Am J Physiol Heart Circ Physiol 290: H807-H812, 2006.
First published September 30, 2005; doi:10.1152/ajpheart.00889.2005
0363-6135/06 $8.00
Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors
Amy M. Kitchen,
Donal S. O'Leary, and
Tadeusz J. Scislo
Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan
Submitted 19 August 2005
; accepted in final form 23 September 2005
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ABSTRACT
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We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist 
,
-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg iv), a 1-selective antagonist, and after atropine methyl bromide (2 mg/kg iv), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After 1-adrenergic blockade, the bradycardia was reduced to just –5.1 ± 0.5 versus –28.8 ± 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both 1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, –37.4 ± 6.4 and –40.6 ± 3.7 beats/min, respectively, compared with –88.0 ± 11 beats/min in control animals. Double blockade of both 1-adrenergic and muscarinic receptors virtually abolished the response (–2.5 ± 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation.
heart rate; nucleus tractus solitarius; ,-methylene adenosine 5'triphosphate
SEVERAL STUDIES indicate that ATP operating via P2X receptors may act in several brain structures, including the NTS, as a fast neurotransmitter or cotransmitter with glutamate (3, 5, 6, 8–10, 12, 14, 16–20, 22–24, 26, 28). Stimulation of P2X purinoceptors located in the subpostremal NTS, via the selective agonist ,-methylene ATP, produces dose-dependent reductions in mean arterial pressure (MAP) and heart rate (HR) (3, 10) and evokes differential sympathoinhibition of regional sympathetic efferent outputs similar to that observed during activation of arterial baroreceptors or microinjection of glutamate, the primary neurotransmitter in baroreflex transmission in the NTS (20, 21, 23). The responses to NTS P2X receptor activation consist of a fast- and short-lasting neuromediator-like component, followed with a less-pronounced and longer-lasting neuromodulator-like component (21, 23, 24). The time course of the fast response to stimulation of NTS P2X receptors closely resembles the response to stimulation of glutamatergic receptors in the same site of the NTS (23). In addition, blockade of ionotropic glutamatergic receptors, involved in baroreflex transmission at the level of the NTS, markedly attenuated the fast neurotransmitter-like component of the response to stimulation of NTS P2X receptors, indicating that these two mechanisms are linked together (24). Finally, blockade of NTS P2X receptors with the nonselective antagonist suramin, in doses that did not affect glutamatergic transmission, virtually abolished baroreflex control of HR (22).
The mechanisms mediating the bradycardia to stimulation of NTS P2X receptors remain unknown. Bradycardia produced by the activation of NTS receptors can be achieved by increasing parasympathetic activity via the nucleus ambiguus, by decreasing sympathetic activity via the ventral lateral medulla, or via both mechanisms. Because stimulation of NTS P2X receptors decreases efferent sympathetic nerve activity, it is likely that a withdrawal in sympathetic nerve activity to the heart contributes to the decrease in HR. However, the rapid nature of the bradycardia suggests that a parasympathetic mechanism may also be involved. The purpose of the present study is to determine the relative contributions of sympathetic withdrawal and parasympathetic activation to the bradycardia evoked by NTS P2X receptor activation.
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MATERIALS AND METHODS
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All protocols and surgical procedures used in this study were reviewed and approved by the Institutional Animal Care and Use Committee and were performed in accordance with the Guide for the Care and Use of Laboratory Animals, endorsed by the American Physiological Society and published by the National Institutes of Health.
Design.
The relative contributions of the sympathetic and parasympathetic nervous systems to the bradycardia caused by P2X purinoceptor activation in the subpostremal NTS were studied in 32 male Sprague-Dawley rats (325–375 g). P2X purinoceptors in the NTS were activated via microinjection of ,-methylene ATP, a selective P2X purinoceptor agonist, at a moderate hypotensive dose (25 pmol/50 nl) and the maximal hypotensive dose (100 pmol/50 nl) (3, 10). Three different groups of animals were studied at both doses of ,-methylene ATP: the intact control group, the post-1-receptor blockade group, and post-muscarinic blockade group. A fourth group was studied at the high dose after blockade of both 1-adrenergic receptors and muscarinic receptors to verify the effectiveness of the blockade.
Instrumentation and measurements.
The rats were anesthetized with a combination of -chloralose (80 mg/kg) and urethane (500 mg/kg) administered intraperitoneally, were intubated endotracheally, and were allowed to respire spontaneously. Rectal temperature was maintained between 37–38°C by a water heating pad (model TP-500, Gaymer Industries). A catheter (PE-50) was placed in the right femoral artery and connected to a TXX-R Viggo-Spectramed pressure transducer to monitor arterial pressure and HR. Two catheters were placed in the right femoral vein to continuously infuse anesthesia (-chloralose, 8–16 mg·kg–1·h–1 and urethane, 50–100 mg·kg–1·h–1, 
0.5 to 1 ml/h) and to administer atenolol and/or methyl-atropine. The pressure transducer was connected to a Beckman Dynograph (R711). The signal was also transmitted to an analog-to-digital converter (Modular Instruments) interfaced to a laboratory computer. MAP and HR were recorded continuously with the use of Biowindows software (Modular Instruments).
The entire procedure for discrete microinjections into the subpostremal NTS has been described previously (3, 20, 23). Briefly, the animals were mounted in a cranial stereotaxic apparatus. The dorsal medulla was exposed at the level of the obex after dissection of the neck muscles and the atlantoccipital membrane. Animals were allowed to stabilize for at least 30 min before microinjection of ,-methylene ATP. Unilateral microinjections were performed by using multibarrel glass micropipettes (15- to 20-µm tip diameter for each barrel) into the middle to caudal one-third of the subpostremal NTS via a pneumatic picopump (model PV820, WPI). A total volume of 50 nl was injected over 5–10 s. With the pipette tip at an angle of 22° from the vertical plane and the rat skull tilted 45°, the pipette was inserted at the level of the caudal tip of the area postrema 0.3 mm lateral from midline and 0.35 mm below the dorsal surface of the brainstem. As a result of this procedure, the tip of the micropipette reached medial subpostremal NTS (Fig. 1). No more than two microinjections were performed in one animal with at least 60 min between microinjections. In response to the lower dose of ,-methylene ATP, seven responses were observed in control experiments, eight after muscarinic receptor blockade, and seven after 1-adrenergic receptor blockade. In response to the higher dose of ,-methylene ATP, seven responses were observed in control experiments, nine after muscarinic receptor blockade, seven after 1-adrenergic receptor blockade, and five after combined muscarinic and 1-adrenergic receptor blockade. At least 10 min were allowed after intravenous infusion of the cardiac autonomic antagonists before the microinjections were performed.
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Fig. 1. Microinjection sites in subpostremal nucleus tractus solitarius (NTS) for all experiments. Schematic diagram of transverse section of medulla oblongata from a rat brain. NTS is shown at level of caudal tip of area postrema (AP). C, central canal; 10, dorsal motor nucleus of the vagus nerve; 12, nucleus of the hypoglossal nerve; Gr, gracile nucleus; Cu, cuneate nucleus. Number on right side of schematic diagram denotes the rostro-caudal position (in mm) of section relative to obex according to atlas of rat subpostremal NTS.
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The carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindo-carbocyanine perchlorate (DiI, 0.1% solution in DMSO, Molecular Probes) was delivered from a separate barrel of the micropipette to mark the injection site for histological analysis. At the completion of the experiments, the animals were perfused transcardially with 10% buffered formalin and subsequently processed histologically in 64-µm coronal sections. The unstained tissue sections were examined via fluorescence microscopy to determine the site of injection marked by the DiI-lipophilic dye. The injection sites were plotted on schematic representations of coronal sections of the rat subpostremal NTS according to the atlas of Barraco et al. (1) (Fig. 1).
Data analysis.
Responses for MAP and HR were quantified in two ways: 1) the maximal change compared with a 60-s basal control period immediately before microinjection and 2) the time from microinjection to peak response. Values are means ± SE. One-way ANOVA for independent measures was used to determine statistical significance. Differences were further evaluated by using a modified Bonferroni test. An alpha-level of P < 0.05 was used to determine significance.
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RESULTS
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The baseline values of MAP and HR are listed in Table 1. Administration of atropine methyl bromide, a muscarinic antagonist, resulted in a large increase in HR and no significant change in MAP. 1-Adrenergic blockade with atenolol produced significant reductions in both the HR and MAP. The combined administration of atropine methyl bromide and atenolol resulted in no significant change in either HR or MAP compared with control.
Tracings from single experiments at the high dose of ,-methylene ATP (100 pmol/50 nl) are shown in Fig. 2. Muscarinic blockade decreased both the magnitude of the bradycardia and the rate of the response. 1-Adrenergic blockade markedly attenuated the bradycardia, but it had no effect on the time course of the response. Double blockade abolished the HR response.
The averaged maximum changes in MAP and HR after stimulation of P2X purinoceptors under the four experimental conditions (control, muscarinic blockade, 1-adrenergic blockade, and double blockade) are shown in Fig. 3. At the low dose of ,-methylene ATP, bradycardia was mediated primarily via sympathetic withdrawal as evidenced by the marked decrease in the bradycardia after 1-adrenergic blockade and the slight, but not significant, decrease (as compared with control) in the HR response after muscarinic blockade. At the high dose of ,-methylene ATP, the bradycardia was mediated equally by sympathetic and vagal mechanisms as indicated by equal decreases of the HR response (approximately half of the control response) after muscarinic and 1-adrenergic blockade. Double blockade virtually abolished the HR response, indicating that the autonomic blockade of the heart was effective. Blockade of the vagal component of the bradycardia did not affect the MAP response. In contrast, blockade of the sympathetic component of the bradycardia significantly reduced the hypotension evoked by activation of NTS P2X receptors at both doses of ,-methylene ATP. Neither atropine nor atenolol significantly altered the time to recovery of the response for either dose of P2X receptor agonist.
1-Adrenergic blockade had no effect on either the time to maximum MAP or the time to maximum HR for both doses of the P2X receptor agonist ,-methylene ATP (Fig. 4). Muscarinic blockade increased the time to maximum MAP and HR responses at the high dose of P2X agonist, but it had no significant effect on the time course of the responses at the low dose.
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DISCUSSION
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This study was the first to examine the autonomic mechanisms mediating the bradycardia evoked by stimulation of P2X receptors in the subpostremal NTS. The major finding was that this bradycardia is mediated by sympathetic withdrawal at low levels of P2X receptor activation and by a combination of sympathetic withdrawal and parasympathetic activation at higher levels of P2X receptor activation. Thus the relative contribution of sympathetic withdrawal and parasympathetic activation to the reduction in HR is dependent on the extent of NTS P2X receptor activation.
Both sympathetic and parasympathetic components of HR control were well preserved in anesthetized rats used in our study. Resting HR and decreases in HR after 1-adrenergic blockade were very similar to those reported by others for conscious animals (7, 11, 27) (Table 2). Increases in HR after muscarinic receptor blockade were only slightly less in our study compared with that observed in conscious animals (7, 11). This indicated that the vagal component was slightly suppressed by urethane-chloralose anesthesia, although not to the extent usually observed under barbiturate anesthesia (30).
Interestingly, the relative contribution of vagal and sympathetic responses observed 25 s after microinjection of the low dose of ,-methylene (when a maximal response developed) was very similar to that reported for a late phase (20–25 s) of baroreceptor stimulation in conscious animals (7). This observation is consistent with our former findings that time courses of hemodynamic and neural responses to moderate stimulation of NTS P2X receptors are very similar to those observed after microinjection of glutamate (a primary neurotransmitter in baroreflex arch) into the same site of the NTS (23). It is also consistent with the release of glutamate from NTS neurons after stimulation of P2X receptors (12) and with marked impairment of the HR baroreflex after blockade of P2 receptors in the NTS (22). Taken together, these observations suggest that ATP operating via P2X receptors may be a cotransmitter with glutamate in the baroreflex arc at the level of the NTS.
A recent study (16) showed that stimulation of NTS P2X receptors with microinjections of ,-methylene ATP also evokes bradycardia in an unanesthetized brain stem-heart preparation. However, sympathetic and parasympathetic components of the bradycardia were not evaluated in that study. Most recently, de Paula and colleagues (8) reported that microinjections of ATP into the NTS of conscious rats evoke bradycardia via the glutamatergic mechanism, which is consistent with a previous report from O'Leary's and Scislo’s laboratory (24). Although de Paula and colleagues did not evaluate the 1-adrenergic component of the bradycardic response, they showed that systemic blockade of muscarinic receptors with atropine reversed ATP-induced bradycardia into a small tachycardia, suggesting that the response was entirely mediated via parasympathetic mechanism. In contrast, in the present study, sympathetic withdrawal contributed to bradycardia elicited with moderate and maximal stimulation of NTS P2X receptors, whereas the parasympathetic component was involved only in responses evoked with maximal stimulation of P2X receptors. However, on microinjection, ATP is rapidly catabolized to adenosine via ectonucleotidazes (33), which may make the results of de Paula and colleagues difficult to interpret. For example, the activation of NTS adenosine A1 and A2a receptors can elicit bradycardia (2–4, 23, 25), although de Paula et al. did report that blockade of adenosine A1 receptors did not affect the responses. Another possible explanation for the differences between the studies may be that in conscious animals parasympathetic activation contributes relatively more to the evoked bradycardia, whereas in anesthetized animals the bradycardia is mediated mostly via sympathetic withdrawal. This could result in a relatively smaller contribution of the parasympathetic system to the responses, especially for the lower dose of the P2X receptor agonist. However, the possible influence of anesthesia was rather minimal in our preparation because the effects of blockade of sympathetic and parasympathetic system on resting HR observed in the present study and the studies performed in conscious animals were similar as discussed above (Table 2).
In the present and our previous studies, we used the noncatabolized ATP analog ,-methylene ATP, which selectively stimulates P2X3, P2X1, and possibly recombinant receptor subtypes containing the P2X subunits (17). The hemodynamic and neural responses evoked by microinjections into the NTS of ,-methylene ATP were completely antagonized with suramin in doses that did not affect glutamatergic transmission (10, 20, 22). In addition, we microinjected the selective P2X receptor analog into the subpostremal NTS, the area where most cardiovascular afferents converge and where P2X3 receptors are densely expressed (31, 32). Therefore, we believe that in the present study the bradycardia was elicited via selective activation of P2X receptors potentially involved in baroreflex transmission (most likely the P2X3 receptor subtype).
In the present study, there was a significant contribution from the parasympathetic nerves to the evoked bradycardia only at the high dose of the P2X agonist. This may suggest that there is a higher threshold to trigger parasympathetic mechanisms for NTS P2X receptors, which is consistent with attenuation of vagal component of baroreflex bradycardia in anesthetized animals. The other possibility is that due to the close proximity, the high dose of ,-methylene ATP may diffuse to and activate some efferent preganglionic motoneurons in the dorsal vagal nucleus, which also contains ATP receptors (15). This would result in an enhanced parasympathetic response. It is unlikely that this occurred at the lower dose of the P2X agonist, because there was little or no parasympathetic effect.
The time to reach the peak change in both MAP and HR was affected by parasympathetic blockade only at the higher dose of ,-methylene ATP. Although the maximum change in HR achieved after 1-adrenergic blockade at the high dose of ,-methylene ATP was not different than that seen after muscarinic blockade, the time to reach that peak response was significantly longer after parasympathetic blockade. The time course of the cardiac responses to changes in parasympathetic tone is markedly faster than that for changes in sympathetic activity (29), which likely explains why the HR responses occurred much more slowly after parasympathetic blockade. However, the total time of the responses was not significantly affected by 1- or muscarinic receptor blockade.
Previous studies (3) have shown that NTS P2X receptor activation produces increases in vascular conductance in the renal, mesenteric, and iliac vascular beds. In addition, decreased efferent sympathetic nerve activity directed to the kidney, adrenal glands, and hindlimb occurred after stimulation of NTS P2X receptors (20, 23). More recently, we (13) have shown that total peripheral resistance decreases in response to moderate and maximal stimulation of NTS P2X receptors, whereas decreases in cardiac output contribute to the depressor responses only after the maximal stimulation. Taken together, these observations suggest that P2X receptors in the subpostremal NTS may exert greater control over sympathetic versus parasympathetic activity.
In conclusion, the relative contribution of sympathetic withdrawal and parasympathetic activation to the bradycardia evoked by stimulation of NTS P2X receptors is dependent on the extent of receptor activation. At the low dose of P2X receptor agonist, bradycardia is mediated primarily via sympathetic withdrawal, whereas at the high dose of P2X agonist, both sympathetic and parasympathetic components contribute similarly to the bradycardia. Only the sympathetic component of bradycardia contributes significantly to the hypotension elicited by NTS P2X receptor stimulation.
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GRANTS
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-67814.
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ACKNOWLEDGMENTS
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The authors gratefully acknowledge the technical assistance of C. Cupps.
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FOOTNOTES
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Address for reprint requests and other correspondence: T. J. Scislo, Dept. of Physiology, Wayne State Univ. School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201 (e-mail: tscislo{at}med.wayne.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2006 by the American Physiological Society.
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ABSTRACT
MATERIALS AND METHODS
