AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 291: H2453-H2461, 2006. First published June 2, 2006; doi:10.1152/ajpheart.00158.2006
0363-6135/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/5/H2453    most recent
00158.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scislo, T. J.
Right arrow Articles by O'Leary, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scislo, T. J.
Right arrow Articles by O'Leary, D. S.

Adenosine receptors located in the NTS contribute to renal sympathoinhibition during hypotensive phase of severe hemorrhage in anesthetized rats

Tadeusz J. Scislo and Donal S. O'Leary

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

Submitted 10 February 2006 ; accepted in final form 30 May 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Stimulation of nucleus of the solitary tract (NTS) A2a-adenosine receptors elicits cardiovascular responses quite similar to those observed with rapid, severe hemorrhage, including bradycardia, hypotension, and inhibition of renal but activation of preganglionic adrenal sympathetic nerve activity (RSNA and pre-ASNA, respectively). Because adenosine levels in the central nervous system increase during severe hemorrhage, we investigated to what extent these responses to hemorrhage may be due to activation of NTS adenosine receptors. In urethane- and {alpha}-chloralose-anesthetized male Sprague-Dawley rats, rapid hemorrhage was performed before and after bilateral nonselective or selective blockade of NTS adenosine-receptor subtypes [A1- and A2a-adenosine-receptor antagonist 8-(p-sulfophenyl)theophylline (1 nmol/100 nl) and A2a-receptor antagonist ZM-241385 (40 pmol/100 nl)]. The nonselective blockade reversed the response in RSNA (–21.0 ± 9.6 {Delta}% vs. +7.3 ± 5.7 {Delta}%) (where {Delta}% is averaged percent change from baseline) and attenuated the average heart rate response (change of –14.8 ± 4.8 vs. –4.4 ± 3.4 beats/min). The selective blockade attenuated the RSNA response (–30.4 ± 5.2 {Delta}% vs. –11.1 ± 7.7 {Delta}%) and tended to attenuate heart rate response (change of –27.5 ± 5.3 vs. –15.8 ± 8.2 beats/min). Microinjection of vehicle (100 nl) had no significant effect on the responses. The hemorrhage-induced increases in pre-ASNA remained unchanged with either adenosine-receptor antagonist. We conclude that adenosine operating in the NTS via A2a and possibly A1 receptors may contribute to posthemorrhagic sympathoinhibition of RSNA but not to the sympathoactivation of pre-ASNA. The differential effects of NTS adenosine receptors on RSNA vs. pre-ASNA responses to hemorrhage supports the hypothesis that these receptors are differentially located/expressed on NTS neurons/synaptic terminals controlling different sympathetic outputs.

nucleus of the solitary tract; tonic activity of purinergic receptors; hypotensive hemorrhage; adrenal sympathetic nerve; renal sympathetic nerve

CARDIOVASCULAR REFLEXES INITIALLY integrated in the nucleus of the solitary tract (NTS) provide rapid compensatory responses to hemorrhage. During the initial, normotensive phase of the response, mean arterial pressure (MAP) is maintained at prehemorrhage level, despite blood loss and gradually increasing hypovolemia. This is achieved via baroreflex-mediated increases in heart rate (HR) and efferent sympathetic vasoconstrictor activity (10, 30). Simultaneous neural stimulation of the adrenal medulla releases epinephrine and additionally helps to maintain cardiac performance under hypovolemic conditions. However, when the decrease of blood volume exceeds 25–35%, the second, hypotensive phase of the response develops abruptly (30). During this phase, a rapid decrease in MAP occurs as a result of active, reflex withdrawal of sympathetic vasoconstrictor activity and accompanying bradycardia (10, 30). The mechanisms triggering the second, hypotensive phase of the response involve cardiopulmonary reflexes and activation of central opioid, nitroxidergic, and vasopressinergic mechanisms (5, 6, 10, 12, 14, 15, 18, 19, 30, 32, 39), whereas central serotoninergic mechanisms seem to postpone/attenuate the development of the second phase (10, 31). The biphasic response to hemorrhage is apparent in conscious animals and humans, whereas under general anesthesia the first, sympathoactivatory phase of the response is usually blunted (10, 30). Interestingly, in conscious and in anesthetized rats, the first sympathoactivatory phase of the response is not fully effective; MAP usually falls from the onset of hemorrhage, and the second phase of the response dominates (30). This may also depend on the rapidity of the hemorrhage. The typical pattern of the response to rapid and severe hemorrhage observed in anesthetized rats involves decreases in HR and efferent renal sympathetic nerve activity (RSNA), whereas the sympathetic output to the adrenal medulla increases (8, 36, 40). This differential pattern of autonomic responses, decreases in MAP, HR, and RSNA with simultaneous increases in preganglionic adrenal sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla, is very similar to that evoked via microinjections of adenosine into the NTS or selective stimulation of adenosine A2a receptors located in the NTS (1, 3, 4, 16, 17, 23–25, 28, 29, 33, 37). In anesthetized animals, adenosine is naturally released into the central nervous system, including the NTS, during ischemia, hypoxia, and severe hemorrhage, during which MAP decreases below the brain autoregulatory range, i.e., below ~50 mmHg (20, 38, 41). Therefore, the similarities between the patterns of autonomic responses elicited by severe hemorrhage and those to stimulation of adenosine receptors operating in the NTS may be not coincidental but physiologically related. In addition, our most recent studies showed that nitric oxide (NO) and vasopressin operating via V1 receptors in the NTS contribute significantly to the depressor, cardiac slowing, and sympathoinhibitory responses elicited via selective stimulation of adenosine A2a receptors in the NTS (28, 29). Importantly, both NO and vasopressin operating in the central nervous system contribute to posthemorrhagic hypotension observed in conscious animals (5, 10, 19, 39). Together, these data strongly suggest that adenosine released into the NTS during severe hemorrhage may contribute to the pattern of autonomic responses observed during the second, hypotensive phase of hemorrhage. Therefore, in the present study, we tested the hypothesis that selective, bilateral blockade of adenosine A2a receptors in the NTS will attenuate the decreases in HR and RSNA evoked by rapid, severe hemorrhage. Stimulation of adenosine A1 receptors located in the NTS evokes predominantly pressor and sympathoactivatory responses (3, 13, 26). However, the stimulation of NTS adenosine A1 receptors may also evoke depressor and sympathoinhibitory responses, consistent with the responses observed during the second, hypotensive phase of hemorrhage (13, 26). Therefore, in addition to the selective blockade of adenosine A2a receptors, we also evaluated the effect of combined blockade of both A1 and A2a adenosine receptors in the NTS. The comparison between the effects of selective vs. nonselective blockades allowed us to evaluate the relative contribution of both adenosine-receptor subtypes to the response to hemorrhage. In addition, the bilateral blockades of adenosine-receptor subtypes located in the NTS allowed us to assess the potential tonic action of these receptors on hemodynamic variables and regional sympathetic nerve activity.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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 effects of bilateral blockade of adenosine receptors located in the NTS or respective volume controls on hemodynamic and regional sympathetic responses to hemorrhage were studied in 23 male Sprague-Dawley rats weighing from 320 to 420 g (mean ± SE = 360.0 ± 5.8 g). In seven rats, we compared the responses to hemorrhage evoked before and after the blockade of adenosine A1 and A2a receptors (A1+A2aX) with bilateral microinjections into the NTS of the nonselective A1- and A2a-receptor antagonist 8-(p-sulfophenyl)theophylline (8-SPT; 1 nmol in 100 nl). In nine rats, the effects of selective blockade of NTS adenosine A2a receptors (A2aX) with the selective antagonist ZM-241385 (40 pmol in 100 nl) on the responses to hemorrhage were assessed. In an additional seven rats, the responses to hemorrhage were observed before and after bilateral microinjections of artificial cerebrospinal fluid (ACF; 100 nl, volume control) into the NTS.

Instrumentation and measurements. All of the procedures were described in detail previously (4, 23–26, 28, 29). Briefly, rats were initially anesthetized with a mixture of {alpha}-chloralose (80 mg/kg) and urethane (500 mg/kg ip), tracheotomized, and artificially ventilated with oxygen-enriched air. After surgery was completed, a continuous intravenous infusion of {alpha}-chloralose (8–16 mg·kg–1·h–1) and urethane (50–100 mg·kg–1·h–1 ip) was applied to maintain a stable level of anesthesia during the experimental protocols as has been performed in all of our previous studies (4, 23–26, 28, 29). The level of anesthesia was monitored via corneal and hindlimb withdrawal reflexes and the stability of hemodynamic and neural variables. Rectal body temperature was maintained at 37–38°C by means of heating pad and heating lamp. Arterial blood gases were tested occasionally (Radiometer, ABL500, OSM3), and ventilation was adjusted to maintain PO2, PCO2, and pH within normal ranges. Average values measured at the end of each experiment were as follows: PO2 = 135.4 ± 5.5 Torr, PCO2 = 39.7 ± 1.0 Torr, pH = 7.357 ± 0.007 (n = 23). Right and left femoral arteries and the left femoral vein were catheterized to monitor arterial blood pressure and withdraw and to reinfuse blood and infuse drugs, respectively.

In 21 experiments, simultaneous recordings from two sympathetic outputs, RSNA and pre-ASNA, were performed. In two experiments, postganglionic ASNA (post-ASNA), directed to the adrenal cortex and vasculature (9), and RSNA were recorded. The adrenal and renal nerves were exposed retroperitoneally, and neural recordings were accomplished as described previously (23–26, 28, 29). Neural signals were initially amplified (2,000–20,000x) 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 before each microinjection was normalized to 100%.

The ratio between preganglionic and total nerve activity was initially tested with bolus intravenous injection of the short-lasting (1–2 min) ganglionic blocker arfonad (Hoffmann La Roche; 2 mg/kg) (23–26, 28, 29) and reevaluated at the end of each experiment with hexamethonium (20 mg/kg iv). RSNA was almost completely postganglionic; only 1.4 ± 0.2% (n = 23) 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 of both types of fibers in each bundle. Therefore, on the basis of criteria established in our previous studies, ASNA was considered as predominantly preganglionic if the activity remaining after ganglionic blockade at the end of each experiment was >75% (23–26, 28, 29). Average pre-ASNA measured after the ganglionic blockade was 124.3 ± 7.3% (n = 21). Pre-ASNA increased over 100% likely because of an arterial baroreflex response caused by the decrease in MAP after the ganglionic blockade. In the two animals in which post-ASNA was recorded, the activity decreased to 49% and 12% after the blockade.

The arterial pressure and neural signals were digitized and recorded with a hemodynamic and neural data analyzer (Biotech Products, Greenwood, Indiana), averaged over 1-s intervals, and stored on hard disk for subsequent analysis.

Microinjections into the NTS. Bilateral microinjections of adenosine antagonists or vehicle (ACF) and carbocyanine dye DiI were made with three-barrel, glass micropipettes into the medial region of the caudal subpostremal NTS as described previously (4, 23–26, 28, 29). Briefly, with the rat skull adjusted to a 45° angle from the horizontal plane of the stereotaxic apparatus and the micropipette barrel held at a 22° angle from the vertical plane, the surface coordinates used for insertion of the micropipette relative to the caudal tip of the area postrema were as follows: anteroposterior = –0.1 mm, mediolateral = 0.3 mm, dorsoventral = 0.35 mm from the dorsal surface of the brain stem. The drugs were dissolved in ACF, and the pH was adjusted to 7.2. Only one microinjection of an antagonist or ACF was performed on each side of the NTS. All microinjection sites were verified histologically as described previously (4, 23–26, 28, 29).

Combined blockade of both A1- and A2a-adenosine-receptor subtypes located in the NTS was accomplished with bilateral microinjections of 8-SPT (1 nmol in 100 nl). Selective blockade of adenosine A2a receptors was achieved by bilateral microinjections into the NTS of selective A2a-receptor antagonist ZM-241385 (40 pmol in 100 nl). The doses of antagonists were similar to those used effectively in previous studies (1, 33–35). The volume of microinjected antagonists was the same as used in our previous studies where other NTS receptors/mechanisms (glutamatergic, nitroxidergic, or vasopressinergic) were effectively antagonized (25, 26, 28, 29).

Hemorrhage. Hemorrhage was performed via rapid withdrawal of arterial blood to decrease and maintain MAP at ~35 mmHg for 5 min, which was followed by reinfusion. This abrupt and severe but short-lasting and fully reversible hemorrhage was applied to induce adenosine release into the central nervous system. It has been shown in anesthetized rats that brain adenosine levels increase significantly when MAP decreases below 50 mmHg, i.e., below the autoregulatory range (38). This rapid, marked hemorrhage evoked typical decreases in HR and RSNA and sustained increases in pre-ASNA under control conditions in all experimental groups (A1+A2aX, A2aX, and ACF) and allowed for complete recovery of all recorded parameters in ~60 min from the reinfusion of the blood. The pattern of the responses observed in the present study was similar to that observed in previous studies performed in anesthetized rats (8, 36, 40). Arterial blood was aspirated into heparinized 5-ml syringe containing ~5 U of heparin in 0.25 ml of saline. Rats were not heparinized before the first hemorrhage to decrease the probability of bleeding from vessels surrounding the exposed brain stem. The temperature of the blood in the syringe was maintained at ~37°C by means of a heating lamp. The initial volume of blood withdrawn to decrease MAP to 35 mmHg and total volume of blood withdrawn to maintain the decreased MAP for 5 min are presented in Table 1. Nonselective (A1+A2aX) and selective (A2aX) blockade of adenosine-receptor subtypes in the NTS significantly increased the initial volumes of blood withdrawn to decrease MAP to ~35 mmHg (P = 0.042 and P = 0.012 for A1+A2aX and A2aX, respectively) and tended to increase the total volume of blood withdrawn during whole period of hemorrhage (5 min), although these differences did not reach statistical significance (P = 0.053 and P = 0.067 for A1+A2aX and A2aX, respectively). ACF also slightly increased the initial but not total volume of withdrawn blood compared with control (P = 0.049 and P = 0.815 for initial and total values, respectively). Nevertheless, this initial increase tended to be smaller than those observed after the blockades (0.5 ± 0.2 vs. 1.3 ± 0.5 and 2.1 ± 0.6 ml/kg; P = 0.170 and P = 0.055 for ACF vs. A1+A2aX and A2aX, respectively).


View this table:
[in this window]
[in a new window]
  		Table 1. Initial volume of arterial blood withdrawn to decrease arterial pressure to ~35 mmHg and total arterial blood withdrawn to maintain the decreased pressure for 5 min

 
Experimental protocols. In three separate experimental groups, the hemodynamic and regional neural responses were evoked via standardized hemorrhage under control conditions and after nonselective (n = 7) and selective (n = 9) blockade of NTS (A1+A2aX and A2aX conditions, respectively) and after bilateral microinjections of ACF into the NTS (volume control; n = 7). In this longitudinal experimental design, each animal served as its own control. This approach decreased interindividual variability of the responses and therefore enhanced the discrimination between random changes in all recorded parameters vs. the effects evoked by the blockade of NTS adenosine receptors. The time line of the protocol is presented in Fig. 1. The control and experimental hemorrhages were evoked in intervals of at least 60–70 min. During this time, all of the recorded parameters returned to the levels measured before the control hemorrhage. In addition, in most animals, the recovery of the responses was assessed ~70 min after the blockade of adenosine receptors in the NTS. The recovery was evaluated in six of seven rats in the A1+A2aX group and in seven of nine rats in the A2aX group. The reasons for not completing the assessment of recovery in three animals were mechanical problems with arterial catheters and/or lack of recovery of all the parameters to the levels recorded before the blockade.


Figure 1
View larger version (8K):
[in this window]
[in a new window]
  		Fig. 1. Protocol timeline. Standard hemorrhages (HMG) followed by reinfusions were evoked under control conditions and after bilateral blockade of nucleus of the solitary tract (NTS) adenosine A1 and A2a receptors [with 8-(p-sulfophenyl)theophylline (8-SPT)], selective blockade of adenosine A2a receptors (with ZM-241385), and microinjections of artificial cerebrospinal fluid (ACF; 100 nl, volume control). In most of the experiments, an additional hemorrhage was performed ~1 h after the blockade of NTS adenosine receptors (recovery). Beginnings of withdrawals of blood and reinfusions are marked with vertical arrows pointed downward and upward, respectively. Bilateral microinjection into the NTS is marked with double vertical arrows.

 
Data analysis. The hemodynamic and regional sympathetic nerve responses to hemorrhage observed under control conditions were compared with the responses observed after nonselective and selective blockade of adenosine receptor subtypes in the A1+A2aX and A2aX groups, respectively, and after bilateral microinjections of ACF into the NTS (volume control). All variables were averaged in 30-s intervals. The responses to hemorrhage were expressed as percent differences from a 30-s basal control periods that were taken immediately before hemorrhage. In addition, the responses were integrated over the period of hemorrhage (5 min) similar to that described previously (4, 23–26, 28, 29) and expressed as averaged percent changes from baseline for the whole period of hemorrhage ({sum}{Delta}% collected in 1-s intervals/300 s). The average responses reflected the overall trends observed under each experimental condition despite the biphasic character of the responses.

The effects of treatment in the A1+A2aX, A2aX, and ACF groups on the resting hemodynamic and neural parameters were evaluated ~5 min after the microinjections of respective antagonists or ACF into the NTS; the last 30 s of the responses preceding subsequent hemorrhage were averaged and compared with respective control values measured during the 30 s preceding the microinjections of the antagonists or ACF. A two-way ANOVA for repeated measures was used to compare control vs. experimental responses to hemorrhage under each experimental condition (A1+A2aX, A2aX, and ACF). Differences observed were further evaluated by t-test with Bonferroni adjustment for repeated measures. The effects of treatment in the A1+A2aX, A2aX, and ACF groups on resting parameters were evaluated with paired t-test. The changes in all recorded variables were also compared with zero by means of SYSTAT univariate F test. An alpha level of P < 0.05 was used to determine statistical significance.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The basal MAP and HR measured before control hemorrhages (n = 23) were as follows: 86.2 ± 1.5 mmHg and 358.0 ± 8.4 beats/min, respectively. Approximately 1 h after control hemorrhage and reinfusion of the blood, the basal parameters, measured before microinjections into the NTS of adenosine-receptor antagonists (8-SPT and ZM-241385) and ACF (volume control) preceding the second hemorrhage, returned to normal levels: 85.9 ± 2.6 mmHg and 362.0 ± 10.8 beats/min for MAP and HR, respectively. Also, in those animals (n = 13) in which a third hemorrhage was performed after the recovery from the blockade (at least 1 h after the second hemorrhage), the basal MAP (81.3 ± 3.0 mmHg) and HR (362.8 ± 10.3 beats/min) were similar to those recorded at the beginning of the experiment. There were no significant differences between basal levels of MAP and HR measured during the three stages of the experiments: control, blockade, and recovery (P > 0.05 for all comparisons).

Effects of blockade of NTS adenosine receptors on basal variables. The effects of nonselective and selective blockade of NTS adenosine-receptor subtypes and the respective volume control on basal MAP, HR, RSNA, pre-ASNA, and post-ASNA are presented in Table 2. The control, bilateral microinjections of ACF (100 nl) into the NTS tended to decrease MAP, HR, and RSNA (P > 0.05 vs. 0) and slightly increased pre-ASNA (P = 0.039 vs. 0). These responses were similar to those observed in our previous studies in which unilateral microinjections of the same volumes of ACF were performed (25, 26, 28, 29). Compared with the effect of vehicle, the bilateral microinjections of nonselective adenosine A1- and A2a-receptor antagonist (8-SPT; 1 nmol/100 nl) and selective adenosine A2a-receptor antagonist (ZM-241385; 40 pmol/100 nl) significantly decreased pre-ASNA but not RSNA (Table 2). RSNA increased significantly after selective blockade of NTS A2a receptors but not after nonselective blockade of both A1 and A2a receptors (Table 2). Similarly to RSNA, post-ASNA, recorded in two experiments, increased by 2.5% and 6.4% after the blockade of adenosine A2a receptors. There was also a tendency for increased HR after the nonselective (A1 and A2a) and selective (A2a) blockade of NTS adenosine receptors (P = 0.069 and P = 0.106, respectively) and a tendency for increased MAP after selective blockade of NTS A2a receptors (P = 0.060) but not following the nonselective, double blockade (P = 0.590).


View this table:
[in this window]
[in a new window]
  		Table 2. Changes in basal levels of MAP, HR, RSNA, and pre-ASNA in response to bilateral microinjections into the NTS of the nonselective adenosine receptor antagonist 8-SPT, the selective A2a adenosine receptor antagonist ZM-241385, and ACF

 
Effects of blockade of NTS adenosine receptors on responses to hemorrhage. Under control conditions, the rapid hemorrhage, which decreased MAP to ~35 mmHg in 60–90 s, evoked typical autonomic responses: after small initial increases, HR and RSNA markedly decreased, whereas pre-ASNA, directed to the adrenal medulla, increased and remained elevated throughout the period of the hemorrhage. The initial phase of the response under control conditions was short lasting and sometime difficult to detect (Fig. 2, left). However, after the blockade of adenosine-receptor subtypes, the initial compensatory increases in RSNA and HR were markedly accentuated and prolonged (Fig. 2, middle). Bilateral nonselective blockade of adenosine A1- and A2a-receptor subtypes in the NTS with 8-SPT (1 nmol/100 nl) attenuated the hemorrhage-elicited decrease in HR and abolished the normal decrease in RSNA observed in the second, sympathoinhibitory phase of hemorrhage. Interestingly, the increase in pre-ASNA evoked by hemorrhage under control conditions remained unaltered or even tended to increase after the blockade (Fig. 2, middle). Selective blockade of NTS A2a-adenosine-receptor subtype with ZM-241385 (40 pmol/100 nl) had similar although less pronounced effects on autonomic responses to severe hemorrhage compared with those observed after nonselective blockade. The antagonist attenuated the hemorrhage-evoked decreases in RSNA and tended to attenuate the cardiac slowing responses. Again, the increases in pre-ASNA remained unaltered after the blockade. The HR and RSNA responses to hemorrhage, altered by the blockade of adenosine receptors, tended to recover ~60 min after the blockade (Fig. 2, right; Table 3). There were no significant differences between hemodynamic and neural responses to hemorrhage observed under control vs. recovery conditions (Table 3).


Figure 2
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Responses to hemorrhage under control conditions, after nonselective blockade of A1 and A2a receptors in the NTS (bilateral microinjections of 8-SPT; 1 nmol in 100 nl), and 70 min after the blockade (recovery). All measurements were performed in the same animal. The blockade attenuated and/or reversed hemorrhage-induced decreases in heart rate (HR) and renal sympathetic nerve activity (RSNA), whereas it did not attenuate the sympathoactivation of preganglionic adrenal sympathetic nerve activity (pre-ASNA). MAP, mean arterial pressure; bpm, beats/min.

 

View this table:
[in this window]
[in a new window]
  		Table 3. Comparison of hemodynamic and neural responses evoked by hemorrhage before the blockade of NTS adenosine receptor subtypes (control, CTR8-SPT, and CTRZM-241385) and 70 min after the nonselective blockade of NTS adenosine A1 and A2a receptors with 8-SPT (recovery, REC8-SPT) and selective blockade of NTS adenosine A2a receptors with ZM-241385 (RECZM-241385)

 
Figure 3 compares the average responses to hemorrhage evoked under control conditions with those observed after nonselective (A1+A2aX) and selective (A2aX) blockade of NTS adenosine-receptor subtypes and after volume control (bilateral microinjections of 100 nl of ACF into the NTS). In addition to the time courses of the responses (averaged in 30-s intervals), the overall responses, averaged for whole period of hemorrhage (5 min), are compared in each panel of Fig. 3. The decreases in MAP were kept virtually identical in all experimental conditions (Fig. 3, top). There were no differences between the magnitude and time courses of decreases in MAP between control vs. experimental conditions and across the experimental groups. Two-way ANOVA did not show significant effects of experimental conditions and experimental conditions x time interactions (P < 0.05 for all comparisons). The combined blockade of adenosine A1 and A2a receptors extended the first, sympathoactivatory phase of the responses; the initial increases in HR and RSNA were markedly enhanced and longer lasting: 120 s for HR and 150 s for RSNA after the blockade compared with 60 s under control conditions for both variables. Two-way ANOVA showed highly significant effect of the blockade (P < 0.001 for HR and RSNA) without interaction between experimental conditions x time (P = 0.835 and P = 0.804 for HR and RSNA, respectively) Selective blockade of adenosine A2a receptors also accentuated the initial increases in HR and RSNA although to a lesser extent (compare left vs. middle of Fig. 3). Two-way ANOVA showed that the effect of the blockade was highly significant (P < 0.001 for both HR and RSNA) without interaction between experimental conditions x time (P = 0.975 and P = 0.942 for HR and RSNA, respectively). Together, these data indicate that biphasic HR and RSNA responses to hemorrhage were shifted in parallel upward after both blockades of NTS adenosine receptors. The shift was greater after nonselective A1- and A2a-receptor blockade than after selective blockade of adenosine A2a receptors compared with respective control conditions.


Figure 3
View larger version (19K):
[in this window]
[in a new window]
  		Fig. 3. Averaged responses of MAP, HR, RSNA, and pre-ASNA evoked by hemorrhage under control conditions, after combined blockade of NTS A1 plus A2a receptors (A1+A2aX; left), after selective blockade of NTS A2a receptors (A2aX; middle), and after volume/time control [microinjections of vehicle (ACF); right]. In addition to the time courses of the responses averaged in 30-s periods (bullet and {circ}), the overall response averaged for the whole period of hemorrhage (5 min) are presented ({blacksquare} and {square}). Values are means ± SE. *Different vs. control. Hemorrhage started at time 0 as marked by vertical dotted lines. The small, short-lasting initial increases in HR and RSNA observed under control conditions were prolonged and accentuated to a greater extent after the nonselective (A1+A2aX) than selective (A2aX) blockade of adenosine-receptor subtypes.

 
The responses averaged for the whole period of hemorrhage (Fig. 3) illustrate the overall effects of the blockades and volume control on both phases of hemorrhage providing simple index of shifts of the curves. The averaged responses in RSNA were reversed from decreases dominating under control conditions to prevailing increases after the combined blockade of adenosine A1 and A2a receptors (P = 0.006) and significantly attenuated decreases after selective blockade of adenosine A2a receptors (P = 0.007). The overall hemorrhage-induced changes in RSNA were not different from zero after both blockades (P = 0.222 and P = 0.191 for A1+A2aX and A2aX groups, respectively). Similarly, the overall decreases in HR observed under control conditions were significantly attenuated after the combined blockade (P = 0.023) and tended to be attenuated following the selective blockade of adenosine A2a receptors, although the differences did not reach statistical significance (P = 0.145). Nevertheless, the overall responses in HR measured after both blockades were not different from zero (P = 0.209 and P = 0.068 for A1+A2aX and A2aX, respectively).

The uniform increases in pre-ASNA remained unaltered after nonselective and selective blockades of NTS adenosine-receptor subtypes. Although the A1+A2aX group tended to show increased responses and the A2aX group tended to show decreased responses, the differences did not reach statistical significance (Fig. 3, bottom) (P > 0.05 for control vs. A1+A2aX and A2aX comparisons of the response curves and averaged responses). The effects of selective blockade of NTS adenosine A2a receptors on post-ASNA were observed in two cases. The post-ASNA (which contained only 12% of preganglionic activity) responded similarly to RSNA; the overall responses to hemorrhage recorded under control vs. blockade conditions were –11.1{Delta}% vs. 15.1{Delta}%, respectively. The other post-ASNA (containing 49% of preganglionic activity) responded similarly to pre-ASNA, although less intensively (30.9{Delta}% vs. 16.4{Delta}% for control vs. blockade conditions, respectively). Volume/time control experiments showed that the responses in HR and RSNA evoked by hemorrhage before and after bilateral microinjections of ACF into the NTS (volume control) remained unaltered. Two-way ANOVA showed no significant ACF effect and no ACF x time interactions for HR and RSNA responses (P > 0.05 for all comparisons).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we have evaluated for the first time the contribution of NTS adenosine-receptor subtypes to the pattern of hemodynamic and regional sympathetic responses evoked by severe, reversible hemorrhage. The major new findings of the present study is that both A1 and A2a adenosine-receptor subtypes operating in the NTS facilitate the paradoxical, sympathoinhibitory responses observed during the second, hypotensive phase of hemorrhage. The selective blockade of adenosine A2a receptors attenuated, whereas nonselective blockade of both A1 and A2a adenosine receptors abolished, hemorrhage-induced decreases in RSNA. The decreases in HR were attenuated to a greater extent after the nonselective (A1+A2aX group) than after the selective (A2aX group) blockade. Neither blockade altered the typical sustained increases in pre-ASNA, directed to the adrenal medulla, which occurred during both phases of the hemorrhage (8, 36, 40). In addition, the effects of bilateral selective and nonselective blockade of NTS adenosine receptors on resting levels of regional sympathetic nerve activity and hemodynamic variables were assessed. The hemodynamic and regional sympathetic responses to blockade of NTS adenosine-receptor subtypes observed in the present study were consistent with the known responses to stimulation of these receptors observed in our previous studies (22–29). To our knowledge, this is the first evidence that both A1 and A2a adenosine receptors may tonically modulate MAP, HR, RSNA, and pre-ASNA at the level of the NTS.

NTS adenosine-receptor subtypes and hemorrhage. As discussed above in detail, several studies from our laboratory and by others have provided indirect evidence suggesting that adenosine operating in the NTS may modulate reflex compensation to hypotensive hemorrhage (8, 10, 24–30, 36, 38, 40). Our present study directly supports this hypothesis. The combined blockade of adenosine A1 and A2a receptors in the NTS attenuated the hemorrhage-induced decreases in RSNA and HR to a greater extent than the selective blockade of adenosine A2a receptors, suggesting that both adenosine-receptor subtypes operating in the NTS may be involved. This observation was unexpected because selective stimulation of NTS A1 adenosine receptors usually evokes pressor and sympathoactivatory responses (3, 13, 26). However, decreases in MAP, HR, and RSNA accompanied with the increases in pre-ASNA may also occur in response to stimulation of NTS adenosine A1 receptors in ~30–35% of cases, as our group has shown recently (13, 26). This less frequent pattern of A1-receptor-elicited responses is consistent with the pattern of responses evoked via stimulation of NTS A2a receptors and that observed during hypotensive hemorrhage (8, 24–29, 36, 40). Interestingly, sustained increases in pre-ASNA were not affected by either of the blockades. This implies that activation of the adrenal medulla during hemorrhage and the preferential increases in pre-ASNA evoked by stimulation of both A1- and A2a-receptor subtypes located in the NTS are mediated via separate mechanisms. For example, different neuronal networks operating in the NTS may mediate these responses or hemorrhage-induced increases in pre-ASNA may be mediated mostly via direct pathways from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla and spinal cord. These pathways, which bypass the NTS, are activated during hypotensive hemorrhage (2, 10).

Previous studies suggested that the sympathoinhibitory and cardiac slowing responses observed during severe hemorrhage are mediated via vagal afferents from cardiopulmonary receptors and modulated by central opioid, serotoninergic, nitroxidergic, and vasopressinergic mechanisms (5, 6, 10, 12, 14, 15, 18, 19, 30–32, 39). Adenosine may be released into the central nervous system during severe hemorrhage (38); thus it may trigger or facilitate all of the mechanisms mentioned above. By operating via A2a receptors, adenosine may facilitate synaptic release of vasopressin, NO, opioids, and glutamate, mediating and/or facilitating the cardiopulmonary reflex pathways in the NTS. Because activation of adenosine A1 receptors attenuates the release of neurotransmitters from synaptic terminals, including the release of GABA, these receptors may contribute to the posthemorrhagic bradycardia and sympathoinhibition via disinhibition of some or all of the above factors participating in the responses.

Adenosine-receptor subtypes operating in the NTS seem to facilitate the second phase of response to hemorrhage (sympathoinhibition and cardiac slowing) as the blockade of these receptors postponed and attenuated the second phase but accentuated and prolonged the first phase of the response (initial sympathoactivation and cardioacceleration). Consistent with this concept was the observation that the initial volume of blood withdrawn to decrease MAP to 35 mmHg was significantly greater after the blockades than under control conditions, although the differences for the total volume of blood withdrawn needed to maintain the decreased blood pressure for 5 min did not reach statistical significance (P = 0.058 and P = 0.067 for control vs. A1+A2aX and A2aX conditions, respectively; Table 1).

Tonic action of adenosine receptors in the NTS. Bilateral, nonselective (A1+A2aX), and selective (A2aX) blockade of adenosine receptors in the NTS significantly decreased pre-ASNA but not post-ASNA and RSNA (Table 2). This observation is consistent with preferential increases in pre-ASNA after stimulation of both A1 and A2a adenosine receptors in the NTS observed in our previous studies (24–29). RSNA increased significantly after selective blockade of NTS A2a receptors but not after nonselective blockade of both A1 and A2a receptors (Table 2). This observation is also consistent with our previous reports showing that selective stimulation of NTS A2a receptors decreases RSNA, whereas selective stimulation of NTS A1 receptors increases RSNA (22–29). Therefore, the effects of blockade of both A1 and A2a receptors on RSNA likely canceled each other. There was also a tendency to increase HR after the nonselective (A1+A2aX) and selective (A2aX) blockade of NTS adenosine receptors (P = 0.069 and P = 0.106, respectively) and a tendency to increase MAP after selective blockade of NTS A2a receptors (P = 0.060) but not after the nonselective, double blockade (P = 0.590). These observations are also consistent with the effects of selective stimulation of NTS adenosine-receptor subtypes, considering that stimulation of both A1 and A2a receptors in the NTS decreases HR, whereas selective stimulation of A1 and A2a receptors increases and decreases MAP, respectively, as reported previously (4, 13, 22–29). Together, the above observations suggest that both A1- and A2a-receptor subtypes may be tonically active in the NTS, providing differential modulation of regional control of sympathetic outputs and vascular beds.

Previous studies usually did not show significant effects of blockade of adenosine receptors in the NTS on hemodynamic and neural variables. However, these studies used unilateral microinjections of respective antagonists in limited volumes (50–60 nl) (1, 3, 16, 17, 33, 35, 37). Therefore, contralateral NTS mechanisms could compensate for the effects of the unilateral blockade. In the present study, bilateral microinjections of adenosine-receptor antagonists in volumes sufficient to effectively block other NTS receptors (100 nl) (25, 28) showed significant effects of the blockades.

Limitations of the method. The present studies were performed in anesthetized animals. Therefore, the first, sympathoactivatory and cardioacceleratory, phases of the response to hemorrhage were likely blunted. However, after the blockades, the first phases of the response were accentuated and prolonged, especially for A1+A2aX conditions. This suggests that adenosine-receptor subtypes operating in the NTS may actively attenuate the first phase and facilitate the second phase of the response to hemorrhage similarly to that observed previously for central opioid and vasopressin receptors and nitric oxide in conscious animals (5, 10, 12, 19, 30, 39).

With the consideration that the antagonists of adenosine receptors were microinjected into the NTS in relatively large volumes (100 nl), it cannot be excluded that they might spread into the adjacent area postrema or other structures. Both A1 and A2a receptors are present in the area postrema (21). Therefore, it is not clear whether the tonic effects exerted by adenosine receptor subtypes on MAP, HR, RSNA, and pre-ASNA observed in the present study were entirely dependent on the blockade of adenosine receptors in the NTS or in the adjacent structures. Further studies with smaller volumes of antagonists microinjected into the NTS and area postrema may answer this question. However, the limited volume of the antagonists may not be sufficient to fully block the receptors, resulting in vague responses similar to those previously observed after the unilateral blockades (1, 3, 16, 17, 33, 35, 37).

It is difficult to precisely evaluate the effective concentrations of microinjected antagonists at adenosine-receptor sites in the NTS. The antagonists would be diluted in the interstitial fluid after microinjections, and their effective concentrations in the interstitial fluid would be expected to decrease with increasing distance from the center of the injection site. Because of the high initial concentrations, both antagonists could bind to both A1- and A2a-receptor subtypes in the immediate proximity of the microinjection sites. However, with increasing distance from the microinjection sites, the selectivity of ZM-241385 toward adenosine A2a receptors may increase much more than the relatively small selectivity of 8-SPT toward adenosine A1 receptors. For example, 8-SPT is 5.8 times more selective toward adenosine A1 than toward A2a receptors (Ki = 15.3 µM and Ki = 2.6 µM for A1 and A2a receptors, respectively), whereas ZM-241385 is 382 times more selective toward adenosine A2a receptors than toward A1 receptors (Ki = 256 nM and Ki = 0.67 nM for A1 and A2a receptors, respectively) (7, 11). The potency of ZM-241385 toward adenosine A1 receptors is ~10 times greater than the potency of 8-SPT. However, regarding adenosine A2a receptors, ZM-241385 is almost 23,000 times more potent than 8-SPT. Because we used 25 times greater concentrations of 8-SPT than ZM-241385, we believe that ZM-241385 blocked predominantly adenosine A2a receptors, whereas 8-SPT blocked both types of receptor subtypes with slightly greater potency for A1 than for A2a receptors. In support of this assumption, the neural and hemodynamic effects evoked by selective and nonselective blockades of NTS A1- and A2a-receptor subtypes in the present study (Table 2) were consistent with the effects evoked by selective stimulations of these receptor subtypes in previous studies from our laboratory (4, 13, 22–29). To our knowledge, the antagonists used in the present study do not interfere with any other neurotransmitters or neuromodulators operating in the NTS except adenosine (7, 11, 21).

In the present study, we compared the responses recorded in two consecutive hemorrhages (control hemorrhage vs. hemorrhage evoked after the blockade); therefore, it was possible that some long-lasting after effects of the first hemorrhage could affect the responses to the subsequent one. However, the hemorrhages were short lasting and fully reversible, as all the recorded variables returned to prehemorrhage levels before the next hemorrhage. In addition, volume and time control showed that HR and RSNA responses to the first hemorrhage were not significantly different from those that occurred after microinjections of respective volumes of ACF into the NTS. Finally, the responses that were altered after the blockade tended to recover after ~60–70 min, during the third consecutive hemorrhage. The control responses were not significantly different from the recovery responses in all analyzed variables (Table 3). Together, these observations strongly suggest that the observed effects of the antagonists on the pattern of the responses to the hemorrhage were caused by the antagonists themselves.

Interestingly, although the blockade of adenosine-receptor subtypes did not alter hemorrhage-evoked increases in pre-ASNA, these responses were significantly attenuated after bilateral microinjections of 100 nl of ACF (Fig. 3). However, the bilateral microinjections of ACF itself increased slightly, but significantly, the resting pre-ASNA (Table 2). When we compensate for these increases (i.e., when the responses in pre-ASNA were calculated toward the resting level recorded before microinjections of ACF), then the pre-ASNA responses in control vs. post-ACF hemorrhages were not significantly different. The increases in pre-ASNA averaged over time of hemorrhage were 37.4 ± 7.8 {Delta}% vs. 25.5 ± 4.0 {Delta}% for control vs. ACF conditions, respectively (P = 0.104).

In conclusion, bilateral combined blockade of adenosine A1 and A2a receptors in the NTS accentuated and prolonged the first, compensatory phase of the response to hemorrhage, whereas it markedly attenuated and postponed sympathoinhibition and cardiac slowing observed in the second phase of the response. Similar although less pronounced effects occurred with selective blockade of NTS adenosine A2a receptors. Therefore, it is likely that both adenosine-receptor subtypes (A1 and A2a) may contribute to the paradoxical sympathoinhibitory and cardiac slowing responses observed during the second phase of hemorrhage. The hemorrhage-induced increases in pre-ASNA were not affected by any of the blockades. Because the blockades altered resting MAP, HR, RSNA, and pre-ASNA in a way that was consistent with the effects of stimulation of adenosine-receptor subtypes located in the NTS, this observation suggests that naturally released adenosine may tonically activate NTS A1 and A2a receptors.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Heart, Lung, and Blood Institute Grant HL-67814.


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge the generous gift of Arfonad by Hoffmann-La Roche (Nutley, NJ). We also gratefully acknowledge the technical assistance of J. McClure.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. J. Scislo, Dept. of Physiology, Wayne State Univ. School of Medicine, 540 East 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.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Abdel-Rahman A and Tao S. Adenosine pressor and depressor systems in the nucleus tractus solitarius of rats. Drug Dev Res 45: 410–419, 1998.[CrossRef]
  2. Badoer E, McKinley MJ, Oldfield BJ, and McAlen RM. A comparison of hypotensive and nonhypotensive hemorrhage on Fos expression in spinally projecting neurons of the paraventricular nucleus and rostral ventrolateral medulla. Brain Res 610: 216–223, 1993.[CrossRef][ISI][Medline]
  3. Barraco RA, El-Ridi MR, Ergene E, and Phillis JW. Adenosine receptor subtypes in the brainstem mediate distinct cardiovascular response patterns. Brain Res Bull 26: 59–84, 1991.[CrossRef][ISI][Medline]
  4. Barraco RA, O'Leary DS, Ergene E, and Scislo TJ. Activation of purinergic subtypes in the nucleus tractus solitarius elicits specific regional vascular response patterns. J Auton Nerv Syst 59: 113–124, 1996.[CrossRef][ISI][Medline]
  5. Budzikowski AS, Paczwa P, and Szczepanska-Sadowska E. Central V1 AVP receptors are involved in cardiovascular adaptation to hypovolemia in WKY but not in SHR. Am J Physiol Heart Circ Physiol 271: H1057–H1064, 1996.[Abstract/Free Full Text]
  6. Burke SL and Dorward PK. Influence of endogenous opiates and cardiac afferents of renal nerve activity during hemorrhage in conscious rabbits. J Physiol 402: 9–27, 1988.[Abstract/Free Full Text]
  7. Bruns RF, Lu GH, and Pugsley TA. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 29: 331–346, 1986.[Abstract]
  8. Carlsson S, Skarphedinsson JO, Delle M, Hoffman P, and Thoren P. Reflex changes in post- and preganglionic sympathetic adrenal nerve activity and postganglionic sympathetic adrenal nerve activity upon arterial baroreceptor activation and during severe haemorrhage in the rat. Acta Physiol Scand 144: 317–323, 1992.[ISI][Medline]
  9. Carlsson S, Skarphedinsson JO, Jennische E, Delle M, and Thoren P. Neurophysiological evidence for and characterization of the post-ganglionic innervation of the adrenal gland in the rat. Acta Physiol Scand 140: 491–499, 1990.[ISI][Medline]
  10. Evans RG, Ventura S, Dampney RA, and Ludbrook J. Neural mechanisms in the cardiovascular responses to acute central hypovolaemia. Clin Exp Pharmacol Physiol 28: 479–487, 2001.[CrossRef][ISI][Medline]
  11. Fredholm BB and Lindstrom K. Autoradiographic comparison of the potency of several structurally unrelated adenosine receptor antagonists at adenosine A1 and A2a receptors. Eur J Pharmacol 380: 197–202, 1999.[CrossRef][ISI][Medline]
  12. Hasser EM and Schadt JC. Sympathoinhibition and its reversal by naloxone during hemorrhage. Am J Physiol Regul Integr Comp Physiol 262: R444–R451, 1992.[Abstract/Free Full Text]
  13. McClure JM, O'Leary DS, and Scislo TJ. Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature. Am J Physiol Heart Circ Physiol 289: H2536–H2542, 2005.[Abstract/Free Full Text]
  14. Morgan DA, Thoren P, Wilczynski EA, Victor RG, and Mark AL. Serotonergic mechanisms mediate renal sympathoinhibition during severe hemorrhage in rats. Am J Physiol Heart Circ Physiol 255: H496–H502, 1988.[Abstract/Free Full Text]
  15. Morita H, Nishida Y, Motochigawa H, Uemura N, Hosomi H, and Vatner SF. Opiate receptor-mediated decrease in renal nerve activity during hypotensive hemorrhage in conscious rabbits. Circ Res 63: 165–172, 1988.[Abstract/Free Full Text]
  16. Mosqueda-Garcia R, Tseng CJ, Appalsamy M, Beck C, and Robertson D. Cardiovascular excitatory effects of adenosine in the nucleus of the solitary tract. Hypertension 18: 494–502, 1991.[Abstract/Free Full Text]
  17. Mosqueda-Garcia R, Tseng CJ, Appalsamy M, and Robertson D. Modulatory effects of adenosine on baroreflex activation in the brainstem of normotensive rats. Eur J Pharmacol 174: 119–122, 1989.[CrossRef][ISI][Medline]
  18. Oberg B and White S. The role of vagal cardiac nerves and arterial baroreceptors in the circulatory adjustments to hemorrhage in the cat. Acta Physiol Scand 80: 395–403, 1970.[Medline]
  19. Paczwa P, Budzikowski AS, and Szczepanska-Sadowska E. Role of endogenous centrally released NO in cardiovascular adaptation to hypovolemia in WHY and SHR. Am J Physiol Heart Circ Physiol 272: H2282–H2288, 1997.[Abstract/Free Full Text]
  20. Phillis JW, Walter GA, O'Regan MH, and Stair RE. Increases in cerebral cortical perfusate adenosine and inosine concentration during hypoxia and ischemia. J Cereb Blood Flow Metab 7: 679–686, 1987.[ISI][Medline]
  21. Ralevic V and Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 50: 413–492, 1998.[Abstract/Free Full Text]
  22. Scislo TJ, Kitchen AM, Augustyniak RA, and O'Leary DS. Differential patterns of sympathetic responses to selective stimulation of nucleus tractus solitarius purinergic receptor subtypes. Clin Exp Physiol Pharmacol 28: 120–124, 2001.
  23. Scislo TJ and O'Leary DS. 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.[CrossRef][ISI][Medline]
  24. Scislo TJ and O'Leary DS. Differential control of renal vs. adrenal sympathetic nerve activity by NTS A2a and P2x purinoceptors. Am J Physiol Heart Circ Physiol 275: H2130–H2139, 1998.
  25. Scislo TJ and O'Leary DS. Differential role of ionotropic glutamatergic mechanisms in responses to NTS P2x- and A2a-receptor stimulation. Am J Physiol Heart Circ Physiol 278: H2057–H2068, 2000.[Abstract/Free Full Text]
  26. Scislo TJ and O'Leary DS. Mechanisms mediating sympathoactivatory responses to stimulation of NTS A1 adenosine receptors. Am J Physiol Heart Circ Physiol 283: H1588–H1599, 2002.[Abstract/Free Full Text]
  27. Scislo TJ and O'Leary DS. Purinergic mechanisms of the nucleus of the solitary tract and neural cardiovascular control. Neurol Res 27: 182–194, 2005.[CrossRef][ISI][Medline]
  28. Scislo TJ and O'Leary DS. Vasopressin V1 receptors contribute to hemodynamic and sympathoinhibitory responses evoked by stimulation of adenosine A2a receptors in the NTS. Am J Physiol Heart Circ Physiol 290: H1889–H1898, 2006.[Abstract/Free Full Text]
  29. Scislo TJ, Tan N, and O'Leary DS. Differential role of nitric oxide in regional sympathetic responses to stimulation of NTS A2a adenosine receptors. Am J Physiol Heart Circ Physiol 288: H638–H649, 2005.[Abstract/Free Full Text]
  30. Schadt JC and Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol Heart Circ Physiol 260: H305–H318, 1991.[Abstract/Free Full Text]
  31. Scrogin KE. 5-HT1A receptor agonist 8-OH-DPAT acts in the hindbrain to reverse the sympatholytic response to severe hemorrhage. Am J Physiol Regul Integr Comp Physiol 284: R782–R791, 2003.[Abstract/Free Full Text]
  32. Skoog P, Mansson J, and Thoren P. Changes in renal sympathetic outflow during hypotensive haemorrhage in rats. Acta Physiol Scand 125: 655–660, 1985.[ISI][Medline]
  33. Tao S and Abdel-Rahman A. Neuronal and cardiovascular responses to adenosine microinjection into the nucleus tractus solitarius. Brain Res Bull 32: 407–417, 1993.[CrossRef][ISI][Medline]
  34. Thomas T and Spyer KM. The role of adenosine receptors in the rostral ventrolateral medulla in the cardiovascular response to defence area stimulation in the rat. Exp Physiol 81: 67–77, 1996.[Abstract]
  35. Thomas T, St Lambert JH, Dashwood MR, and Spyer KM. Localization and action of adenosine A2a receptors in regions of the brainstem important in cardiovascular control. Neuroscience 95: 513–518, 2000.[CrossRef][ISI][Medline]
  36. Togashi H, Yoshioka M, Tochihara M, Matsumoto M, and Saito H. Differential effects of hemorrhage on adrenal and renal nerve activity in anesthetized rats. Am J Physiol Heart Circ Physiol 259: H1134–H1141, 1990.[Abstract/Free Full Text]
  37. Tseng CJ, Biaggioni I, Appalsamy M, and Robertson D. Purinergic receptors in the brainstem mediate hypotension and bradycardia. Hypertension 11: 191–197, 1988.[Abstract/Free Full Text]
  38. Van Wylen DGL, Park TS, Rubio R, and Berne RM. Cerebral blood flow and interstitial fluid adenosine during hemorrhagic hypotension. Am J Physiol Heart Circ Physiol 255: H1211–H1218, 1988.[Abstract/Free Full Text]
  39. Ventura S and Ludbrook J. N-nitro-L-arginine methyl ester blocks the decompensatory phase of acute hypovolemia in conscious rabbit by a brainstem mechanism. Eur J Pharmacol 277: 265–269, 1993.
  40. Victor RG, Thoren P, Morgan DA, and Mark AL. Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats. Circ Res 64: 686–694, 1989.[Abstract/Free Full Text]
  41. Yan S, Laferriere A, Zhang C, and Moss IR. Microdialyzed adenosine in nucleus tractus solitarii and ventilatory response to hypoxia in piglets. J Appl Physiol 79: 405–410, 1995.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. J. Scislo, T. K. Ichinose, and D. S. O'Leary
Stimulation of NTS A1 adenosine receptors differentially resets baroreflex control of regional sympathetic outputs
Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H172 - H182.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. M. Abu-Shaweesh
Activation of central adenosine A2A receptors enhances superior laryngeal nerve stimulation-induced apnea in piglets via a GABAergic pathway
J Appl Physiol, October 1, 2007; 103(4): 1205 - 1211.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/5/H2453    most recent
00158.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scislo, T. J.
Right arrow Articles by O'Leary, D. S.