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Am J Physiol Heart Circ Physiol 275: H2130-H2139, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 6, H2130-H2139, December 1998

Differential control of renal vs. adrenal sympathetic nerve activity by NTS A2a and P2x purinoceptors

Tadeusz J. Scislo and Donal S. O'Leary

Department of Physiology, Wayne State University, School of Medicine, Detroit, Michigan 48201

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Activation of adenosine A2a and ATP P2x purinoceptors in the subpostremal nucleus tractus solitarii (NTS) via microinjection of the selective agonists CGS-21680 and alpha ,beta -methylene ATP (alpha ,beta -MeATP), respectively, elicits large dose-dependent decreases in arterial pressure and heart rate, differential regional vasodilation, and differential inhibition of regional sympathetic outputs. With marked hypotensive hemorrhage, preganglionic adrenal sympathetic nerve activity (pre-ASNA) increases, whereas renal (RSNA) and postganglionic adrenal sympathetic nerve activity (post-ASNA) decrease. In this setting, adenosine levels in the brain stem increase. Therefore, we investigated whether stimulation of specific purinoceptors in the NTS may evoke differential sympathetic responses. RSNA was recorded simultaneously with pre-ASNA or post-ASNA in chloralose-urethan-anesthetized male Sprague-Dawley rats. CGS-21680 (2 and 20 pmol in 50 nl) inhibited RSNA and post-ASNA, whereas pre-ASNA increased markedly. alpha ,beta -MeATP (25 and 100 pmol in 50 nl) inhibited all sympathetic outputs. Sinoaortic denervation plus vagotomy markedly prolonged the responses to P2x-purinoceptor stimulation. Glutamate (100 pmol in 50 nl) caused differential inhibition of all sympathetic outputs similar to that evoked by alpha ,beta -MeATP. We conclude that NTS A2a-purinoceptor activation evokes differential sympathetic responses similar to those observed during hemorrhage, whereas P2x-purinoceptor and glutamate-receptor activation evokes differential inhibition of sympathetic outputs similar to arterial baroreflex responses.

adrenal sympathetic nerve; renal sympathetic nerve; purinergic receptor subtypes; nucleus of the solitary tract; cardiovascular control

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

THE NUCLEUS TRACTUS SOLITARII (NTS), the primary integrative center for cardiovascular control and other autonomic functions, contains a great variety of neurotransmitters/neuromodulators and is organized in a viscerotopic manner (21, 27, 36). The combination of these two factors (neurochemical and neuroanatomic) may create specific regional patterns of cardiovascular and neuroregulatory responses to different physiological and pathological stimuli.

Among the numerous neuroactive substances operating in the NTS, the purines ATP and adenosine recently have been shown to play an important role in central cardiovascular control (24). Several lines of evidence from our laboratory and from others suggest that ATP, operating via P2x purinoceptors, may act as a fast neurotransmitter in NTS interneurons, whereas adenosine operating via A1 and A2a purinoceptors plays a neuromodulatory role in NTS mechanisms of cardiovascular control (1, 2, 5, 6, 10, 12-14, 17, 22-24, 28, 31, 33, 34). Neuronally released ATP may subsequently become a source of adenosine when catabolized by ectonucleotidases (42). This was recently confirmed in vivo at the level of the NTS and rostral ventrolateral medulla (33). Microinjection of ATP and its synthetic analogs, alpha ,beta -methylene ATP (alpha ,beta -MeATP) and 2-methylthio-ATP, into the subpostremal NTS in vivo produce abrupt, marked, dose-related reductions in mean arterial blood pressure (MAP), heart rate (HR), and sympathetic activity, simulating baroreflex responses (5, 14, 28). Similarly, microinjection of adenosine into the subpostremal and caudal NTS decreases MAP, HR, and efferent sympathetic nerve activity (1, 22, 23, 34); however, the responses develop slower and last longer than those evoked by ATP. This depressor action of adenosine is mediated via A2a purinoceptors (2, 5, 31). Recently we have shown that selective activation of P2x and A2a purinoceptors in the subpostremal NTS elicits distinct patterns of dose-dependent, differential regional vasodilation and differential inhibition of renal (RSNA) versus lumbar sympathetic nerve activity (LSNA) (5, 28, 31).

Specific physiological mechanisms (e.g., hemorrhage, stress, exercise, etc.) have characteristic regional distribution of vascular and neuroregulatory effects (15, 26, 35, 39, 41). A most impressive example of differential sympathetic regulation is the dissociation between adrenal sympathetic nerve activity (ASNA) versus RSNA observed in several physiological and pathological situations. For example, early stages of hemorrhage or hypoglycemia lead to a greater increase in ASNA than RSNA (9, 35, 39), whereas during prolonged severe hemorrhage, stimulation of cardiac chemoreceptors or the paraventricular nucleus of the hypothalamus, or intravenous injections of morphine, ASNA increases while RSNA decreases (8, 11, 16, 18, 35, 39). These differential response patterns were usually related to specific reflex mechanisms or certain central neurotransmitters/neuromodulators. Because adenosine is naturally released into the NTS and other central structures under conditions of severe hemorrhage, central hypoxia, or ischemia (25, 38, 40), it is possible that this neuromodulator may facilitate the dissociation between ASNA and RSNA. Adenosine, acting via A2a purinoceptors, may stimulate neuronal release of serotonin in the NTS (4) or facilitate cardiopulmonary reflexes via an increase in glutamate release from primary afferents terminating on NTS neurons (10). Both these mechanisms may elicit an increase in ASNA and a simultaneous decrease in RSNA (16, 32). To test this hypothesis, we compared ASNA and RSNA responses to selective stimulation of A2a purinoceptors in the subpostremal NTS. To evaluate whether the pattern of sympathetic responses (ASNA vs. RSNA) is specific to stimulation of A2a purinoceptors, we compared these responses with those evoked by selective stimulation of P2x purinoceptors and nonselective stimulation of glutamate receptors in the same site of the NTS. To distinguish between primary responses to stimulation of the purinoceptor subtypes in the NTS and reflex compensation to these responses via arterial and cardiopulmonary afferents, the effects evoked by microinjections of selective A2a- and P2x-purinoceptor agonists (CGS-21680 and alpha ,beta -MeATP, respectively) were compared in intact versus sinoaortic denervated and vagotomized (SAD + VX) animals.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

All protocols and surgical procedures employed in this study were reviewed and approved by the Institutional Animal Care and Use Committee and were performed in accordance with the "Guiding Principles in the Care and Use of Animals" endorsed by the American Physiological Society and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.

Design. The effect of activation of A2a and P2x purinoceptors in the subpostremal region of the NTS on simultaneously recorded sympathetic nerve activity directed to the adrenal gland and the kidney was investigated in 26 intact and 11 SAD + VX male Sprague-Dawley rats (350-400 g) (Charles River Laboratories, Wilmington, MA). MAP and HR responses were also recorded. Activation of purinoceptors was accomplished via microinjections of the selective A2a- and P2x-purinoceptor agonists CGS-21680 and alpha ,beta -MeATP, respectively. In some animals the effects of microinjection of vehicle [artificial cerebrospinal fluid (ACF)] (5, 28, 31) on cardiovascular and neural parameters were observed over the average time of the response to the maximal dose of CGS-21680 or alpha ,beta -MeATP, respectively. In an additional five animals with intact baroreceptor and vagal afferents, nonselective glutamatergic receptors were stimulated via microinjections of sodium glutamate into various sites of subpostremal and immediately adjacent commissural NTS. This was performed to compare responses evoked by selective activation of purinoceptor subtypes with a standard "nonspecific" stimulation of NTS neurons in this area.

Instrumentation and measurements. All the procedures were described in detail previously (2, 5, 14, 28, 29, 31). Briefly, rats were anesthetized with a mixture of alpha -chloralose (80 mg/kg) and urethan (500 mg/kg ip) and tracheotomized. Intact animals breathed spontaneously, similar to our previous studies (28, 31). SAD + VX animals were connected to a small animal respirator (SAR-830, CWE, Ardmore, PA) to compensate for the changes in respiratory pattern. All animals breathed oxygen-enriched air. Arterial blood gases were tested occasionally (ABL500, OSM3; Radiometer), and ventilation was adjusted to maintain PO2, PCO2, and pH within normal ranges. The right femoral artery and vein were catheterized to monitor arterial blood pressure and infuse drugs. SAD + VX was accomplished and its completeness tested as described previously (29).

The adrenal and renal nerves were exposed retroperitoneally, and neural recordings were accomplished as described previously (28, 31). Neural signals were initially amplified (2,000-20,000×) with bandwidth set at 100-1,000 Hz, digitized, rectified, and averaged in 1-s intervals. Background noise was determined 30-60 min after the animal was euthanized. Resting nerve activity was normalized to 100%.

The ratio between preganglionic and total nerve activity was initially tested with a bolus injection of the short-lasting (1-2 min) ganglionic blocker arfonad (2 mg/kg) (8, 9) and reevaluated at the end of each experiment with hexamethonium (20 mg/kg iv). RSNA was almost completely postganglionic; only 4.3 ± 1.1% (n = 42) of the activity persisted after the ganglionic blockade. The adrenal nerve consists of several separate bundles containing both pre- and postganglionic fibers, with a very different ratio for each bundle (8, 9). Therefore, ASNA was considered predominantly preganglionic if the activity remaining after ganglionic blockade at the end of each experiment was >75% or predominantly postganglionic if the remaining activity was <50%. These criteria were set because, in some experiments, ASNA slightly increased in response to arfonad at the beginning of surgery and then decreased slightly in response to hexamethonium after 6-10 h of the experiment. Data from animals that exhibited ASNA between 50 and 75% after ganglionic blockade were excluded from further calculations. Average ASNA after ganglionic blockade was 121.4 ± 5.1 (n = 36) and 38.8 ± 2.4% (n = 6) of control level immediately preceding administration of hexamethonium for "preganglionic" (pre-ASNA) and "postganglionic" ASNA (post-ASNA), respectively. Pre-ASNA increased over 100%, likely because of an arterial baroreflex response caused by the decrease in MAP after ganglionic blockade.

The arterial pressure and neural signals were digitized and recorded with a Hemodynamic and Neural Data Analyzer (Biotech Products, Greenwood, IN), averaged over 1-s intervals, and stored on a hard disk for subsequent analysis.

Microinjections into the NTS. Unilateral microinjections of CGS-21680, alpha ,beta -MeATP, glutamate, or vehicle (ACF) were made with multibarrel glass micropipettes into the medial region of the caudal subpostremal NTS as described previously (2, 5, 28, 31). Some microinjections of glutamate were made into the adjacent portions of the NTS, i.e., commissural and rostral subpostremal NTS. Nonselective activation of glutamatergic receptors allowed evaluation of whether the relative ratio between regional neural responses (ASNA vs. RSNA) to a nonspecific stimulus (glutamate) depends on the precise anatomic location of the stimulus in this area of the NTS. All microinjection sites were verified histologically as described previously (28, 30, 31) and presented schematically in Fig. 1.


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  		Fig. 1.   Microinjection sites in subpostremal nucleus tractus solitarii (NTS) for all experiments. Schematic diagrams of transverse sections of medulla oblongata from a rat brain. AP, area postrema; c, central canal; 10, dorsal motor nucleus of vagus nerve; 12, nucleus of hypoglossal nerve; ts, tractus solitarius; gr, gracile fasciculus; Gr, gracile nucleus; cu, cuneate fasciculus; Cu, cuneate nucleus. Scale is shown in bottom left panel; numbers on left denote rostrocaudal position (in mm) of section relative to obex according to the atlas of rat subpostremal NTS by Barraco et al. (3). Left and middle panels show microinjection sites for experiments in which adrenal nerve activity was predominantly preganglionic. Right panels show microinjection sites for experiments in which predominantly postganglionic adrenal nerve activity was recorded. Left panels show microinjection sites for low doses of purinoceptor agonists and artificial cerebrospinal fluid (ACF) control, whereas middle and right panels show microinjection sites for high doses of purinoceptor agonists and glutamate. Microinjection sites for each drug were marked with fluorescent dye and are denoted by symbols [ACF: ×; CGS-21680: , intact animals; , sinoaortic denervated and vagotomized (SAD + VX) animals; alpha ,beta -methylene ATP (alpha ,beta -MeATP): open circle , intact animals; bullet , SAD + VX animals; triangle , glutamate].

The doses of CGS-21680 and alpha ,beta -MeATP were the same as those used in our previous studies (5, 28, 31): 1) the approximate threshold hypotensive dose (2 and 25 pmol for CGS-21680 and alpha ,beta -MeATP, respectively), and 2) the maximally effective hypotensive dose (20 and 100 pmol for CGS-21680 and alpha ,beta -MeATP, respectively) (5, 28, 31). We have previously shown that the effects elicited with the high doses of both purinoceptor agonists were completely and selectively blocked by microinjection of the selective A2a-purinoceptor antagonist CGS-15943A (2) or P2-purinoceptor antagonist suramin, respectively (14, 28). To avoid the effect of desensitization of purinoceptors, in all experiments only one dose of purinoceptor agonist was microinjected into the left and/or right side of the NTS. If purinergic agonists were injected bilaterally, at least a 90-min interval between the injections was allowed. Because glutamate (100 pmol in 50 nl) elicits relatively short-lasting responses, the effects of up to three unilateral microinjections into separate areas of the NTS (comissural, rostral subpostremal, and caudal subpostremal) were performed. All the drugs were dissolved in ACF and the pH adjusted to 7.2. Microinjections of ACF (50 nl) served as a vehicle control.

Data analysis. Hemodynamic and sympathetic nerve responses were quantified in two ways: 1) the maximal percent difference from a 30-s basal control period taken immediately before microinjection, and 2) integration of the percent changes from control over the period of the change in MAP. The HR responses, calculated from pulse intervals, were expressed in absolute values (beats/min). Neural recordings were additionally filtered using a running average in 10-s intervals to minimize the effect of random spikes on maximum response values. Because the responses to alpha ,beta -MeATP frequently exhibited a biphasic pattern, i.e., fast recovery to ~80% of the depressor response followed by variable residual depression, only the fast part of the response (to 80% of recovery in MAP) was analyzed, similar to our previous study (28). However, time to recovery was measured for both fast and slow components of the response. Maximal and integral responses to control microinjections of ACF were measured over the time to recovery of MAP after the high dose of CGS-21680 and/or alpha ,beta -MeATP, respectively. One-way ANOVA for independent measures was used to compare MAP and HR responses to ACF versus different doses of CGS-21680 and alpha ,beta -MeATP. A two-way ANOVA for independent measures was used to compare neural responses versus doses of the drug and ASNA versus RSNA. Differences observed were further evaluated by the test of simple effect. An alpha -level of P < 0.05 was used to determine statistical significance.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

The resting values for MAP and HR measured in intact animals (n = 31) before microinjection of drugs or vehicle into the subpostremal NTS were 81.8 ± 1.3 mmHg and 367 ± 4 beats/min. The effects of microinjections of CGS-21680 and alpha ,beta -MeATP at the high doses (20 and 100 pmol/rat, respectively) on MAP, HR, and simultaneously recorded pre-ASNA and RSNA are presented in Fig. 2. Microinjection of CGS-21680 produced gradually developing and long-lasting reductions in MAP, HR, and RSNA; however, pre-ASNA increased markedly. In contrast to the directionally opposite responses of RSNA and pre-ASNA to CGS-21680, alpha ,beta -MeATP evoked decreases in both sympathetic outputs. The responses to alpha ,beta -MeATP started abruptly and usually showed a biphasic pattern of recovery (fast and slow components), especially for the high dose of the drug (Fig. 2). Fast recovery, to ~80% of the depressor response, was followed by a weak residual depression, cardiac slowing, and sympathoinhibition, lasting several times longer than the fast component of the response (Fig. 2 and Table 1). Both drugs demonstrated a dose dependency of the duration of the depressor responses (Table 1).


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  		Fig. 2.   Mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and predominantly preganglionic adrenal sympathetic nerve activity (pre-ASNA) responses to microinjection of CGS-21680 (20 pmol in 50 nl) and alpha ,beta -MeATP (100 pmol in 50 nl) into subpostremal NTS, recorded in an intact animal. Responses evoked with microinjections of CGS-21680 developed much slower and lasted several times longer than those evoked with alpha ,beta -MeATP. Note that response of pre-ASNA to CGS-21680 is opposite that observed after microinjection of alpha ,beta -MeATP.

                              
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  		Table 1.   Time to recovery of mean arterial blood pressure after microinjections of alpha ,beta -MeATP and CGS-21680 into the NTS in intact and sinoaortic baroreceptor-denervated plus vagotomized animals

A2a-purinoceptor stimulation. The average neural and hemodynamic responses to ACF (50 nl) and both doses of CGS-21680 (2 and 20 pmol in 50 nl) are shown in Fig. 3. Microinjections of CGS-21680 evoked substantial dose-dependent increases in pre-ASNA, whereas RSNA and hemodynamic parameters markedly decreased in a dose-dependent manner. The differences between neural responses were highly significant for both methods of evaluation of the effect (i.e., maximum and integral responses, P < 0.0001). HR and RSNA responses were similar in magnitude and time course to those observed in previous studies from our laboratory (5, 31). However, the decrease in MAP was ~30-50% smaller compared with that previously observed for both doses of the drug in terms of both the maximal and integral responses (5, 31; see DISCUSSION). Microinjections of the same volume of ACF did not evoke marked integral responses measured over the average time to recovery of MAP for the high dose of CGS-21680 (Fig. 3). The integral RSNA, pre-ASNA, and HR responses to ACF were not different from zero (P > 0.05), and the integral response of MAP did not decrease but rather tended to increase slightly (P = 0.034). Because hemodynamic and neural parameters fluctuate spontaneously, some decreases and equivalent increases in all parameters were observed over the relatively long time period of measurement (almost a half hour); however, these minor spontaneous fluctuations were significantly smaller than the responses to even the low dose of CGS-21680 (P < 0.05) (Fig. 3). Note that pre-ASNA responses to CGS-21680 (increases) were compared with the maximal, spontaneous increases in the activity recorded after microinjections of ACF, whereas responses in RSNA and hemodynamic parameters (decreases) were compared with maximal spontaneous decreases in these parameters. The magnitude of spontaneous increases was not different from the magnitude of spontaneous decreases for all recorded parameters (P > 0.05; the remaining data for all these comparisons are not presented).


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  		Fig. 3.   Average maximum responses (maxDelta %; top panels) and integral responses (<LIM><OP>∫</OP></LIM>Delta %; bottom panels) of MAP, HR, RSNA, and pre-ASNA evoked by microinjections of vehicle (ACF, 50 nl, n = 8) and 2 doses of CGS-21680 (2 and 20 pmol in 50 nl, n = 8 and 9, respectively) into caudal subpostremal NTS in intact animals. * P < 0.05 vs. ACF; # P < 0.05 vs. 25 pmol; $ P < 0.05 vs. RSNA. Note that microinjections of CGS-21680 decreased MAP, HR, and RSNA but increased pre-ASNA. bpm, Beats/min.

P2x-purinoceptor stimulation. Averaged fast components of hemodynamic and neural responses to both doses of alpha ,beta -MeATP compared with respective vehicle control (ACF) are presented in Fig. 4. Microinjection of alpha ,beta -MeATP produced powerful, dose-related reductions in the activity of both sympathetic outputs and decreases in MAP and HR. The decreases in MAP, HR, and RSNA were similar in magnitude and time course to those observed in our previous studies (5, 28). The responses evoked by the high dose of alpha ,beta -MeATP were significantly greater than those caused by the low dose for both maximal and integral changes (P < 0.05 for all comparisons). However, dose-related differences were much more pronounced for integral changes, especially for the neural activity, which was abruptly inhibited, sometimes to virtually zero levels for a very short time (a few seconds) just after the microinjection. Large dose-related differences for integral responses and small dose-related differences for maximum responses reflect the observation that higher doses of alpha ,beta -MeATP evoked much longer-lasting inhibitory effects compared with those evoked with low doses (Table 1; compare also Fig. 2, right, and Fig. 5, left). The fast responses to alpha ,beta -MeATP were several times shorter than those evoked by CGS-21680, especially for the small, near-threshold doses of both drugs (Table 1).


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  		Fig. 4.   Average fast component of maximum responses (top panels) and integral responses (bottom panels) of MAP, HR, RSNA, and pre-ASNA evoked by microinjections of vehicle (ACF, 50 nl, n = 10) and 2 doses of alpha ,beta -MeATP (25 and 100 pmol in 50 nl, n = 9 and 8, respectively) into caudal subpostremal NTS in intact animals. * P < 0.05 vs. ACF; # P < 0.05 vs. 25 pmol; $ P < 0.05 vs. RSNA. Note that RSNA was inhibited to a slightly greater extent than was pre-ASNA.

RSNA was inhibited to a slightly greater extent than pre-ASNA for both high and low doses of alpha ,beta -MeATP and for both methods of evaluation of the effects (P < 0.05).

Microinjection of vehicle (ACF) into the same site of the NTS had no marked effect on any of the parameters measured over the average time of fast depressor responses to the higher dose of alpha ,beta -MeATP (Fig. 4).

Sinoaortic denervation and vagotomy. Bilateral sinoaortic denervation and subsequent vagotomy resulted in a marked, sustained increase in HR and transient elevation in MAP. HR measured in SAD + VX animals (n = 11) just before the microinjections of the drugs (3-10 h after denervation) remained elevated compared with HR measured in intact animals (441 ± 6 vs. 367 ± 4 beats/min, respectively; P < 0.0001). In contrast, MAP returned gradually toward resting values during the 30-60 min after denervation, and no differences between SAD + VX vs. intact animals were observed throughout the time course of experiments (82.9 ± 1.3 vs. 81.8 ± 1.3 mmHg, respectively; P = 0.681).

The comparison of average maximum and integral responses evoked by microinjections of the high doses of CGS-21680 and alpha ,beta -MeATP in intact and SAD + VX animals is presented in Table 2. The opposite regional neural responses to stimulation of A2a purinoceptors, i.e., a decrease in RSNA and an increase in pre-ASNA, were not affected by SAD + VX. Also, the magnitude of hemodynamic responses to CGS-21680 was not markedly changed by SAD + VX, although the maximum responses tended to decrease (Table 2). However, SAD + VX slightly increased the time to recovery of MAP (Table 1).

                              
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  		Table 2.   Effect of SAD + VX on hemodynamic and neural responses to microinjections of alpha ,beta -MeATP and CGS-21680 into the subpostremal NTS

SAD + VX significantly increased the fast component of integral neural and MAP responses to stimulation of P2x purinoceptors, reflecting the much longer-lasting inhibitory effects of alpha ,beta -MeATP in SAD + VX versus intact animals (Tables 1 and 2). However, HR responses were not significantly altered with SAD + VX. A slight tendency to decrease maximum HR responses and to increase integral HR responses in SAD + VX versus intact animals did not reach statistical significance (P = 0.429 and P = 0.0968, respectively).

Glutamate microinjections. Similarities between neural and hemodynamic responses evoked by the low dose of alpha ,beta -MeATP (25 pmol in 50 nl) and a moderate dose of glutamate (100 pmol in 50 nl) are shown in Fig. 5 (left). The microinjection of glutamate elicited a short-lasting decrease in MAP, HR, RSNA, and ASNA. The time course of these responses was very similar to that of the fast component of the responses evoked by a low dose of alpha ,beta -MeATP. Both drugs inhibited pre-ASNA to a slightly lesser extent than RSNA. The ratio between maximal neural responses (Delta %pre-ASNA/Delta %RSNA) was virtually the same for both agonists microinjected into the same area of the caudal subpostremal NTS [0.668 ± 0.055 vs. 0.641 ± 0.063 for alpha ,beta -MeATP (n = 9) and glutamate (n = 7), respectively; P = 0.750].


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  		Fig. 5.   Comparison of glutamate and alpha ,beta -MeATP effects on hemodynamic and neural variables (examples of recordings; left) and average maximum responses to microinjections of glutamate into 3 different subregions of NTS (rostral subpostremal, caudal subpostremal, and comissural; right). * P < 0.05 vs. RSNA; # P < 0.05 vs. rostral subpostremal. A typical, short-lasting decrease in MAP, HR, RSNA, and pre-ASNA that followed microinjection of glutamate (100 pmol in 50 nl) was very similar to the fast component of response evoked by a small dose of alpha ,beta -MeATP (25 pmol in 50 nl). Rostrocaudal location of microinjections of glutamate had no significant effect on neural and MAP responses; however, HR responses evoked from rostral sites of subpostremal NTS were significantly greater. Glutamate inhibited pre-ASNA to a lesser extent than RSNA, similar to that observed for alpha ,beta -MeATP (compare with Fig. 4). Differential neural response to glutamate (pre-ASNA vs. RSNA) was independent of anatomic location of microinjection in caudal subpostremal and immediately adjacent areas of NTS.

Averaged responses to glutamate microinjected into the caudal subpostremal NTS and immediately adjacent areas of the NTS, i.e., rostral subpostremal and comissural, are presented as bar graphs in Fig. 5 (see also microinjection sites in Fig. 1). Neural and MAP responses did not differ between specific microinjection sites; however, HR responses tended to increase toward the rostral subpostremal NTS (P = 0.039). The ratio between pre-ASNA and RSNA responses was similar regardless of the specific location of the microinjections (0.685 ± 0.063, 0.641 ± 0.063, and 0.668 ± 0.55 for rostral subpostremal, caudal subpostremal, and comissural NTS, respectively; P > 0.05 for each comparison).

Post-ASNA responses. In contrast to pre-ASNA, post-ASNA responded similarly to RSNA. Stimulation of A2a purinoceptors evoked a decrease in predominantly post-ASNA in contrast to the increase observed in predominantly pre-ASNA (compare Figs. 3 and 6). The inhibition of post-ASNA was smaller than that for RSNA; however, predominantly post-ASNA exhibited almost 40% of preganglionic activity, which presumably increased in response to stimulation of A2a purinoceptors, whereas RSNA was ~96% postganglionic.


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  		Fig. 6.   Comparison of average maximum responses (top panel) and integral responses (bottom panel) of renal and predominantly postganglionic adrenal sympathetic nerve activity (post-ASNA) evoked by microinjections of alpha ,beta -MeATP (n = 5), CGS-21680 (n = 5), and glutamate (n = 4) into subpostremal NTS. * P < 0.05 vs. RSNA. Glutamate was microinjected in intact animals, whereas both purinergic agonists were microinjected in SAD + VX animals. In contrast to predominantly pre-ASNA, which was enhanced as a result of microinjection of CGS-21680 (compare Table 2 and Fig. 3), predominantly post-ASNA was inhibited.

The high dose of alpha ,beta -MeATP evoked virtually the same inhibition of post-ASNA and RSNA in terms of both maximal and integral responses (P > 0.05 for both comparisons). Also, the responses to glutamate were very similar for both post-ASNA and RSNA. Integral neural responses to glutamate were virtually the same between post-ASNA and RSNA, although a very small (3.2%) "significant" (P = 0.047) difference for the maximum responses was observed. The ratio between post-ASNA and RSNA responses to glutamate (Delta %post-ASNA/Delta %RSNA) was significantly closer to 1 than that calculated for all (n = 17) pre-ASNA versus RSNA responses (0.953 ± 0.016 vs. 0.676 ± 0.036, respectively, P = 0.006).

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

This is the first study to investigate the effects of selective stimulation of A2a and P2x purinoceptors located in subpostremal NTS on pre- and postganglionic sympathetic nerve activity directed to the adrenal gland. Also, for the first time, hemodynamic and neural responses to stimulation of purinoceptor subtypes in the NTS were compared in intact versus SAD + VX animals. The major new finding of the present study is that pre-ASNA increased in response to stimulation of NTS A2a purinoceptors and decreased in response to stimulation of P2x and glutamate receptors, whereas simultaneously recorded RSNA and post-ASNA decreased in response to stimulation of all of these receptor subtypes. These differential neural responses were dose dependent and were accompanied by respective decreases in MAP and HR, as observed previously (5, 28, 31). In addition, SAD + VX markedly prolonged the responses to activation of P2x purinoceptors and slightly extended the responses to activation of A2a-purinoceptor stimulation without marked changes in their initial magnitudes. SAD + VX experiments demonstrate that the increase in pre-ASNA after stimulation of A2a purinoceptors was not a baroreflex response to the concomitant decrease in MAP but a primary response to central stimulation of these receptors.

Differential sympathetic control via NTS neurons. Stimulation of P2x purinoceptors in the subpostremal NTS inhibited pre-ASNA to a lesser extent than RSNA; however, there was no difference between the inhibition of post-ASNA and RSNA. More dramatic differences among these regional sympathetic outputs were observed in response to A2a-purinoceptor stimulation: pre-ASNA increased, whereas post-ASNA decreased and RSNA decreased to an even greater extent. In addition, our previous studies showed that stimulation of P2x purinoceptors inhibited RSNA to a lesser extent than LSNA (directed mostly to the hindlimb), whereas stimulation of A2a purinoceptors, which inhibited RSNA to an extent similar to that in the present study, caused no significant change in LSNA (28, 31). The ratio between regional sympathetic responses to selective stimulation of A2a and P2x purinoceptors was different and characteristic for each pair of sympathetic outputs (Delta %pre-ASNA/Delta %RSNA, Delta %post-ASNA/Delta %RSNA, and Delta %LSNA/Delta %RSNA) and each purinoceptor subtype (A2a and P2x). These differential sympathetic responses to stimulation of different purinoceptor subtypes were evoked from the same anatomic site of the NTS. It is worthwhile to note that the relative ratio between inhibitory neural responses to nonselective glutamatergic stimulation (Delta %pre-ASNA/Delta %RSNA) remained virtually the same for all the microinjection sites located in various parts of subpostremal NTS and the immediately adjacent comissural NTS. This indicates that the differential neural response patterns were not related to a very discrete anatomic location of neurons targeting different sympathetic output. Instead, it is likely that NTS neurons finally targeting sympathetic outputs directed to different organs exhibited differential expression of A2a versus P2x and glutamate receptor subtypes. In support of this concept, a recent study confirmed that relative expression of various types of K+ channels was different for subpostremal and comissural NTS neurons that are involved in arterial baroreflex versus cardiopulmonary reflex control of the circulation (7). Taken together, the results of the present and our previous studies support the hypothesis that different neurotransmitters/neuromodulators operating in the same site of the NTS may be related to specific functional subsystems differentially controlling regional sympathetic outputs.

Physiological implications. Stimulation of A2a purinoceptors in subpostremal NTS created a very similar pattern of hemodynamic and differential sympathetic neural responses to that observed during the latter hypotensive stage of severe hemorrhage, i.e., hypotension accompanied with a large and long-lasting decrease in HR and RSNA and a contrasting, marked increase in pre-ASNA (8, 35, 39). Adenosine naturally accumulates in the brain stem, including the NTS, during severe hemorrhage, hypoxia, or cerebral ischemia (38, 40). This coincidence strongly suggests that adenosine naturally released in the NTS during hemorrhage may participate via its A2a-purinoceptor action in creating specific regional responses that occur during hemorrhagic shock.

Interestingly, the decreases in MAP in response to stimulation of NTS adenosine receptors recorded in the present study were ~30-50% smaller than those observed previously, whereas the decreases in HR and RSNA were virtually the same (5, 31). One major difference among the experimental preparations was that in the present study the left adrenal nerve was cut for recording ASNA, whereas in previous studies sympathetic innervation of both adrenal glands remained intact. Considering that stimulation of A2a purinoceptors in the subpostremal NTS evoked large, long-lasting increases in pre-ASNA directed predominantly to the adrenal medulla, it is likely that release of epinephrine is increased in this setting. In the rat, stimulation of pre-ASNA results in a 4:1 increase in the release of epinephrine versus norepinephrine as measured in the adrenal vein (20). Epinephrine operating via vascular beta -receptors located preferentially in the muscle vascular bed (37) may contribute to the depressor response evoked by stimulation of A2a purinoceptors in the NTS via preferential vasodilation of skeletal muscle. We previously observed that stimulation of NTS A2a purinoceptors evoked marked, preferential vasodilation of the hindlimb versus the renal and mesenteric vascular beds (5). In the present study, because one adrenal gland was denervated, less epinephrine would be released, thereby limiting peripheral vasodilation and hypotension via this mechanism. In support of this concept, we recently reported that the hypotensive and hindlimb vasodilator responses to stimulation of NTS A2a purinoceptors were abolished by systemic beta -adrenergic blockade (19).

Stimulation of P2x purinoceptors exerted MAP and HR depression and sympathoinhibition of a very rapid onset and biphasic pattern of recovery; the first ~80% of the response recovered relatively fast (in 28 s for the low dose of alpha ,beta -MeATP), whereas weak residual depression lasted several times longer (Table 1). This biphasic time course of the responses suggests that two different mechanisms were triggered by stimulation of P2x purinoceptors in the NTS; presumably, neuromediator-like action was followed by neuromodulator-like action. Interestingly, the fast response elicited by the low, near-threshold dose of alpha ,beta -MeATP was similar to that evoked by microinjection of glutamate and mimicked baroreflex response (Fig. 5). The ratio between these neuroinhibitory responses of pre-ASNA and RSNA was virtually the same for alpha ,beta -MeATP and glutamate. In addition, blockade of P2 purinoceptors with suramin microinjected into the same site of the NTS markedly impaired HR baroreflex responses (30). Previous studies indicate that ATP operating via P2x purinoceptors may serve as a fast neurotransmitter between central neurons (12, 13, 17) and that ATP is neuronally released into the NTS (33). Therefore, it is possible that ATP may act as a fast neurotransmitter between NTS interneurons possibly linked in chain with glutamatergic neurons operating in the baroreflex arc. Alternatively, stimulation of P2x purinoceptors may trigger the release of glutamate in the baroreflex arc at the level of the NTS, as was postulated for hippocampal structures (17). The secondary weak, slow, and long-lasting response may be mediated via triggering of the release of one of numerous neuromodulators operating in the NTS (21). This interesting possibility awaits further, detailed investigations.

In summary, different neurotransmitters/neuromodulators microinjected into the same site of the NTS evoked different patterns of regional sympathetic responses. Differential neural response to stimulation of A2a purinoceptors resembled differential neural response to severe hemorrhage, whereas the rapid onset and fast initial recovery of the responses to stimulation of P2x purinoceptors were similar to typical responses evoked with stimulation of glutamate receptors and resembled rapid baroreflex responses. The ratio between neural responses to selective stimulation of A2a and P2x purinoceptors was characteristic for each pair of sympathetic outputs and each purinoceptor subtype. We believe that a comparison of specific patterns of regional peripheral responses to administration of specific neurotransmitters/neuromodulators into discrete groups of central neurons performed in vivo in a whole animal may help explain the physiological role and significance of molecular mechanisms described at the cellular level in vitro.

    ACKNOWLEDGEMENTS

The authors gratefully acknowledge the generous gift of arfonad by Hoffmann-La Roche (Nutley, NJ). We also gratefully acknowledge the technical assistance of C. Cupps.

    FOOTNOTES

This study was supported by National Institutes of Health Grants MH-47181, GM-08167, and HL-02844.

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. §1734 solely to indicate this fact.

Address for reprint requests: D. S. O'Leary, Dept. of Physiology, Wayne State Univ., School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201.

Received 5 May 1998; accepted in final form 25 August 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

1.   Abdel-Rahman, A. A., and S. Tao. Differential alteration of neuronal and cardiovascular responses to adenosine microinjected into the nucleus tractus solitarius of spontaneously hypertensive rats. Hypertension 27: 939-948, 1996[Abstract/Free Full Text].

2.   Barraco, R. A., M. R. El-Ridi, E. Ergene, and J. W. Phillis. Adenosine receptor subtypes in the brainstem mediate distinct cardiovascular response patterns. Brain Res. Bull. 26: 59-84, 1991[Medline].

3.   Barraco, R., M. El-Ridi, E. Ergene, M. Parizon, and D. Bradley. An atlas of the rat subpostremal nucleus tractus solitarius. Brain Res. Bull. 29: 703-765, 1992[Medline].

4.   Barraco, R. A., C. C. Helfman, and G. F. Anderson. Augmented release of serotonin by adenosine A2a receptor activation and desensitization by CGS 21680 in the rat nucleus tractus solitarius. Brain Res. 733: 155-161, 1996[Medline].

5.   Barraco, R. A., D. S. O'Leary, E. Ergene, and T. J. Scislo. Activation of purinergic subtypes in the nucleus tractus solitarius elicits specific regional vascular response patterns. J. Auton. Nerv. Syst. 59: 113-124, 1996[Medline].

6.   Bo, X., and G. Burnstock. Distribution of [3H]alpha ,beta -methylene ATP binding sites in rat brain and spinal cord. Neuroreport 5: 1601-1604, 1994[Medline].

7.   Butcher, J. W., and J. F. R. Paton. K+ channel blockade in the NTS alters efficacy of two cardiorespiratory reflexes in vivo. Am. J. Physiol. 274 (Regulatory Integrative Comp. Physiol. 43): R677-R685, 1998[Abstract/Free Full Text].

8.   Carlsson, S., J. O. Skarphedinsson, M. Delle, P. Hoffman, and P. Thoren. Reflex changes in post- and preganglionic sympathetic adrenal nerve activity and postganglionic sympathetic renal nerve activity upon arterial baroreceptor activation and during severe haemorrhage in the rat. Acta Physiol. Scand. 144: 317-323, 1992[Medline].

9.   Carlsson, S., J. O. Skarphedinsson, M. Delle, P. Hoffman, and P. Thoren. Differential responses in post- and preganglionic adrenal sympathetic nerve activity and renal sympathetic nerve activity after injection of 2-deoxy-D-glucose and insulin in rats. Acta Physiol. Scand. 145: 169-175, 1992[Medline].

10.   Castillo-Melendez, M., E. Krstew, A. J. Lawrence, and B. Jarrott. Presynaptic adenosine A2a receptors on soma and central terminals of rat vagal afferent neurons. Brain Res. 652: 137-144, 1994[Medline].

11.   Delle, M., P. Thoren, J. O. Skarphedinsson, P. Hoffman, S. Carlsson, and E. Ricksten. Differentiated responses of renal and adrenal sympathetic nerve activity to intravenous morphine administration in anesthetized rats. J. Pharmacol. Exp. Ther. 253: 655-660, 1990[Abstract/Free Full Text].

12.   Edwards, F. A., and A. J. Gibb. ATP---a fast neurotransmitter. FEBS Lett. 325: 86-89, 1993[Medline].

13.   Edwards, F. A., A. J. Gibb, and D. Colquhoun. ATP receptor-mediated synaptic currents in the central nervous system. Nature 359: 144-147, 1992[Medline].

14.   Ergene, E., J. C. Dunbar, D. S. O'Leary, and R. A. Barraco. Activation of P2-purinoceptors in the nucleus tractus solitarius mediate depressor responses. Neurosci. Lett. 174: 188-192, 1994[Medline].

15.   Herd, J. A. Cardiovascular responses to stress. Physiol. Rev. 71: 305-330, 1991[Abstract/Free Full Text].

16.   Higuchi, S., D. A. Morgan, and A. L. Mark. Contrasting reflex effects of chemosensitive and mechanosensitive vagal afferents. Hypertension 11: 674-679, 1988[Abstract/Free Full Text].

17.   Inoue, K., S. Koizumi, and S. Ueno. Implication of ATP receptors in brain functions. Prog. Neurobiol. 50: 483-492, 1996[Medline].

18.   Katafuchi, T., Y. Oomura, and M. Kurosawa. Effects of chemical stimulation of paraventricular nucleus on adrenal and renal nerve activity in rats. Neurosci. Lett. 86: 195-200, 1988[Medline].

19.   Kitchen, A. M., T. J. Scislo, and D. S. O'Leary. Stimulation of adenosine A2a receptors in the subpostremal nucleus tractus solitarius (NTS) elicits hindlimb vasodilation via a beta -adrenergic mechanism (Abstract). FASEB J. 12: A62, 1998.

20.   Kurosawa, M., A. Sato, R. S. Swenson, and Y. Takahashi. Sympatho-adrenal medullary functions in response to intracerebroventricularly injected corticotropin-releasing factor in anesthetized rats. Brain Res. 367: 250-257, 1986[Medline].

21.   Lawrence, A. J., and B. Jarrott. Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius. Prog. Neurobiol. 48: 21-53, 1996[Medline].

22.   Mosqueda-Garcia, R., C.-J. Tseng, M. Appalsamy, C. Beck, and D. Robertson. Cardiovascular excitatory effects of adenosine in the nucleus of the solitary tract. Hypertension 18: 494-502, 1991[Abstract/Free Full Text].

23.   Mosqueda-Garcia, R., C.-J. Tseng, M. Appalsamy, and D. Robertson. Modulatory effects of adenosine on baroreflex activation in the brainstem of normotensive rats. Eur. J. Pharmacol. 174: 119-122, 1989[Medline].

24.   Phillis, J. W., T. J. Scislo, and D. S. O'Leary. Purines and the nucleus tractus solitarius: effects on cardiovascular and respiratory function. Clin. Exp. Pharmacol. Physiol. 24: 738-742, 1997[Medline].

25.   Phillis, J. W., G. A. Walter, M. H. O'Regan, and R. E. Stair. Increases in cerebral cortical perfusate adenosine and inosine concentration during hypoxia and ischemia. J. Cereb. Blood Flow Metab. 7: 679-686, 1987[Medline].

26.   Rowell, L. B., D. S. O'Leary, and D. L. Kellog, Jr. Integration of cardiovascular control systems in dynamic exercise. In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 17, p. 770-838.

27.   Ruggiero, D. A., V. M. Pickel, T. A. Milner, M. Anwar, K. Otake, E. P. Mutui, and D. Park. Viscerosensory processing in nucleus tractus solitarii: structural and neurochemical substrates. In: Nucleus of the Solitary Tract, edited by R. Barraco. Boca Raton, FL: CRC, 1994, p. 3-34.

28.   Scislo, T. J., R. A. Augustyniak, R. A. Barraco, D. J. Woodbury, and D. S. O'Leary. Activation of P2x-purinoceptors in the nucleus tractus solitarius elicits differential inhibition of lumbar and renal sympathetic nerve activity. J. Auton. Nerv. Syst. 62: 103-110, 1997[Medline].

29.   Scislo, T. J., and S. E. DiCarlo. Gender difference in cardiopulmonary reflex inhibition of sympathetic nerve activity. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H1537-H1543, 1994[Abstract/Free Full Text].

30.   Scislo, T. J., E. Ergene, and D. S. O'Leary. Impaired arterial baroreflex regulation of heart rate after blockade of P2-purinoceptors in the nucleus tractus solitarius. Brain Res. Bull. 47: 63-67, 1998[Medline].

31.   Scislo, T. J., and D. S. O'Leary. Activation of adenosine A2a receptors in the nucleus tractus solitarius inhibits renal but not lumbar sympathetic nerve activity. J. Auton. Nerv. Syst. 68: 145-152, 1998[Medline].

32.   Scrogin, K. E., R. Veelken, and A. K. Johnson. Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H43-H51, 1998[Abstract/Free Full Text].

33.   St. Lambert, J. H., T. Thomas, G. Burnstock, and K. M. Spyer. A source of adenosine involved in cardiovascular responses to defense area stimulation. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R195-R200, 1997[Abstract/Free Full Text].

34.   Tao, S., and A. Abdel-Rahman. Neuronal and cardiovascular responses to adenosine microinjection into the nucleus tractus solitarius. Brain Res. Bull. 32: 407-417, 1993[Medline].

35.   Togashi, H., M. Yoshioka, M. Tochihara, M. Matsumoto, and H. Saito. Differential effects of hemorrhage on adrenal and renal nerve activity in anesthetized rats. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1134-H1141, 1990[Abstract/Free Full Text].

36.   Van Giersbergen, P. L., M. Palkovits, and W. De Jong. Involvement of neurotransmitters in the nucleus tractus solitarii in cardiovascular regulation. Physiol. Rev. 72: 789-824, 1992[Free Full Text].

37.   Vanhoutte, B. Heterogeneity in vascular smooth muscle. In: Microcirculation, edited by G. Kaley, and B. M. Altura. Baltimore, MD: University Park Press, 1978, p. 181-310.

38.   Van Wylen, D. G., T. S. Park, R. Rubio, and R. M. Berne. Cerebral blood flow and interstitial fluid adenosine during hemorrhagic hypotension. Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H1211-H1218, 1988[Abstract/Free Full Text].

39.   Victor, R. G., P. Thoren, D. A. Morgan, and A. L. Mark. Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats. Circ. Res. 64: 686-694, 1989[Abstract/Free Full Text].

40.   Yan, S., A. Laferriere, C. Zhang, and I. R. Moss. Microdialyzed adenosine in nucleus tractus solitarii and ventilatory response to hypoxia in piglets. J. Appl. Physiol. 79: 405-410, 1995[Abstract/Free Full Text].

41.   Yardley, C. P., and S. M. Hilton. Vasodilation in hind-limb skeletal muscle evoked as a part of defense reaction in the rat. J. Auton. Nerv. Syst. 19: 127-136, 1987[Medline].

42.   Zimmerman, H. Signalling via ATP in the nervous system. Trends Neurosci. 17: 420-426, 1994[Medline].

Am J Physiol Heart Circ Physiol 275(6):H2130-H2139
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