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Alpha2 adrenoceptors modulate histamine release from sympathetic nerves in the guinea pig vas deferens
Neuropharmacology 57 (2009) 506–510
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Alpha2 adrenoceptors modulate histamine release from sympathetic nerves in the guinea pig vas deferens Gonghao He, Xue Ma, Jun Lu, Jingru Meng, Yingying Chen, Min Jia, Xiaoxing Luo* Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Rd, Xi’ an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 April 2009 Received in revised form 21 July 2009 Accepted 21 July 2009
In our previous studies, we have identified that histamine (HA) is co-released with noradrenaline (NA) from the sympathetic nerve terminals and acts as a novel sympathetic neurotransmitter. However, the modulation of sympathetic HA release by sympathetic prejunctional receptors is still unknown. Therefore, in this study, we explored the modulation effect of a2 adrenoceptors on sympathetic HA release and the interaction of a2 adrenoceptors with HA H3 receptors in vas deferens isolated from guinea pig. The selective a2 adrenoceptor agonist brimonidine decreased the HA overflow in a concentration-dependent manner and abolished the contractile responses mediated by sympathetic HA release. Yohimbine competitively blocked the effect of brimonidine on HA release. Similarly, the HA H3 receptor agonist R-(a)-methylhistamine also decreased HA release, and thioperamide blocked the effect of R-(a)-methylhistamine. When used singly, both yohimbine and thioperamide facilitated HA release. In addition, the inhibitory effect of brimonidine on HA release was stronger in the presence of thioperamide, while it was reduced when HA H3 receptors were activated by R-(a)-methylhistamine. Our findings indicate for the first time that sympathetic HA release is negatively modulated both by prejunctional a2 receptors and HA H3 receptors and that these two prejunctional receptors interact with each other in modulating sympathetic HA release. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Histamine Sympathetic nerves Vas deferens a2 adrenoceptor Histamine H3 receptor Guinea pig
1. Introduction It is now widely accepted that sympathetic nerve terminals contain and release more than one neurotransmitter (Ellis and Burnstock, 1990; Bradley et al., 2003; Burnstock, 2004, 2006). Our recent findings have gradually confirmed histamine (HA) as a novel sympathetic co-transmitter. First, HA synthesizing enzyme, histidine decarboxylase, and HA itself are known to co-exist with noradrenaline (NA) in sympathetic nerves (Li et al., 2003, 2006, 2007; Hu et al., 2007). Second, upon appropriate stimulation of the sympathetic nerves, HA is released that leads to the activation of the pre- and postjunctional HA receptors (He et al., 2008). Finally, exogenous-applied HA can mimic endogenous sympathetic HA effects (He et al., 2008). Therefore, after the activation of sympathetic neurons, it is reasonable to believe that HA, along with other co-transmitters (NA and ATP), will participate in certain sympathetic functions. Nevertheless, sympathetic functions can also be modulated on their own through a feedback system via a series of Abbreviations: CPM, chlorpheniramine; EFS, electrical field stimulation; HA, histamine; aMeHA, R-(a)-methylhistamine; NA, noradrenaline. * Corresponding author. Tel.: þ86 29 84776813; fax: þ86 29 84774591. E-mail address: [email protected] (X. Luo). 0028-3908/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2009.07.029
prejunctional receptors (Boehm and Kubista, 2002), among which the prejunctional a2 adrenoceptor is considered as one of the most important inhibitory receptors modulating NA release and sympathetic effects, for which it has been widely investigated and reviewed (Starke, 2001; Boehm and Kubista, 2002). Furthermore, besides the autoinhibitory effect of NA release, the effects of prejunctional a2 adrenoceptors on the release of other already acknowledged sympathetic neurotransmitters and/or neuromodulators such as ATP (Driessen et al., 1993; Mihaylova-Todorova et al., 2001) and NPY (Pernow and Lundberg, 1989) have also been reported. For these reasons, prejunctional a2 adrenoceptor has long been considered a very important target for the treatment of diseases related to sympathetic overactivation (Berlan et al., 1992; Flordellis et al., 2004). However, since HA is a newly discovered sympathetic neurotransmitter, it is still poorly understood whether prejunctional a2 adrenoceptors can also modulate sympathetic HA release. We previously found that prejunctional HA H3 receptors inhibit HA release from sympathetic nerve terminals (Li et al., 2006, 2007) and that HA H3 receptors are important sympathetic modulating factors (Imamura et al., 1995, 1996; Levi and smith, 2000; Kulkarni et al., 2006). Whether these two inhibitory receptors have interactive effects on sympathetic HA release remains to be investigated.
G. He et al. / Neuropharmacology 57 (2009) 506–510
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In the present study, we provide evidence of the modulation of sympathetic HA release by prejunctional a2 adrenoceptors and HA H3 receptors, and confirm that these two receptors interact with each other in the guinea pig vas deferens. 2. Material and methods 2.1. Animals and tissue preparation All experiments and animal care procedures were reviewed and approved by the Animal Resource Center of the Fourth Military Medical University in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978). Male guinea pigs weighing 300–400 g were sacrificed by cervical dislocation under deep CO2 anaesthesia. Each vas deferens was quickly dissected out; placed in a Krebs solution of the following composition (mM): NaCl 150, KCl 4.6, MgCl2 1.2, CaCl2 2.5, NaHCO3 24.8, KH2PO4 1.2, and glucose 5.6 (pH ¼ 7.4); and cleared of surrounding fat, blood vessels, and loose connective tissues. About 5 mm of the prostatic end of each vas deferens was removed to avoid the interference of the nearby hypogastric ganglia (Solanki et al., 2007). The solution was constantly bubbled with 95% O2 and 5% CO2 at 37 C. 2.2. Release of HA from guinea pig vas deferens Each vas deferens was placed between two parallel platinum plate electrodes and mounted in a 5 ml jacketed organ bath containing the Krebs solution. The specimens were first equilibrated for a period of 1 h and then subjected to electrical field stimulation (EFS) at 25 Hz for 60 s with pulse duration of 1 ms and supramaximal voltage. At the end of EFS, the perfused Krebs solution was collected for HA assay with a spectrofluorometer (Vidal-Carou et al., 1990). Specimens were weighed after experiments for result standardization and data were represented as pmol/ ml mg. Drugs or vehicle controls were applied 10 min before EFS to explore their effects. 2.3. Recording of contractile responses of guinea pig vas deferens Each vas deferens was bathed with Krebs solution and suspended vertically between two parallel platinum plate electrodes with one end of the vas deferens fixed and the other attached by silk surgical suture to a force-displacement transducer to record contractile responses. An initial tension of 1 g was applied to the tissue. After an equilibration period of 1 h, the vas deferens was stimulated twice (S1 and S2) by EFS (25 Hz; pulse duration: 1 ms; supramaximal voltage) for 30 s. To allow for full recovery of the preparations, the time interval between S1 and S2 was 30 min. The contractile responses evoked by EFS were recorded and the areas under the contractile wave were calculated and represented as S2/S1 ratios. When the effects of agonists and/or antagonists were determined, reagents were applied 10 min before S1 or S2. Vehicles were used as controls.
Fig. 1. The effects of selective a2 adrenoceptor agonist brimonidine and antagonist yohimbine on EFS-evoked (25 Hz for 60 s) release of HA from guinea pig isolated vas deferens. (A) Brimonidine (0.01–10 mM) concentration-dependently inhibited the release of HA, and this effect was competitively blocked by yohimbine (1 mM). Points represent the means S.D. values of the concentration of HA released in the perfused Krebs solution, n ¼ 5. (B) Yohimbine (1 mM) used alone increased HA overflow from guinea pig isolated vas deferens. Bars represent the means S.D. values of concentration of HA released in the perfused Krebs solution, n ¼ 5. **P < 0.01 vs. control by Student’s t test.
2.4. Chemicals and data analysis Brimonidine, yohimbine, R-(a)-methylhistamine, thioperamide, and chlorpheniramine were purchased from Sigma–Aldrich Company Ltd. (St. Louis, MO, U.S.A.). Experiment data were expressed as mean SD and statistical differences between groups were determined by Student’s t test or by ANOVA analysis followed by Student-Newman-Keuls t test. A value of P < 0.05 was considered statistically significant.
3. Results 3.1. The effects of brimonidine and yohimbine on the release of HA from the guinea pig vas deferens The selective a2 adrenoceptor agonist brimonidine (0.01–10 mM) exhibited a concentration-dependent inhibitory effect on the EFSevoked release of HA from guinea pig isolated vas deferens. The IC50 of brimonidine was 85.7 nM, The 95% confidence interval of IC50 was from 37.2 nM to 198 nM, and the maximal inhibitory effect of brimonidine was 0.58 pmol/ml mg (95% Confidence Interval of the maximal inhibitory effect was from 0.48 to 0.67 pmol/ml mg) according to non-linear regression analysis. The inhibitory effect of brimonidine was antagonized competitively by the selective a2 adrenoceptor blocker yohimbine (1 mM) (Fig. 1A). Furthermore, treatment with yohimbine (1 mM) alone increased the HA overflow from guinea pig isolated vas deferens (Fig. 1B).
3.2. The effects of brimonidine and chlorpheniramine on the contraction of guinea pig isolated vas deferens As shown in Fig. 2, in the absence of brimonidine, the selective HA H1 receptor antagonist chlorpheniramine (CPM) (100 nM) significantly decreased the EFS-evoked contraction. The S2/S1 ratio decreased from 1.01 0.04 to 0.78 0.11. In the presence of brimonidine (1 mM), the inhibitory effect of CPM was abolished. The S2/S1 ratio of the two groups in the presence of brimonidine was 1.00 0.06 and 0.96 0.04, respectively, and did not show any significant difference (P > 0.05). Furthermore, the percentage of EFS-evoked contraction induced by CPM was 77 11% (n ¼ 6) in the absence of brimonidine, and 95 4% (n ¼ 6) in presence of brimonidine, the difference between both of them being statistically significant (P < 0.01).
3.3. The effects of (R)-a-methylhistamine and thioperamide on the release of HA from the guinea pig vas deferens Similar to the effects of brimonidine and yohimbine, the EFS-evoked release of HA from guinea pig isolated vas deferens was also inhibited (from 1.16 0.11 to 0.52 0.11 pmol/ml mg) by the selective HA H3 receptor agonist (R)-a-methylhistamine
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Fig. 3. The effects of the selective HA H3 receptor agonist (R)-a-methylhistamine (aMeHA, 1 mM) and the antagonist thioperamide (1 mM), used either alone or in combination, on the EFS-evoked (25 Hz for 60 s) HA release from guinea pig isolated vas deferens. The release of HA from guinea pig isolated vas deferens was inhibited by aMeHA (1 mM), which was then abolished by 1 mM of thioperamide. Thioperamide (1 mM) used alone increased the HA overflow from guinea pig isolated vas deferens. Bars represent the means S.D. values of concentration of HA released in the perfused Krebs solution, n ¼ 5. #P > 0.05 vs. control; **P < 0.01 vs. control by ANOVA followed Student-Newman-Keuls t test.
Fig. 2. The effects of brimonidine and chlorpheniramine (CPM) on EFS-evoked (pulse duration of 1 ms; 25 Hz for 30 s) contraction of guinea pig isolated vas deferens. The typical original recordings of contractile responses in the presence (A) or absence (B) of brimonidine were displayed. (C) CPM (100 nM) used alone significantly decreased the EFS-evoked contractile responses while in the presence of brimonidine (1 mM), the inhibiting effect of CPM was abolished. Bars represent the means S.D. values of the ratio between two evoked contractions (S2/S1), n ¼ 6. #P > 0.05, **P < 0.01 by Student’s t test.
(aMeHA, 1 mM), whose effect was abolished by 1 mM of the selective HA H3 receptor antagonist thioperamide with HA concentration back to 1.20 0.27 pmol/ml mg. Only thioperamide (1 mM) also increased the HA overflow from guinea pig isolated vas deferens (from 1.16 0.11 to 1.93 0.12 pmol/ml mg) (Fig. 3).
3.4. The effects of aMeHA and thioperamide on the inhibitory effect of brimonidine on the release of HA from the guinea pig vas deferens The inhibitory effect of brimonidine on HA release was augmented when the guinea pig vas deferens was pretreated with the selective HA H3 receptor antagonist thioperamide (1 mM) (Fig. 4A). In absence of thioperamide, the decreased percentage of HA concentration caused by brimonidine was 35 3% (n ¼ 5); while in presence of thioperamide, the decreased percentage was significantly increased and nearly doubled (61 7%, n ¼ 5, P < 0.01). On the contrary, the inhibitory effect was attenuated when the vas deferens was exposed to the selective HA H3 receptor agonist aMeHA and brimonidine caused no significant decrease (P > 0.05) of HA release (Fig. 4B). The decreased percentage was 15 14% (n ¼ 5) in the presence of aMeHA, significantly lower than that in absence of aMeHA (P < 0.01).
Fig. 4. The effects of the selective HA H3 receptor antagonist thioperamide (1 mM) (A) and the agonist (R)-a-methylhistamine (aMeHA, 1 mM) (B) on the inhibitory effect of brimonidine on EFS-evoked (25 Hz for 60 s) HA release from guinea pig isolated vas deferens. The inhibitory effect on HA release of brimonidine (1 mM) was augmented in the presence of 1 mM of thioperamide (A) and was attenuated in the presence of 1 mM of aMeHA (B). Bars represent the means S.D. values of the concentration of HA released in the perfused Krebs solution, n ¼ 5. #P > 0.05; **P < 0.01 vs. correspondence control by ANOVA followed Student-Newman-Keuls t test.
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4. Discussion Guinea pig vas deferens is widely used for the investigation of release and modulation of sympathetic co-transmitters (Bell et al., 1984; Driessen et al., 1993; Todorov et al., 1999; Westfall and Westfall, 2001). In our previous study, we have found that EFSevoked HA release from guinea pig isolated vas deferens was entirely neurogenic and independent of mast cells (He et al., 2008). Hence, in the present study, we continued to use this model to further investigate the modulation of sympathetic HA release. Prejunctional inhibitory a2 adrenoceptors are of great importance for the negative modulation of release of NA and the function of sympathetic nerves (Starke, 1987; Driessen et al., 1993; Todorov et al., 1999). Since HA is also released from sympathetic nerves, it is reasonable to assume that a2 adrenoceptors may play some roles in the modulation of HA release. Therefore, we investigated the effect of a2 adrenoceptors on sympathetic HA release by two means. The first aim was to directly detect the HA release in either the presence or absence of the a2 adrenoceptor agonist brimonidine. We have found that brimonidine concentration-dependently decreased the release of HA from guinea pig vas deferens and that its effect could be competitively blocked by yohimbine. This result indicates that the prejunctional a2 adrenoceptors can also negatively modulate the release of HA. Additionally, yohimbine used alone could increase HA release, which indicates that a2 adrenoceptors are activated by the corresponding endogenous ligand (i.e. NA) in this condition. The second aim was to detect the effect of brimonidine on the contractile responses mediated by sympathetic HA in order to further prove the inhibitory effect of a2 adrenoceptors on sympathetic HA release. This part of experiment was designed to observe the effect of the selective HA H1 receptor antagonist CPM on EFS-evoked contractile responses in the presence or absence of brimonidine. We found in our previous study that only when the frequency of the EFS was above 25 Hz could the postjunctional HA H1 receptors be activated by released sympathetic HA in guinea pig vas deferens (He et al., 2008). Therefore, we chose this transitional stimulation frequency point in the present study. In the absence of brimonidine, the EFS-evoked contractile responses could be significantly decreased by pretreatment with CPM. In the presence of brimonidine, contractile responses of vasa deferentia were attenuated to some extent (Fig. 2A). This is rational because a2 adrenoceptors activation can negatively modulate the sympathetic neurotransmission. However, in this condition, the inhibitory effect of CPM was also abolished. This result indicates from another angle that prejunctional a2 adrenoceptors activation can decrease sympathetic HA release and that this decreased HA release will in turn lead to deactivation of postjunctional HA H1 receptors. Therefore, it can be concluded that a2 adrenoceptors can inhibit sympathetic HA release and HA-mediated sympathetic functions. Furthermore, in order to explore the interactive effect of a2 adrenoceptors and HA H3 receptors on sympathetic HA release, we first investigated the modulation of HA release by H3 receptors. The results showed similar effects compared with that of a2 adrenoceptors, which indicates that HA H3 receptors also inhibit the release of HA. These findings are consistent with our previous work in the cardiac synaptosome model (Li et al., 2006, 2007). The selective HA H3 receptor antagonist thioperamide used alone also increased the release of HA, suggesting that the receptors are activated by endogenous HA. It should be mentioned that both aMeHA and thioperamide showed certain affinity to HA H4 receptors (Liu et al., 2001). However, according to our previous study, HA H4 receptors are not involved in the modulation of sympathetic HA release or EFS-evoked contractile responses in guinea pig isolated vas deferens (He et al., 2008). Additionally, it was recently recognized that H3 receptors show constitutive
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activity in the absence of an agonist and most of the compounds originally classified as H3 receptor antagonists, such as thioperamide, are in fact inverse agonists in many different preparations (Morisset et al., 2000; Moreno-Delgado et al., 2006; Arrang et al., 2007). But respecting that many H3 ligands exhibit ‘‘protean’’ agonism and that the constitutive activities of H3 receptors vary from one preparation to another (Gbahou et al., 2003), it is not easy to determine whether the sympathetic prejunctional H3 receptors of the guinea pig vas deferens also show constitutive activity. Further work is needed to resolve this problem. We further investigated the interactive effect of these two inhibitory receptors on HA release. Interactive effects between prejunctional receptors are common phenomena in modulation of neurotransmission in both the central (Grilli et al., 2009) and the peripheral nerve system (Boehm and Kubista, 2002). Moreover, the interactive effect between a2 adrenoceptors and HA H3 receptors on sympathetic NA release has been demonstrated and reviewed previously, and interruption of the noradrenergic inhibitory feedback has been found to be a prerequisite for the prejunctional inhibition via H3 receptors to occur (Schlicker et al., 1990; Godlewski et al., 1997; Schlicker and Go¨thert, 1998; Blandizzi et al., 2000; Boehm and Kubista, 2002). However, the findings of our present work showed that these two receptors also interacted with each other on the EFS-evoked release of HA. The prejunctional inhibitory effect of HA release via a2 adrenoceptors increases when H3 receptors are blocked. In contrast, activation of H3 receptors reduces the inhibitory effect of a2 adrenoceptors. The mechanism may be that these two kinds of receptors share common points in their signal pathways. It was well documented that both a2 adrenoceptors and H3 receptors are coupled with Gi/o proteins and share the same second messenger (i.e., cAMP) (Starke, 2001; MacGlashan, 2003; Parsons and Ganellin, 2006). Activation of H3 receptors may lead to Gi/o protein-mediated inhibition of cAMP synthesis and voltage-gated Ca2þ channels, which leaves little room for the a2 adrenoceptors to exert their own inhibitory effect. Furthermore, this result also indicated that HA and NA, as co-transmitters of sympathetic nervous system, may display a mutual inhibitory effect on each other via their own prejunctional receptors, the understanding of which may be helpful in understanding of the treatment of sympathetic-related diseases. However, modulation of sympathetic nerve functions would certainly involve other factors and may be a more complicated network. Further studies are still needed. In summary, this study demonstrates for the first time that, in addition to HA H3 receptors, sympathetic HA can also be negatively modulated by a2 adrenoceptors. Furthermore, a2 adrenoceptors and H3 receptors have an interactive effect on sympathetic HA release. Acknowledgements This work was supported by the National Natural Science Foundation of China (NO. 30770669 and NO. 30800310). References Arrang, J.M., Morisset, S., Gbahou, F., 2007. Constitutive activity of the histamine H3 receptor. Trends Pharmacol. Sci. 28, 350–357. Bell, C., Gillespie, J.S., Macrae, I.M., 1984. Release of noradrenaline and dopamine by nerve stimulation in the guinea-pig and rat vas deferens. Br. J. Pharmacol. 81, 563–569. Berlan, M., Montastruc, J.L., Lafontan, M., 1992. Pharmacological prospects for alpha 2-adrenoceptor antagonist therapy. Trends Pharmacol. Sci. 13, 277–282. Blandizzi, C., Tognetti, M., Colucci, R., Del Tacca, M., 2000. Histamine H (3) receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves. Br. J. Pharmacol. 129, 1387–1396. Boehm, S., Kubista, H., 2002. Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol. Rev. 54, 43–99.
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Alpha2 adrenoceptors modulate histamine release from sympathetic nerves in the guinea pig vas deferens Gonghao He, Xue Ma, Jun Lu, Jingru Meng, Yingying Chen, Min Jia, Xiaoxing Luo* Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Rd, Xi’ an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 April 2009 Received in revised form 21 July 2009 Accepted 21 July 2009
In our previous studies, we have identified that histamine (HA) is co-released with noradrenaline (NA) from the sympathetic nerve terminals and acts as a novel sympathetic neurotransmitter. However, the modulation of sympathetic HA release by sympathetic prejunctional receptors is still unknown. Therefore, in this study, we explored the modulation effect of a2 adrenoceptors on sympathetic HA release and the interaction of a2 adrenoceptors with HA H3 receptors in vas deferens isolated from guinea pig. The selective a2 adrenoceptor agonist brimonidine decreased the HA overflow in a concentration-dependent manner and abolished the contractile responses mediated by sympathetic HA release. Yohimbine competitively blocked the effect of brimonidine on HA release. Similarly, the HA H3 receptor agonist R-(a)-methylhistamine also decreased HA release, and thioperamide blocked the effect of R-(a)-methylhistamine. When used singly, both yohimbine and thioperamide facilitated HA release. In addition, the inhibitory effect of brimonidine on HA release was stronger in the presence of thioperamide, while it was reduced when HA H3 receptors were activated by R-(a)-methylhistamine. Our findings indicate for the first time that sympathetic HA release is negatively modulated both by prejunctional a2 receptors and HA H3 receptors and that these two prejunctional receptors interact with each other in modulating sympathetic HA release. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Histamine Sympathetic nerves Vas deferens a2 adrenoceptor Histamine H3 receptor Guinea pig
1. Introduction It is now widely accepted that sympathetic nerve terminals contain and release more than one neurotransmitter (Ellis and Burnstock, 1990; Bradley et al., 2003; Burnstock, 2004, 2006). Our recent findings have gradually confirmed histamine (HA) as a novel sympathetic co-transmitter. First, HA synthesizing enzyme, histidine decarboxylase, and HA itself are known to co-exist with noradrenaline (NA) in sympathetic nerves (Li et al., 2003, 2006, 2007; Hu et al., 2007). Second, upon appropriate stimulation of the sympathetic nerves, HA is released that leads to the activation of the pre- and postjunctional HA receptors (He et al., 2008). Finally, exogenous-applied HA can mimic endogenous sympathetic HA effects (He et al., 2008). Therefore, after the activation of sympathetic neurons, it is reasonable to believe that HA, along with other co-transmitters (NA and ATP), will participate in certain sympathetic functions. Nevertheless, sympathetic functions can also be modulated on their own through a feedback system via a series of Abbreviations: CPM, chlorpheniramine; EFS, electrical field stimulation; HA, histamine; aMeHA, R-(a)-methylhistamine; NA, noradrenaline. * Corresponding author. Tel.: þ86 29 84776813; fax: þ86 29 84774591. E-mail address: [email protected] (X. Luo). 0028-3908/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2009.07.029
prejunctional receptors (Boehm and Kubista, 2002), among which the prejunctional a2 adrenoceptor is considered as one of the most important inhibitory receptors modulating NA release and sympathetic effects, for which it has been widely investigated and reviewed (Starke, 2001; Boehm and Kubista, 2002). Furthermore, besides the autoinhibitory effect of NA release, the effects of prejunctional a2 adrenoceptors on the release of other already acknowledged sympathetic neurotransmitters and/or neuromodulators such as ATP (Driessen et al., 1993; Mihaylova-Todorova et al., 2001) and NPY (Pernow and Lundberg, 1989) have also been reported. For these reasons, prejunctional a2 adrenoceptor has long been considered a very important target for the treatment of diseases related to sympathetic overactivation (Berlan et al., 1992; Flordellis et al., 2004). However, since HA is a newly discovered sympathetic neurotransmitter, it is still poorly understood whether prejunctional a2 adrenoceptors can also modulate sympathetic HA release. We previously found that prejunctional HA H3 receptors inhibit HA release from sympathetic nerve terminals (Li et al., 2006, 2007) and that HA H3 receptors are important sympathetic modulating factors (Imamura et al., 1995, 1996; Levi and smith, 2000; Kulkarni et al., 2006). Whether these two inhibitory receptors have interactive effects on sympathetic HA release remains to be investigated.
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In the present study, we provide evidence of the modulation of sympathetic HA release by prejunctional a2 adrenoceptors and HA H3 receptors, and confirm that these two receptors interact with each other in the guinea pig vas deferens. 2. Material and methods 2.1. Animals and tissue preparation All experiments and animal care procedures were reviewed and approved by the Animal Resource Center of the Fourth Military Medical University in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978). Male guinea pigs weighing 300–400 g were sacrificed by cervical dislocation under deep CO2 anaesthesia. Each vas deferens was quickly dissected out; placed in a Krebs solution of the following composition (mM): NaCl 150, KCl 4.6, MgCl2 1.2, CaCl2 2.5, NaHCO3 24.8, KH2PO4 1.2, and glucose 5.6 (pH ¼ 7.4); and cleared of surrounding fat, blood vessels, and loose connective tissues. About 5 mm of the prostatic end of each vas deferens was removed to avoid the interference of the nearby hypogastric ganglia (Solanki et al., 2007). The solution was constantly bubbled with 95% O2 and 5% CO2 at 37 C. 2.2. Release of HA from guinea pig vas deferens Each vas deferens was placed between two parallel platinum plate electrodes and mounted in a 5 ml jacketed organ bath containing the Krebs solution. The specimens were first equilibrated for a period of 1 h and then subjected to electrical field stimulation (EFS) at 25 Hz for 60 s with pulse duration of 1 ms and supramaximal voltage. At the end of EFS, the perfused Krebs solution was collected for HA assay with a spectrofluorometer (Vidal-Carou et al., 1990). Specimens were weighed after experiments for result standardization and data were represented as pmol/ ml mg. Drugs or vehicle controls were applied 10 min before EFS to explore their effects. 2.3. Recording of contractile responses of guinea pig vas deferens Each vas deferens was bathed with Krebs solution and suspended vertically between two parallel platinum plate electrodes with one end of the vas deferens fixed and the other attached by silk surgical suture to a force-displacement transducer to record contractile responses. An initial tension of 1 g was applied to the tissue. After an equilibration period of 1 h, the vas deferens was stimulated twice (S1 and S2) by EFS (25 Hz; pulse duration: 1 ms; supramaximal voltage) for 30 s. To allow for full recovery of the preparations, the time interval between S1 and S2 was 30 min. The contractile responses evoked by EFS were recorded and the areas under the contractile wave were calculated and represented as S2/S1 ratios. When the effects of agonists and/or antagonists were determined, reagents were applied 10 min before S1 or S2. Vehicles were used as controls.
Fig. 1. The effects of selective a2 adrenoceptor agonist brimonidine and antagonist yohimbine on EFS-evoked (25 Hz for 60 s) release of HA from guinea pig isolated vas deferens. (A) Brimonidine (0.01–10 mM) concentration-dependently inhibited the release of HA, and this effect was competitively blocked by yohimbine (1 mM). Points represent the means S.D. values of the concentration of HA released in the perfused Krebs solution, n ¼ 5. (B) Yohimbine (1 mM) used alone increased HA overflow from guinea pig isolated vas deferens. Bars represent the means S.D. values of concentration of HA released in the perfused Krebs solution, n ¼ 5. **P < 0.01 vs. control by Student’s t test.
2.4. Chemicals and data analysis Brimonidine, yohimbine, R-(a)-methylhistamine, thioperamide, and chlorpheniramine were purchased from Sigma–Aldrich Company Ltd. (St. Louis, MO, U.S.A.). Experiment data were expressed as mean SD and statistical differences between groups were determined by Student’s t test or by ANOVA analysis followed by Student-Newman-Keuls t test. A value of P < 0.05 was considered statistically significant.
3. Results 3.1. The effects of brimonidine and yohimbine on the release of HA from the guinea pig vas deferens The selective a2 adrenoceptor agonist brimonidine (0.01–10 mM) exhibited a concentration-dependent inhibitory effect on the EFSevoked release of HA from guinea pig isolated vas deferens. The IC50 of brimonidine was 85.7 nM, The 95% confidence interval of IC50 was from 37.2 nM to 198 nM, and the maximal inhibitory effect of brimonidine was 0.58 pmol/ml mg (95% Confidence Interval of the maximal inhibitory effect was from 0.48 to 0.67 pmol/ml mg) according to non-linear regression analysis. The inhibitory effect of brimonidine was antagonized competitively by the selective a2 adrenoceptor blocker yohimbine (1 mM) (Fig. 1A). Furthermore, treatment with yohimbine (1 mM) alone increased the HA overflow from guinea pig isolated vas deferens (Fig. 1B).
3.2. The effects of brimonidine and chlorpheniramine on the contraction of guinea pig isolated vas deferens As shown in Fig. 2, in the absence of brimonidine, the selective HA H1 receptor antagonist chlorpheniramine (CPM) (100 nM) significantly decreased the EFS-evoked contraction. The S2/S1 ratio decreased from 1.01 0.04 to 0.78 0.11. In the presence of brimonidine (1 mM), the inhibitory effect of CPM was abolished. The S2/S1 ratio of the two groups in the presence of brimonidine was 1.00 0.06 and 0.96 0.04, respectively, and did not show any significant difference (P > 0.05). Furthermore, the percentage of EFS-evoked contraction induced by CPM was 77 11% (n ¼ 6) in the absence of brimonidine, and 95 4% (n ¼ 6) in presence of brimonidine, the difference between both of them being statistically significant (P < 0.01).
3.3. The effects of (R)-a-methylhistamine and thioperamide on the release of HA from the guinea pig vas deferens Similar to the effects of brimonidine and yohimbine, the EFS-evoked release of HA from guinea pig isolated vas deferens was also inhibited (from 1.16 0.11 to 0.52 0.11 pmol/ml mg) by the selective HA H3 receptor agonist (R)-a-methylhistamine
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Fig. 3. The effects of the selective HA H3 receptor agonist (R)-a-methylhistamine (aMeHA, 1 mM) and the antagonist thioperamide (1 mM), used either alone or in combination, on the EFS-evoked (25 Hz for 60 s) HA release from guinea pig isolated vas deferens. The release of HA from guinea pig isolated vas deferens was inhibited by aMeHA (1 mM), which was then abolished by 1 mM of thioperamide. Thioperamide (1 mM) used alone increased the HA overflow from guinea pig isolated vas deferens. Bars represent the means S.D. values of concentration of HA released in the perfused Krebs solution, n ¼ 5. #P > 0.05 vs. control; **P < 0.01 vs. control by ANOVA followed Student-Newman-Keuls t test.
Fig. 2. The effects of brimonidine and chlorpheniramine (CPM) on EFS-evoked (pulse duration of 1 ms; 25 Hz for 30 s) contraction of guinea pig isolated vas deferens. The typical original recordings of contractile responses in the presence (A) or absence (B) of brimonidine were displayed. (C) CPM (100 nM) used alone significantly decreased the EFS-evoked contractile responses while in the presence of brimonidine (1 mM), the inhibiting effect of CPM was abolished. Bars represent the means S.D. values of the ratio between two evoked contractions (S2/S1), n ¼ 6. #P > 0.05, **P < 0.01 by Student’s t test.
(aMeHA, 1 mM), whose effect was abolished by 1 mM of the selective HA H3 receptor antagonist thioperamide with HA concentration back to 1.20 0.27 pmol/ml mg. Only thioperamide (1 mM) also increased the HA overflow from guinea pig isolated vas deferens (from 1.16 0.11 to 1.93 0.12 pmol/ml mg) (Fig. 3).
3.4. The effects of aMeHA and thioperamide on the inhibitory effect of brimonidine on the release of HA from the guinea pig vas deferens The inhibitory effect of brimonidine on HA release was augmented when the guinea pig vas deferens was pretreated with the selective HA H3 receptor antagonist thioperamide (1 mM) (Fig. 4A). In absence of thioperamide, the decreased percentage of HA concentration caused by brimonidine was 35 3% (n ¼ 5); while in presence of thioperamide, the decreased percentage was significantly increased and nearly doubled (61 7%, n ¼ 5, P < 0.01). On the contrary, the inhibitory effect was attenuated when the vas deferens was exposed to the selective HA H3 receptor agonist aMeHA and brimonidine caused no significant decrease (P > 0.05) of HA release (Fig. 4B). The decreased percentage was 15 14% (n ¼ 5) in the presence of aMeHA, significantly lower than that in absence of aMeHA (P < 0.01).
Fig. 4. The effects of the selective HA H3 receptor antagonist thioperamide (1 mM) (A) and the agonist (R)-a-methylhistamine (aMeHA, 1 mM) (B) on the inhibitory effect of brimonidine on EFS-evoked (25 Hz for 60 s) HA release from guinea pig isolated vas deferens. The inhibitory effect on HA release of brimonidine (1 mM) was augmented in the presence of 1 mM of thioperamide (A) and was attenuated in the presence of 1 mM of aMeHA (B). Bars represent the means S.D. values of the concentration of HA released in the perfused Krebs solution, n ¼ 5. #P > 0.05; **P < 0.01 vs. correspondence control by ANOVA followed Student-Newman-Keuls t test.
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4. Discussion Guinea pig vas deferens is widely used for the investigation of release and modulation of sympathetic co-transmitters (Bell et al., 1984; Driessen et al., 1993; Todorov et al., 1999; Westfall and Westfall, 2001). In our previous study, we have found that EFSevoked HA release from guinea pig isolated vas deferens was entirely neurogenic and independent of mast cells (He et al., 2008). Hence, in the present study, we continued to use this model to further investigate the modulation of sympathetic HA release. Prejunctional inhibitory a2 adrenoceptors are of great importance for the negative modulation of release of NA and the function of sympathetic nerves (Starke, 1987; Driessen et al., 1993; Todorov et al., 1999). Since HA is also released from sympathetic nerves, it is reasonable to assume that a2 adrenoceptors may play some roles in the modulation of HA release. Therefore, we investigated the effect of a2 adrenoceptors on sympathetic HA release by two means. The first aim was to directly detect the HA release in either the presence or absence of the a2 adrenoceptor agonist brimonidine. We have found that brimonidine concentration-dependently decreased the release of HA from guinea pig vas deferens and that its effect could be competitively blocked by yohimbine. This result indicates that the prejunctional a2 adrenoceptors can also negatively modulate the release of HA. Additionally, yohimbine used alone could increase HA release, which indicates that a2 adrenoceptors are activated by the corresponding endogenous ligand (i.e. NA) in this condition. The second aim was to detect the effect of brimonidine on the contractile responses mediated by sympathetic HA in order to further prove the inhibitory effect of a2 adrenoceptors on sympathetic HA release. This part of experiment was designed to observe the effect of the selective HA H1 receptor antagonist CPM on EFS-evoked contractile responses in the presence or absence of brimonidine. We found in our previous study that only when the frequency of the EFS was above 25 Hz could the postjunctional HA H1 receptors be activated by released sympathetic HA in guinea pig vas deferens (He et al., 2008). Therefore, we chose this transitional stimulation frequency point in the present study. In the absence of brimonidine, the EFS-evoked contractile responses could be significantly decreased by pretreatment with CPM. In the presence of brimonidine, contractile responses of vasa deferentia were attenuated to some extent (Fig. 2A). This is rational because a2 adrenoceptors activation can negatively modulate the sympathetic neurotransmission. However, in this condition, the inhibitory effect of CPM was also abolished. This result indicates from another angle that prejunctional a2 adrenoceptors activation can decrease sympathetic HA release and that this decreased HA release will in turn lead to deactivation of postjunctional HA H1 receptors. Therefore, it can be concluded that a2 adrenoceptors can inhibit sympathetic HA release and HA-mediated sympathetic functions. Furthermore, in order to explore the interactive effect of a2 adrenoceptors and HA H3 receptors on sympathetic HA release, we first investigated the modulation of HA release by H3 receptors. The results showed similar effects compared with that of a2 adrenoceptors, which indicates that HA H3 receptors also inhibit the release of HA. These findings are consistent with our previous work in the cardiac synaptosome model (Li et al., 2006, 2007). The selective HA H3 receptor antagonist thioperamide used alone also increased the release of HA, suggesting that the receptors are activated by endogenous HA. It should be mentioned that both aMeHA and thioperamide showed certain affinity to HA H4 receptors (Liu et al., 2001). However, according to our previous study, HA H4 receptors are not involved in the modulation of sympathetic HA release or EFS-evoked contractile responses in guinea pig isolated vas deferens (He et al., 2008). Additionally, it was recently recognized that H3 receptors show constitutive
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activity in the absence of an agonist and most of the compounds originally classified as H3 receptor antagonists, such as thioperamide, are in fact inverse agonists in many different preparations (Morisset et al., 2000; Moreno-Delgado et al., 2006; Arrang et al., 2007). But respecting that many H3 ligands exhibit ‘‘protean’’ agonism and that the constitutive activities of H3 receptors vary from one preparation to another (Gbahou et al., 2003), it is not easy to determine whether the sympathetic prejunctional H3 receptors of the guinea pig vas deferens also show constitutive activity. Further work is needed to resolve this problem. We further investigated the interactive effect of these two inhibitory receptors on HA release. Interactive effects between prejunctional receptors are common phenomena in modulation of neurotransmission in both the central (Grilli et al., 2009) and the peripheral nerve system (Boehm and Kubista, 2002). Moreover, the interactive effect between a2 adrenoceptors and HA H3 receptors on sympathetic NA release has been demonstrated and reviewed previously, and interruption of the noradrenergic inhibitory feedback has been found to be a prerequisite for the prejunctional inhibition via H3 receptors to occur (Schlicker et al., 1990; Godlewski et al., 1997; Schlicker and Go¨thert, 1998; Blandizzi et al., 2000; Boehm and Kubista, 2002). However, the findings of our present work showed that these two receptors also interacted with each other on the EFS-evoked release of HA. The prejunctional inhibitory effect of HA release via a2 adrenoceptors increases when H3 receptors are blocked. In contrast, activation of H3 receptors reduces the inhibitory effect of a2 adrenoceptors. The mechanism may be that these two kinds of receptors share common points in their signal pathways. It was well documented that both a2 adrenoceptors and H3 receptors are coupled with Gi/o proteins and share the same second messenger (i.e., cAMP) (Starke, 2001; MacGlashan, 2003; Parsons and Ganellin, 2006). Activation of H3 receptors may lead to Gi/o protein-mediated inhibition of cAMP synthesis and voltage-gated Ca2þ channels, which leaves little room for the a2 adrenoceptors to exert their own inhibitory effect. Furthermore, this result also indicated that HA and NA, as co-transmitters of sympathetic nervous system, may display a mutual inhibitory effect on each other via their own prejunctional receptors, the understanding of which may be helpful in understanding of the treatment of sympathetic-related diseases. However, modulation of sympathetic nerve functions would certainly involve other factors and may be a more complicated network. Further studies are still needed. In summary, this study demonstrates for the first time that, in addition to HA H3 receptors, sympathetic HA can also be negatively modulated by a2 adrenoceptors. Furthermore, a2 adrenoceptors and H3 receptors have an interactive effect on sympathetic HA release. Acknowledgements This work was supported by the National Natural Science Foundation of China (NO. 30770669 and NO. 30800310). References Arrang, J.M., Morisset, S., Gbahou, F., 2007. Constitutive activity of the histamine H3 receptor. Trends Pharmacol. Sci. 28, 350–357. Bell, C., Gillespie, J.S., Macrae, I.M., 1984. Release of noradrenaline and dopamine by nerve stimulation in the guinea-pig and rat vas deferens. Br. J. Pharmacol. 81, 563–569. Berlan, M., Montastruc, J.L., Lafontan, M., 1992. Pharmacological prospects for alpha 2-adrenoceptor antagonist therapy. Trends Pharmacol. Sci. 13, 277–282. Blandizzi, C., Tognetti, M., Colucci, R., Del Tacca, M., 2000. Histamine H (3) receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves. Br. J. Pharmacol. 129, 1387–1396. Boehm, S., Kubista, H., 2002. Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol. Rev. 54, 43–99.
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