endothelial-dependent vasodilatation compared with males.
An atropine-resistant vasodilatation in salivary glands was originally demonstrated by Heidenhain (1872), and this phenomenon has subsequently been observed in every species tested, including the cat (Darke & Smaje, 1972; Edwards et al. 1996), ferret (Tobin et al. 1991) and rat (Thulin, 1976; Templeton & Thulin, 1978; Anderson & Garrett, 1998; Mizuta et al. 2000). The atropine-resistant vasodilatation is mediated by the release of peptidergic transmitters, such as substance P and VIP. In the cat, ferret and sheep the major contributor to the atropine-resistant vasodilatation is VIP, and the actions of VIP appear to be largely, if not exclusively, due to the release of NO (Tobin et al. 1991; Schachter et al. 1992; Edwards & Garrett, 1993; Edwards et al. 1996, 1998, 2003). Substance P, however, plays only a minor role in vasodilatation in these species.
In the present study, atropine-resistant vasodilatation in male rat submandibular glands was reduced but not abolished by L-NAME (see Fig. 6), and these data suggest that VIP contributes, at least in part, to parasympathetic vasodilatation in this gland. The remaining vasodilatory response was abolished by the administration of the competitive tachykinin receptor antagonist (spantide I), which blocks the actions of substance P. Thus, unlike the situation in cat, ferret and sheep, substance P is responsible for a significant portion of the atropine-resistant vasodilatation seen in the rat submandibular gland. These observations are consistent with previous findings by Kerezoudis et al. (1993) and Anderson & Garrett (1998), and are supported by the immunolocalization of substance P in perivascular nerves within the submandibular gland of the rat (Ekström et al. 1994; Jia et al. 1997).
Atropine-resistant vasodilatation was seen in the presence of both L-NAME and indomethacin (Fig. 5), suggesting that the vasodilatory effect of substance P in the rat submandibular gland is mediated by the release of EDHF. The vasodilatory actions of substance P may also be due, at least in part, to the release of NO. Substance P-induced increases in blood flow are mediated by both NO and EDHF in forearm (Tagawa et al. 1977; Inokuchi et al. 2003) and mesenteric arteries (Tøttrup & Kraglund, 2004), and Kerezoudis et al. (1993) reported that L-NAME partly blocked the substance P-induced vasodilatation in the rat submandibular gland. There is little evidence, however, to support a role for prostacyclin in substance P-mediated vasodilatation. These observations, coupled with the finding that atropine-resistant vasodilatation was more prominent at 10 Hz than at either 5 or 2 Hz, may also explain the relative inability of L-NAME and cyclo-oxygenase to significantly inhibit parasympathetic vascular responses at 10 Hz.
Finally, endothelial cells are assumed to be the source of NO acting on vascular smooth muscle, but NO synthase-immunoreactive nerves have been described in rat salivary glands (Soinila et al. 1996; Alm et al. 1997; Takai et al. 1999). Further, parasympathetic denervation caused an almost complete loss of NO synthase immunoreactivity in the rat parotid gland (Alm et al. 1997). Thus, it is possible that NO release from parasympathetic nerve terminals might also contribute to the observed vasodilatation. In contradiction to this hypothesis, NO synthase-immunoreactive nerves in the rat submandibular gland are richly distributed around acini, but are relatively sparse around blood vessels (Alm et al. 1997; Takai et al. 1999), which suggests that they are secretomotor in nature rather than vasomotor.
In conclusion, the data demonstrate that NO, arachidonic acid metabolites (cyclo-oxygenase pathway) and EDHF all play a role in parasympathetic vasodilatation in the rat submandibular gland. Owing to potential interactions between metabolic pathways, however, the relative contributions of each factor under physiological conditions are difficult to estimate. Our observations also suggest that EDHF makes a greater contribution to parasympathetic vasodilatation in females than in males. Finally, atropine-resistant vasodilatation in the rat submandibular gland is due to the release of both VIP and substance P. In summary, our study may contribute significantly to our understanding of rat submandibular gland physiology and offers additional insights into the effects of gender on submandibular gland secretory function and blood flow.
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