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 290: H1889-H1898, 2006. First published December 9, 2005; doi:10.1152/ajpheart.01030.2005
0363-6135/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
290/5/H1889    most recent
01030.2005v1
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 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.

Vasopressin V1 receptors contribute to hemodynamic and sympathoinhibitory responses evoked by stimulation of adenosine A2a receptors in NTS

Tadeusz J. Scislo and Donal S. O'Leary

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

Submitted 29 September 2005 ; accepted in final form 6 December 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Activation of adenosine A2a receptors in the nucleus of the solitary tract (NTS) decreases mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas increases in preganglionic adrenal sympathetic nerve activity (pre-ASNA) occur, a pattern similar to that observed during hypotensive hemorrhage. Central vasopressin V1 receptors may contribute to posthemorrhagic hypotension and bradycardia. Both V1 and A2a receptors are densely expressed in the NTS, and both of these receptors are involved in cardiovascular control; thus they may interact. The responses elicited by NTS A2a receptors are mediated mostly via nonglutamatergic mechanisms, possibly via release of vasopressin. Therefore, we investigated whether blockade of NTS V1 receptors alters the autonomic response patterns evoked by stimulation of NTS A2a receptors (CGS-21680, 20 pmol/50 nl) in {alpha}-chloralose-urethane anesthetized male Sprague-Dawley rats. In addition, we compared the regional sympathetic responses to microinjections of vasopressin (0.1–100 ng/50 nl) into the NTS. Blockade of V1 receptors reversed the normal decreases in MAP into increases (–95.6 ± 28.3 vs. 51.4 ± 15.7 {int}{Delta}%), virtually abolished the decreases in HR (–258.3 ± 54.0 vs. 18.9 ± 57.8 {int}{Delta}beats/min) and RSNA (–239.3 ± 47.4 vs. 15.9 ± 36.1 {int}{Delta}%), and did not affect the increases in pre-ASNA (279.7 ± 48.3 vs. 233.1 ± 54.1 {int}{Delta}%) evoked by A2a receptor stimulation. The responses partially returned toward normal values ~90 min after the blockade. Microinjections of vasopressin into the NTS evoked dose-dependent decreases in HR and RSNA and variable MAP and pre-ASNA responses with a tendency toward increases. We conclude that the decreases in MAP, HR, and RSNA in response to NTS A2a receptor stimulation may be mediated via release of vasopressin from neural terminals in the NTS. The differential effects of NTS V1 and A2a receptors on RSNA versus pre-ASNA support the hypothesis that these receptor subtypes are differentially located/expressed on NTS neurons/neural terminals controlling different sympathetic outputs.

nucleus tractus solitarii; purinoceptors; vasopressin V1 receptor antagonist; adrenal sympathetic nerve; renal sympathetic nerve

IT IS GENERALLY ACCEPTED that among the numerous neuroactive substances operating in the nucleus of the solitary tract (NTS), adenosine, acting via A2a receptors, and vasopressin, acting via V1 receptors, play important roles in the mechanisms of cardiovascular control (4–6, 11, 14–16, 20–24, 32, 37, 40, 41, 47). However, the specific physiological roles of NTS adenosine A2a and vasopressin V1 receptors remain unclear, and potential interactions between these two neuromodulators have not been studied.

Several studies have suggested that the hypotensive action of adenosine in the NTS is mediated mostly via stimulation of presynaptic A2a receptors and the release of glutamate from afferent terminals and/or from intrinsic NTS interneurons involved in baroreflex transmission (11, 23, 25, 40). However, evidence from our laboratory (31–35, 37) showed that the pattern of regional sympathetic responses evoked by activation of arterial baroreceptors is different from that evoked by selective stimulation of adenosine A2a receptors in the NTS. Specifically, although the stimulation of NTS A2a receptors decreased mean arterial pressure (MAP), heart rate (HR), renal (RSNA), and postganglionic adrenal sympathetic nerve activity (post-ASNA), which was consistent with baroreflex responses, activation of these receptors did not change lumbar sympathetic nerve activity (33) and markedly increased preganglionic ASNA (pre-ASNA) (34, 35), effects inconsistent or opposite to those evoked by activation of arterial baroreceptors (31). Furthermore, bilateral sinoaortic denervation combined with vagotomy or blockade of ionotropic glutamatergic transmission in the NTS did not markedly change the pattern of the responses evoked by stimulation of NTS A2a receptors (34, 35). Taken together, these observations suggested that the hemodynamic and sympathetic responses to stimulation of A2a receptors in the NTS may be mediated mostly via release of nonglutamatergic neurotransmitters/neuromodulators from nerve terminals descending into the NTS from higher centers.

Among the many possible mechanisms that may mediate the depressor and sympathoinhibitory responses to stimulation of NTS adenosine A2a receptors, facilitation of vasopressin release from dense vasopressinergic fibers descending from hypothalamic paraventricular nucleus (PVN) into the NTS (30) should be considered, as we suggested previously (35, 37). In support of this concept, dense expression of pre- and postsynaptic vasopressin V1 receptors in the NTS has been reported (28), and vasopressin is released into the NTS upon stimulation of the PVN (45). Microinjections of picomolar doses of vasopressin into the NTS evoke baroreflex-like depressor responses and cardiac slowing, via activation of vasopressin V1 receptors (7, 8). Vasopressin activates NTS neurons in vitro and the majority of NTS barosensitive neurons in vivo (16, 28). Blockade of vasopressin V1 receptors in the NTS decreases the activity of NTS baroreflex neurons and attenuates responses to activation of arterial baroreceptors (14, 16, 22, 47). However, microinjections of exogenous vasopressin in doses exceeding 1 ng evoke pressor responses and may also attenuate baroreflex responses (18, 20, 21, 41). The above observations suggest that exogenous vasopressin may exert different cardiovascular effects than those mediated via naturally released vasopressin in the NTS circuitry.

Interestingly, central vasopressin V1 receptors and adenosine A2a receptors may contribute to the pattern of autonomic responses observed during hypotensive hemorrhage when paradoxical decompensatory responses occur. For example, the pattern of hemodynamic and neural responses to stimulation of NTS A2a receptors resembles the pattern observed during hypotensive stage of severe hemorrhage. In both situations, decreases in MAP are accompanied by decreases in HR and RSNA and sustained increases in pre-ASNA (34, 35, 44). The similarities between the patterns of the responses may be physiologically relevant because adenosine is released into the central nervous system, including the NTS, during hypoxia, ischemia, and severe hemorrhage (26, 43, 46). Consistent with this concept, our preliminary data showed that blockade of adenosine receptors attenuates the bradycardic and sympathoinhibitory responses to severe hemorrhage (38). It has been also demonstrated that central blockade of vasopressin V1 receptors and nitric oxide (NO) synthase (NOS) attenuates posthemorrhagic hypotension (10, 25). In addition, activation of both adenosine A2a and vasopressin V1 receptors may activate NOS because they both increase intracellular calcium levels (9, 17, 27, 29). Therefore, adenosine, vasopressin, and NO may interact in creating the pattern of autonomic responses observed during hypotensive hemorrhage.

Recently, we have shown that adenosine A2a receptor-mediated release of NO contributes to the depressor and sympathoinhibitory responses evoked by stimulation of NTS A2a receptors (39). However, the potential interactions between adenosine A2a receptors and vasopressin V1 receptors operating in the NTS have not been studied. Also, the effect of activation of vasopressin receptors in the NTS on sympathetic activity directed to the adrenal medulla has not been studied, although the reported increases in plasma epinephrine in response to microinjections of vasopressin into the NTS suggest that the increases in pre-ASNA likely occur (18). Therefore, in the present study, we analyzed the effects of blockade of vasopressin V1 receptors in the NTS on hemodynamic and regional sympathetic responses evoked by stimulation of NTS adenosine A2a receptors. In addition, we compared the pattern of regional sympathetic responses evoked by stimulation of NTS adenosine A2a receptors with the pattern evoked by microinjections of vasopressin into the NTS.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 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 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 effect of blockade of vasopressin V1 receptors or the respective volume control, artificial cerebrospinal fluid (ACF), on hemodynamic and regional sympathetic responses to stimulation of adenosine A2a receptors in the subpostremal NTS was studied in seven male Sprague-Dawley rats (350–400 g; Charles River). The responses to stimulation of NTS A2a receptors with microinjections of selective agonist CGS-21680 were compared after microinjection of ACF and the selective V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclo-pentamethylene propionic acid)-2-(O-methyl1)tyrosine]Arg8-vasopressin (20 ng in 100 nl). In an additional 13 animals, the effects of microinjections into the subpostremal NTS of vasopressin and glutamate on hemodynamic and regional sympathetic responses were assessed.

Instrumentation and measurements. All the procedures were previously described in detail (6, 33–36, 39). 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 the completion of the surgery, 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 (6, 33–36, 39). 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 a 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 = 129.0 ± 5.4, PCO2 = 39.2 ± 1.0, and pH = 7.409 ± 0.009 (n = 20 animals). Right femoral artery and vein were catheterized to monitor arterial blood pressure and to infuse drugs.

In each experiment simultaneous recordings from two sympathetic outputs, RSNA and pre-ASNA, were performed. The renal and adrenal nerves were exposed retroperitoneally, and neural recordings were accomplished as described previously (34–36, 39). Neural signals were initially amplified (x2,000–20,000) 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 before each microinjection was normalized to 100%.

The ratio between preganglionic versus total nerve activity was initially tested with bolus intravenous injection of the short-lasting (1–2 min) ganglionic blocker arfonad (2 mg/kg, Hoffmann-La Roche) (34–36, 39) and reevaluated at the end of each experiment with hexamethonium (20 mg/kg iv). RSNA was almost completely postganglionic, only 1.85 ± 0.41% (n = 20 animals) 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, with the use 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% (34–36, 39). Average pre-ASNA after ganglionic blockade was 112.7 ± 5.7% (n = 20 animals). Pre-ASNA increased over 100%, likely due to an arterial baroreflex response caused by the decrease in MAP after the ganglionic blockade.

The arterial pressure and neural signals were digitized and recorded with 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 NTS. Unilateral microinjections of drugs, 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 (6, 34–36, 39). 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 (AP) were as follows: anteroposterior = –0.1 mm, mediolateral = 0.3 mm, and dorsoventral = 0.35 mm from the dorsal surface of the brain stem. The drugs were dissolved in ACF, and the pH adjusted to 7.2. All microinjection sites were verified histologically as described previously (6, 34–36, 39) and presented in Fig. 1, according to the atlas of the rat subpostremal NTS by Barraco et al. (3).


Figure 1
View larger version (25K):
[in this window]
[in a new window]
  		Fig. 1. Microinjection sites in caudal subpostremal NTS for all experiments. Schematic diagrams of transverse sections of medulla oblongata from rat brain. AP, area postrema; c, central canal; 10, dorsal motor nucleus of the vagus nerve; 12, nucleus of the hypoglossal nerve; ts, tractus solitarius; Gr, gracile nucleus; Cu, cuneate nucleus. Scale is shown at bottom; number on left side of schematic diagram denotes rostro-caudal position in millimeters of section relative to obex according to the atlas of the rat subpostremal NTS by Barraco et al. (see Ref. 3). Microinjection sites were marked with fluorescent dye. A: microinjections of CGS-21680 after blockade of VP V1 receptors (bullet) and after pretreatment with ACF before blockade (control) and 90 min after blockade ({circ}; recovery). B: microinjections of different doses of VP ({blacktriangleup}) and glutamate ({blacksquare}). Because 1–3 microinjections of different doses of VP or VP and glutamate were performed into same site of NTS, number of microinjection sites is smaller than total number of microinjections presented in Table 3.

 
Our previous studies have shown that microinjections of the selective A2a receptor agonist CGS-21680 into the subpostremal NTS evoke dose-related responses in all hemodynamic and neural parameters recorded in the present study (6, 34–36, 39). The effects elicited with the highest dose of the agonist (20 pmol) were previously shown to be completely and selectively blocked by microinjection of the A2a purinoceptor antagonist CGS-15943A (4). Responses to stimulation of mostly presynaptic NTS A2a receptors may be mediated via release of glutamate or other neurotransmitters operating in the NTS circuitry, for example, release of norepinephrine or serotonin upon stimulation of NTS A2a receptors (1, 2). Therefore, we used the maximal effective dose of the selective A2a receptor agonist CGS-21680 (20 pmol in 50 nl) to maximally activate possible mechanisms triggered by A2a receptor stimulation and evaluate the contribution of vasopressin V1 receptors to this response (4, 29).

Experimental protocol. The selective blockade of vasopressin V1 receptors (V1X) was accomplished with unilateral microinjection of [1-(beta-mercapto-beta,beta-cyclo-pentamethylene propionic acid)-2-(O-methyl-1) tyrosine]Arg8-vasopressin (20 ng in 100 nl, Peninsula Laboratories, Belmont, CA). The volume of the antagonists was twice as much as the volume of A2a receptor agonists to ensure that the agonist will not spread further than the antagonist. The time line of the protocol is presented in Fig. 2. The microinjections of ACF plus CGS-21680 and V1X plus CGS-21680 were performed on contralateral sides of the NTS in a random manner. This design allowed us to compare the responses to stimulation of A2a receptors under control, V1 blockade, and recovery conditions in the same animal. In our previous studies (39), we have shown that two subsequent stimulations of A2a receptors in the 90 min interval evoke comparable hemodynamic and neural responses.


Figure 2
View larger version (4K):
[in this window]
[in a new window]
  		Fig. 2. Timeline of protocol. Stimulation of nucleus tractus solitarii (NTS) adenosine A2a receptors after pretreatment with artificial cerebrospinal fluid (ACF; control), after NTS vasopressin (VP) V1 receptor blockade (V1X), and after recovery. Pairs of microinjections were repeated in 90-min intervals.

 
To compare the patterns of regional neural responses evoked by stimulation of NTS adenosine A2a receptors and vasopressin receptors, we microinjected increasing doses of arginine vasopressin (0.1–100 ng in 50 nl of ACF, Sigma-Aldrich) in an additional group of 13 animals. Different doses of vasopressin were microinjected into the same site of the NTS in 30-min intervals in a random order. Vasopressin operates in the NTS mainly via V1 receptors (14, 16, 27, 28). In some experiments the differential neural responses to microinjections of vasopressin were compared with the responses to microinjections of sodium glutamate (500 pmol in 50 nl of ACF, Sigma-Aldrich) into the same site of the NTS. No more than three microinjections of different doses of vasopressin and glutamate were performed on each side of the NTS.

Data analysis. Hemodynamic and sympathetic nerve responses were quantified in two ways as described previously (6, 34–36, 39). First, the maximal percent difference from a 30-s basal control period was taken immediately before microinjection. Second, integration of the percent changes from the control level was measured over the period of 10 min for CGS-21680, 5 min for vasopressin, and 30 s for glutamate. Different times of integration of the responses evoked by different drugs were used to reflect different maximal durations of the responses: 15–30 min for CGS-21680, 3–10 min for vasopressin, and 30–40 s for glutamate. The time of integration affects integrated values, and the end of the responses is not clear-cut for the drugs used; therefore, we always compared the same time period of the responses evoked by the same drug to decrease variability caused by spontaneous, small, slow, and variable changes in each parameter occurring during the experiments. The integral reflects the predominant trend of the response despite transient, sometimes bidirectional fluctuations in each variable. The maximum values of the responses were measured over the time of integration for each drug. Maximum decreases were calculated for those variables in which the integral response decreased and, vice versa, maximum increases were calculated for those variables in which the integral response increased.

The most prominent, consistent responses to stimulation of NTS A2a receptors occur during the first 10 min after the microinjection of CGS-21680. Therefore, we compared these initial portions of the responses obtained under control conditions (after pretreatment with ACF) with the same portion of the response after pretreatment with V1X. This approach optimized the discrimination between clearly distinguished control responses and attenuated, biphasic, reversed, or unchanged responses observed in different variables after pretreatment with the V1 receptor antagonist. The effects of V1X and ACF on the resting hemodynamic and neural parameters were evaluated ~5 min after the microinjection; the last 30 s of the responses preceding subsequent stimulation of NTS A2a receptors were averaged. The HR responses, calculated from the pulse intervals, were expressed in absolute values (in beats/min). Neural recordings were additionally filtered by using a running average in 10-s intervals to minimize the effect of random spikes on maximum response values. All presented values are means ± SE. One-way ANOVA for independent measures was used to compare MAP and HR responses versus different doses of vasopressin. A two-way ANOVA for independent measures was used to compare the responses of the sympathetic outputs (RSNA and post-ASNA) versus doses of vasopressin. Also, a one-way ANOVA for independent measures was used to compare hemodynamic responses, and a two-way ANOVA for independent measures was used to compare neural responses to microinjections of CGS-21680 after pretreatment with ACF and V1X. A two-way ANOVA for repeated measures was used to compare the responses of RSNA vs. pre-ASNA recorded simultaneously. Differences observed were further evaluated by t-test with Bonferroni adjustment for independent measures. 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 microinjections (58 microinjections in 20 animals) were 88.7 ± 1.4 mmHg and 360.9 ± 5.0 beats/min, respectively. Microinjections into the NTS of the selective A2a receptor agonist CGS-21680 evoked characteristic patterns of neural responses similar to those described previously (33–35, 39). Stimulation of NTS A2a receptors inhibited RSNA and markedly increased pre-ASNA (see Figs. 3 and 4). Microinjections of ACF in this and previous studies (35, 36, 39) evoked changes smaller than those randomly occurring in all recorded parameters during the experiments (Table 1). Responses to microinjections of V1X were not different than those evoked by ACF (Table 1).


Figure 3
View larger version (18K):
[in this window]
[in a new window]
  		Fig. 3. Responses to stimulation of NTS A2a receptors with CGS-21680 (20 pmol in 50 nl) after pretreatment with artificial cerebrospinal fluid (ACF, 100 nl; left), after selective blockade of VP V1 receptors in NTS (20 nmol in 100 nl; middle) and 90 min after blockade (right). All measurements were performed in the same animal. Blockade abolished decreases in heart rate (HR) and renal sympathetic nerve activity (RSNA), reversed normal decrease in mean arterial pressure (MAP) into an increase, and did not affect sympathoactivation in preganglionic adrenal sympathetic nerve activity (pre-ASNA). bpm, beats/min.

 

Figure 4
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 4. Comparison of neural and hemodynamic integral responses to stimulation of NTS A2a receptors with CGS-21680 (20 pmol in 50 nl) measured during control conditions (CTR), after NTS V1X, and 90 min after blockade (recovery condition, REC). Data are means ± SE. *P < 0.05 vs. CTR; #P < 0.05 vs. RSNA. Blockade reversed decreases in MAP into increases, abolished decreases in HR and RSNA, and did not affect sympathoactivation in pre-ASNA. Approximately 90 min after blockade, decreases in MAP, HR, and RSNA tended to recover.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Changes in resting values of MAP, HR, RSNA, and pre-ASNA in response to microinjections into the NTS of ACF and V1X

 
Effects of V1 receptor blockade on A2a receptor-mediated responses. Blockade of vasopressin V1 receptors in the NTS markedly altered the hemodynamic and sympathoinhibitory responses to selective stimulation of NTS A2a receptors. V1X reversed the normal depressor responses into pressor responses and abolished A2a receptor-elicited decreases in HR and RSNA (Figs. 3 and 4 and Table 2). However, V1X did not significantly affect A2a receptor-elicited increases in pre-ASNA. The maximal increases in pre-ASNA were very similar under control, V1-blockade, and recovery conditions (Table 2). The integral pre-ASNA responses tended to decrease with subsequent stimulations of NTS A2a receptors, mostly because of the shorter lasting activation of pre-ASNA with each repetition of the stimulation. However, this tendency did not reach statistical significance (P > 0.05) (Figs. 3 and 4). The hemodynamic and neural responses partially recovered ~90 min after V1 blockade; the responses observed under control conditions were not significantly different from those evoked after the recovery (Table 2 and Fig. 4).


View this table:
[in this window]
[in a new window]
  		Table 2. Maximal hemodynamic and neural responses evoked by microinjections into NTS of selective adenosine A2a receptor agonist CGS-21680 after pretreatment with vehicle (ACF), subsequent pretreatment with vasopressin V1 receptor antagonist V1X, and subsequent pretreatment with vehicle ~90 min after the blockade (recovery)

 
Differential pattern of neural responses to vasopressin. The differential neural response patterns evoked by microinjections of vasopressin into the NTS (Figs. 5 and 6 and Table 3) were similar to those evoked by stimulation of NTS adenosine A2a receptors in this and our previous studies (33–35, 39). Vasopressin inhibited RSNA in a dose-dependent manner and tended to increase pre-ASNA. The differences between the neural responses were statistically significant (P < 0.05) (Figs. 5 and 6 and Table 3). However, the integral increases in pre-ASNA were not different from zero for all doses of vasopressin. A two-way ANOVA confirmed that RSNA and pre-ASNA responded differently to increasing doses of vasopressin, showing a significant nerve effect (P < 0.001 for both maximal and integral responses) and a dose versus nerve interaction effect (P = 0.001 and P = 0.035 for maximal and integral responses, respectively).


Figure 5
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 5. MAP, HR, RSNA, and pre-ASNA responses to microinjection of VP into subpostremal NTS. VP in doses >10 ng/50 nl inhibited RSNA and tended to increase pre-ASNA.

 

Figure 6
View larger version (8K):
[in this window]
[in a new window]
  		Fig. 6. Integral responses of MAP, HR, RSNA, and pre-ASNA evoked by microinjections into subpostremal NTS of VP. Data are means ± SE. *P < 0.05 vs. 0; #P < 0.05 vs. RSNA. VP decreased RSNA and HR in dose-dependent manner, increased MAP, and tended to increase pre-ASNA; however, changes in pre-ASNA were not different from 0 (P > 0.05 vs. 0).

 

View this table:
[in this window]
[in a new window]
  		Table 3. Maximal hemodynamic and neural responses evoked by microinjections of vasopressin and glutamate into the NTS

 
In contrast to the differential pattern of neural responses evoked by stimulation of NTS A2a and vasopressin receptors, the injections of glutamate into the same site of the NTS resulted in uniform sympathoinhibition in both sympathetic outputs (RSNA and pre-ASNA) and typical depressor and cardiac slowing responses, a pattern similar to that reported previously (34, 39) (Table 3).

Both vasopressin and adenosine A2a receptor agonist (CGS-21680) significantly decreased HR; however, A2a receptor agonist markedly decreased MAP, whereas vasopressin resulted in variable MAP responses not different from zero for doses from 0.1 to 10 ng and slight pressor responses to the highest dose of the drug (100 ng) (Figs. 4 and 6). The maximal changes in MAP and HR evoked by microinjections of vasopressin were dose dependent (one-way ANOVA, P = 0.024 and P = 0.03, respectively), whereas integral dose-response effects reached the border of statistical significance for HR (P = 0.052) and remained insignificant for MAP (P = 0.105), probably because of the biphasic pattern of the pressor/depressor responses.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, for the first time, the contribution of NTS vasopressin V1 receptors to hemodynamic and regional sympathetic responses evoked by selective stimulation of NTS adenosine A2a receptors was evaluated. Also, for the first time the effects of vasopressin microinjected into the NTS on different sympathetic outputs were assessed. There are two major new findings of the present study. First, blockade of vasopressin V1 receptors in the NTS abolished or even reversed the depressor, cardiac slowing, and renal sympathoinhibitory responses evoked by selective stimulation of NTS A2a receptors. Second, the blockade did not affect A2a receptor-mediated increases in sympathetic activity directed to the adrenal medulla. In addition, exogenous vasopressin microinjected into the NTS decreased RSNA and HR in a dose-dependent manner, increased MAP, and tended to increase pre-ASNA. Taken together, the above observations suggest that in the NTS, vasopressin operating via V1 receptors interacts with adenosine operating via A2a receptors. These two neuromodulators differentially contribute to the control of sympathetic output to the kidney and the adrenal medulla.

Responses to microinjections of vasopressin into NTS. Previous studies showed that microinjections of vasopressin into the NTS evoke variable hemodynamic responses. Small increases, no effects, or decreases in MAP and HR have been reported (18, 20–22, 41, 47). Usually small doses of vasopressin (<0.1 ng) evoked dose-dependent depressor responses (7, 8), whereas vasopressin in doses of 1–20 ng evoked small pressor responses with or without tachycardia (18, 20, 21, 41). However, decreases in MAP, HR, and splanchnic nerve activity were noted in response to large doses of vasopressin (2–10 ng) (15, 47). In the present study, vasopressin in doses of 0.1–10 ng evoked variable, nonsignificant responses in MAP, whereas the highest dose of vasopressin (100 ng) evoked small pressor responses. We did not observe marked decreases in MAP and HR reported by Brattstrom and colleagues (7, 8) in response to vasopressin at the dose of 0.1 ng. The reason for the differences between the present study and those of Brattstrom and colleagues remains unclear and may be related to unilateral versus bilateral microinjections, respectively. It may also reflect the differences between strains (Wistar vs. Sprague-Dawley rats in the present study), different size (and age) of the animals (body weight: 200–250 vs. 350.6 +5.1 g in the present study), or, most likely, relatively large volumes of microinjections (400 nl, bilaterally) used by Brattstrom and colleagues, which could exert mechanical effects or spread to adjacent areas (7, 8).

In the present study, microinjections of vasopressin increased MAP, tended to increase pre-ASNA, and significantly decreased HR and RSNA in a dose-dependent manner. The significant differences between RSNA versus pre-ASNA response patterns evoked by microinjections of vasopressin suggest that vasopressin receptors may be differentially expressed on the NTS neurons/neural terminals controlling different sympathetic outputs as proposed in Fig. 7. For example, vasopressin V1 receptors may be located on pre- and postsynaptic sites of NTS neurons mediating baroreflex inhibition of RSNA but not on those NTS neurons that directly activate the neurons located in the rostral ventrolateral medulla (RVLM) that mediate, for example, chemoreflex activation of RSNA. In contrast, vasopressin V1 receptors may be located on baroreflex and chemoreflex-like NTS neurons/afferents controlling pre-ASNA with slight dominance of chemoreflex-like activation. This hypothesis explains why stimulation of vasopressin V1 receptors in the NTS decreased RSNA but tended to increase pre-ASNA. In support of this concept, vasopressin activates, whereas vasopressin V1 receptor antagonist attenuates activity of NTS baroreflex as well as nonbaroreflex neurons and baroreflex responses of RSNA (14, 16, 28). In contrast to the differential pattern of hemodynamic and neural responses to vasopressin, microinjections of glutamate into the same site of the NTS evoked uniform decreases in all recorded variables, similar responses to those reported previously (34, 39). Uniform sympathoinhibition in both RSNA and pre-ASNA evoked by microinjections of glutamate suggests that glutamatergic mechanisms controlling these two sympathetic outputs at the level of the NTS are similar (Fig. 7). The comparison of the effects evoked by microinjections of vasopressin and glutamate into the same sites of the NTS additionally suggests that the differential pattern of the responses to vasopressin was specific for this neuromodulator.


Figure 7
View larger version (23K):
[in this window]
[in a new window]
  		Fig. 7. Potential interactions between adenosine A2a receptors and other neurotransmitters/neuromodulators operating in NTS. Simplified NTS circuitry controlling sympathetic output to adrenal medulla (pre-ASNA) and kidney (RSNA). RVLM, rostral ventrolateral medulla; CVLM, caudal ventrolateral medulla. Glutamatergic neurons ({circ}) and GABA-ergic neurons (bullet) are shown. NTS contains interneurons that increase sympathetic activity via direct NTS-RVLM connections (for example, those mediating chemoreflex responses) and interneurons mediating sympathoinhibition (for example, those mediating baroreflex responses); intrinsic GABA-ergic neurons are activated via descending pathways from hypothalamus and inhibit baroreflex transmission, causing disinhibition (increase) of efferent sympathetic activity. This diagram presents possible differential location of A2a and V1 receptors and nitric oxide (NO)-releasing mechanisms on NTS neurons/neural terminals controlling pre-ASNA and RSNA. Differential location of these receptors/mechanisms may explain differential effects evoked by microinjections into NTS of A2a receptor agonist, VP, and NO donors, as well as differential effects of blockade of vasopresinergic and nitroxidergic mechanisms on regional sympathetic responses evoked by selective stimulation of adenosine A2a receptors in NTS. For clarity, V1 receptors are marked only on second-order baroreflex neurons/neural terminals, although they may be present also on primary baroreflex neurons/afferents in NTS. Diagram provides hypothetical explanation of why blockade of VP V1 receptors or NO synthase abolishes/reverses responses of RSNA but not pre-ASNA evoked by selective stimulation of adenosine A2a receptors in NTS. Adenosine A2a receptors interact with vasopresinergic and nitroxidergic transmission in baroreflex but not chemoreflex pathway controlling RSNA. Adenosine A2a receptors may be expressed also on those NTS neurons that activate RSNA via direct NTS-RVLM connections, although in smaller amounts than those expressed along baroreflex pathway. Therefore microinjections of adenosine A2a receptor agonist, NO donors, and VP decreases RSNA, whereas blockade of VP V1 receptors and NO synthase may abolish or reverse normal decreases in RSNA evoked by selective stimulation of A2a receptors into increases. In contrast, adenosine A2a receptors activate/disinhibit pre-ASNA via mechanism independent of vasopressinergic and nitroxidergic transmission. Therefore, microinjections of adenosine A2a receptor agonist, NO donors, and, to some extent, also VP increase pre-ASNA, whereas blockade of both VP V1 receptors and NO synthases does not affect increases in pre-ASNA evoked by selective stimulation of adenosine A2a receptors.

 
Interactions between vasopressin and adenosine in NTS. The pattern of responses evoked via microinjections of vasopressin into the NTS was consistent with the effects of the blockade of vasopressin V1 receptors on the pattern of responses to stimulation of adenosine A2a receptors. The blockade abolished A2a receptor-mediated decreases in RSNA and HR, whereas it did not alter the responses in pre-ASNA, similarly as the microinjections of vasopressin evoked dose-dependent decreases in RSNA and HR, whereas they did not significantly increase pre-ASNA. Taken together, these observations suggest that the decreases in RSNA and HR observed after activation of NTS A2a receptors may be mediated via facilitation of vasopressin release and V1 receptor activation. However, this mechanism does not contribute to A2a receptor-elicited increases in pre-ASNA. Vasopressin V1 receptor-mediated decreases in RSNA and HR may contribute to the overall depressor responses evoked by stimulation NTS A2a receptors; however, stimulation of NTS vasopressin receptors did not change or increase MAP. Our previous study (19) showed that ~80% of the depressor effect evoked by stimulation of NTS A2a receptors is mediated via large increases in pre-ASNA, activation of the adrenal medulla, increases in circulating epinephrine, and subsequent beta-adrenergic vasodilation. Vasopressin did not contribute to A2a receptor-mediated increases in pre-ASNA. Therefore, it is likely that although vasopressin, operating via V1 receptors, contributes to some components of the depressor responses evoked by stimulation of NTS A2a receptors (decreases in RSNA and HR), it mediates vasoconstriction in other vascular beds, and these pressor responses to vasopressin prevail because they are not opposed by beta-adrenergic vasodilation.

In our previous studies (34, 35, 37), we postulated that the hemodynamic and reciprocal neural responses (decreases in RSNA vs. increases in pre-ASNA) may be mediated via facilitation of vasopressin release from terminals descending to the NTS from higher structures. We felt this was likely because bilateral sinoaortic deafferentation combined with vagotomy as well as glutamatergic blockade did not significantly affect the responses to stimulation of NTS adenosine A2a receptors (34, 35). According to the above hypothesis, we expected that vasopressin operating via V1 receptors may contribute to the responses evoked by stimulation of adenosine A2a receptors in the NTS and that the blockade of NTS V1 receptors may attenuate A2a receptor-mediated hemodynamic and reciprocal neural responses. Therefore, it was surprising that the blockade of vasopressin V1 receptors completely abolished/reversed the depressor, cardiac slowing, and sympathoinhibitory responses evoked by stimulation of NTS A2a receptors. A possible explanation for these qualitative changes in the responses after the blockade of NTS V1 receptors is proposed in Fig. 7. Because glutamate operates as a primary mediator in both baro- and chemoreflex pathways at the level of the NTS (12), the overall depressor and sympathoinhibitory responses, mediated via A2a receptors located in NTS circuitry, may be a net effect of both depressor (baroreflex-like) and pressor (chemoreflex-like) components. Adenosine A2a receptors may facilitate release of glutamate from afferent fibers terminating on those NTS neurons that directly activate pre-ASNA and on those GABA-ergic neurons that inhibit baroreflex restraint of this sympathetic output. In contrast, A2a receptors may facilitate glutamatergic transmission to a greater extent in the baroreflex pathway than that in the chemoreflex pathway controlling RSNA (and perhaps other sympathetic outputs). This concept is consistent with activation of pre-ASNA and inhibition of RSNA observed after selective stimulation of adenosine A2a receptors in the NTS and with previous studies (11, 23) that showed that activation of NTS adenosine A2a receptors releases glutamate into the NTS. Thus vasopressin V1 receptors may be located on baroreflex but not chemoreflex neurons/terminals controlling RSNA. Release of vasopressin from descending fibers terminating on baroreflex neurons may be facilitated via presynaptic adenosine A2a receptors. Vasopressin operating via V1 receptors may directly activate those NTS glutamatergic neurons that send their axons to the caudal ventrolateral medulla (CVLM) and inhibit RSNA (14–16, 28). This hypothesis is consistent with our previous observation (35) that ionotropic glutamatergic blockade does not prevent A2a receptor-mediated inhibition of RSNA. According to this hypothesis, blockade of vasopressin V1 receptors may remove an activatory component of vasopressin and uncover an activatory action of adenosine A2a receptors exerted via activation of the chemoreflex pathway. This may explain why initial decreases in RSNA, evoked by stimulation of NTS adenosine A2a receptors, were abolished or reversed after blockade of vasopressin V1 receptors in the NTS.

The effects of blockade of NTS V1 receptors on the hemodynamic and neural responses, evoked by stimulation of adenosine A2a receptors, resemble those exerted by the blockade of nitroxidergic mechanisms in the NTS (39). It is possible that both A2a and V1 receptors may act via stimulation of NOS because the activation of both of these receptors increases intracellular calcium (9, 17, 27, 29). NO released from NTS neurons/synaptic terminals after activation of A2a and V1 receptors may activate pre- or postsynaptically those glutamatergic neurons that send their axons to the CVLM and finally inhibit RSNA (Fig. 7). The blockade of nitroxidergic mechanisms in the NTS, as well as vasopressin V1 receptors, may shift the balance toward the pressor, chemoreflex-like component of the responses and consequently abolish the depressor and sympathoinhibitory responses or even reverse them into pressor and sympathoactivatory responses, as it was observed in the present and our previous studies (39).

The blockade of vasopressin V1 receptors, as well as blockade of nitroxidergic mechanisms (39), affected A2a receptor-elicited cardiovascular and neural responses in a regionally selective manner. Although the sympathoinhibition in RSNA was completely abolished and tended to be reversed after these blockades, the responses in pre-ASNA, directed toward the adrenal medulla, remained unaffected. This suggests that the interaction between adenosine A2a receptors and vasopressin operating via V1 receptors is selective for different groups of NTS neurons targeting different sympathetic outputs. As proposed in Fig. 7, adenosine A2a receptors may interact with vasopressin and NO along the baroreflex pathway controlling RSNA. In contrast, although NO and vasopressin affect pre-ASNA at the level of the NTS, the effects exerted by adenosine A2a receptors on this sympathetic output are independent of those exerted by NO and vasopressin (Fig. 7). Taken together, our present and previous studies (39) suggest that neurotransmitters other than vasopressin, NO, and glutamate are involved in NTS A2a receptor-mediated activation of the adrenal medulla. Among many possibilities, serotonin operating via 5-hydroxytryptamine (5-HT3) receptors, norepinephrine operating via {alpha}2 receptors, and GABA inhibiting baroreflex restraint of pre-ASNA should be considered. In addition, although adenosine A2a receptors have been found in the NTS mostly on the presynaptic side (11, 29), it is possible that some of these receptors may be located also on the postsynaptic side of those NTS neurons that directly stimulate RVLM neurons controlling pre-ASNA. All these possibilities await further investigation.

The schematic diagram presented in Fig. 7, based on the present and previous studies from our laboratory, illustrates one of many possible explanations of the complex interactions between adenosine operating via A2a receptors and other neurotransmitters/neuromodulators operating in the NTS. The hypotheses presented in Fig. 7 await further studies on the cellular/synaptic level.

Although unilateral microinjections of vasopressin V1 receptor antagonist into the subpostremal NTS markedly affected the responses to stimulation of adenosine A2a receptors, they did not alter baseline levels of hemodynamic and neural variables (Table 1). Blockade of vasopressin V1 receptors attenuates arterial baroreflex reactivity and activity of NTS neurons (14, 16, 28); therefore, one may expect that the blockade should increase baseline hemodynamic and sympathetic variables. However, bilateral but not unilateral blockade of NTS vasopressin V1 receptors attenuates baroreflex responses (14). In addition, only a fraction of NTS baroreflex neurons are activated via vasopressin V1 receptors (16). Therefore, the lack of changes in baseline variables after unilateral V1 receptor blockade in the NTS was not surprising because unilateral attenuation of baroreflex mechanisms was most likely compensated via intact contralateral mechanisms. Nevertheless, it is possible that presynaptic adenosine A2a receptors may facilitate the release of vasopressin from tonically active and/or inactive neural terminals descending to the NTS from the PVN and/or other central structures (30, 42, 45).

Limitations of method. Taking into consideration that the antagonist of vasopressin V1 receptors was microinjected into the NTS in relatively large volumes (100 nl), it cannot be excluded that it might spread into the adjacent area postrema (AP). However, vasopressin acts similarly in both structures. It inhibits sympathetic nerve activity, shifting the baroreflex response curve toward lower MAP via AP-NTS connections utilizing {alpha}2-adrenoceptors (13), and it directly facilitates baroreflex sympathoinhibition at the level of the NTS (14, 27, 28). Therefore, the possible blockade of vasopressin V1 receptors located in the AP did not oppose the effects evoked solely at the level of the NTS, although it could exaggerate them. However, the effects of unilateral blockade of vasopressin V1 receptors performed in the present study did not alter baseline variables (Table 1), indicating that the effect of the blockade on baroreflex function was negligible. Therefore, we do not believe that the potential spread of the antagonist of vasopressin V1 receptors into the AP could significantly influence the results.

It is possible, although unlikely, that the observed changes in the responses to stimulation of NTS A2a receptors after V1 receptor blockade may be caused by experimental factors other than the blockade (i.e., desensitization after multiple stimulation of A2a receptors or changes in stability of the preparation with time). The time control previously reported showed that two consecutive microinjection of ACF + CGS-21680, separated by a 90-min interval, evoked similar hemodynamic and regional neural responses (39). In addition, although the responses in MAP, HR, and RSNA were abolished after V1 blockade, the pre-ASNA responses remained virtually unaltered. Finally, the responses tended to recover ~90 min after the blockade. The control responses were not significantly different from the recovery responses in all analyzed variables (Fig. 4 and Table 2).

In conclusion, blockade of vasopressin V1 receptors abolished the depressor, cardiac slowing, and sympathoinhibitory responses evoked by stimulation of adenosine A2a receptors in the NTS; however, A2a receptor-mediated increases in pre-ASNA were not affected by the blockade. This suggests that A2a receptor-mediated facilitation of release of vasopressin from nerve fibers terminating in the NTS may differentially contribute to neural and hemodynamic responses evoked by stimulation of NTS 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
 
We gratefully acknowledge the generous gift of arfonad by Hoffmann-La Roche (Nutley, NJ) and 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 E. Canfield Ave., Detroit, MI 48201 (e-mail: tscislo{at}med.wayne.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Barraco RA, Clough-Helfman C, and Anderson GF. 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.[CrossRef][ISI][Medline]
  2. Barraco RA, Clough-Helfman C, Goodwin BP, and Anderson GF. Evidence for presynaptic adenosine A2a receptors associated with norepinephrine release and their desensitization in the rat nucleus tractus solitarius. J Neurochem 65: 1604–1611, 1995.[ISI][Medline]
  3. Barraco R, el-Ridi M, Ergene E, Parizon M, and Bradley D. An atlas of the rat subpostremal nucleus tractus solitarius. Brain Res Bull 29: 703–765, 1992.[CrossRef][ISI][Medline]
  4. 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]
  5. Barraco RA and Phillis JW. Subtypes of adenosine receptors in the brainstem mediate opposite pressure responses. Neuropharmacology 30: 403–407, 1991.[CrossRef][ISI][Medline]
  6. 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]
  7. Brattstrom A, De Jong W, and Wied DD. Vasopressin micro-injections into the nucleus tractus solitarii decrease heart rate and blood pressure in anesthetized rats. J Hypertens 6: S521–S524, 1988.
  8. Brattstrom A, De Jong W, Burbach JPH, and Wied DD. Vasopressin, vasopressin fragments and a C-terminal peptide of the vasopressin precursor share cardiovascular effects when microinjected into the nucleus tractus solitarii. Psychoneuroendocrinology 14: 461–467, 1989.[CrossRef][ISI][Medline]
  9. Bryan PT and Marshall JM. Cellular mechanisms by which adenosine induces vasodilation in skeletal muscle: significance for systemic hypoxia. J Physiol 514: 163–175, 1999.[Abstract/Free Full Text]
  10. 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]
  11. Castillo-Melendez M, Krstew E, Lawrence AJ, and Jarrot B. Presynaptic adenosine A2a receptors on soma and central terminals of rat vagal afferent neurons. Brain Res 652: 137–144, 1994.[CrossRef][ISI][Medline]
  12. Dampney RAL. Functional organization of central pathways regulating the cardiovascular system. Physiol Rev 74: 323–364, 1994.[Free Full Text]
  13. Hasser EM, Cunningham JT, Sullivan MJ, Curtis KS, Blaine EH, and Hay M. Area postrema and sympathetic nervous system effects of vasopressin and angiotensin II. Clin Exp Pharmacol Physiol 27: 432–436, 2000.[CrossRef][ISI][Medline]
  14. Hegarty AA and Felder RB. Antagonism of vasopressin V1 receptors in the NTS attenuates baroreflex control of renal nerve activity. Am J Physiol Heart Circ Physiol 269: H1080–H1086, 1995.[Abstract/Free Full Text]
  15. Hegarty AA and Felder RB. Cardiovascular responses to microinjections of arginine vasopressin into the nucleus tractus solitarius of the spontaneously hypertensive rat (Abstract). Soc Neurosci Abstr 21: 888, 1995.
  16. Hegarty AA and Felder RB. Vasopressin and V1-receptor antagonist modulate the activity of NTS neurons receiving baroreceptor input. Am J Physiol Regul Integr Comp Physiol 273: R142–R152, 1997.
  17. Hirata Y, Hakayawa H, Kakoki M, Tojo A, Suzuki E, Nagata D, Kimura K, Goto A, Kikuchi K, Nagano T, Hirobe M, and Omata M. Receptor subtype for vasopressin-induced release of nitric oxide from rat kidney. Hypertension 29: 58–64, 1997.[Abstract/Free Full Text]
  18. King KA and Pang CCY. Cardiovascular effects of injections of vasopressin into the nucleus tractus solitarius in conscious rats. Br J Pharmacol 90: 531–536, 1987.[ISI][Medline]
  19. Kitchen AM, Scislo TJ, and O'Leary DS. NTS purinoceptor activation elicits hindlimb vasodilation primarily via a beta-adrenergic mechanism. Am J Physiol Heart Circ Physiol 278: H1775–H1782, 2000.[Abstract/Free Full Text]
  20. Kubo T and Kihara M. Modulation of the aortic baroreceptor reflex by neuropeptide Y, neurotensin and vasopressin microinjected into the nucleus tractus solitarii of the rat. Naunyn Schmiedebergs Arch Pharmacol 342: 182–188, 1990.[CrossRef][ISI][Medline]
  21. Matsuguchi H, Sharabi FM, Gordon FJ, Johnson AK, and Schmid PG. Blood pressure and heart rate responses to microinjections of vasopressin into the nucleus tractus solitarius region of the rat. Neuropharmacology 21: 687–693, 1982.[CrossRef][ISI][Medline]
  22. Michelini LC and Bonagamba GH. Baroreflex modulation by vasopressin microinjected into the nucleus tractus solitarii of conscious rats. Hypertension 11, Suppl I: I75–I79, 1988.
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. Raggenbass M. Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vivo systems. Prog Neurobiol 64: 307–326, 2001.[CrossRef][ISI][Medline]
  28. Raggenbass M, Tribollet E, Dubois-Dauphin M, and Dreifuss JJ. Vasopressin receptors of the vasopressin V1 type in the nucleus of the solitary tract of the rat mediate direct neuronal excitation. J Neurosci 9: 3929–3926, 1989.[Abstract]
  29. Ralevic V and Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 50: 413–492, 1998.[Abstract/Free Full Text]
  30. Sawchenko PE and Swanson LW. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol 205: 260–272, 1982.[CrossRef][ISI][Medline]
  31. Scislo TJ, Augustyniak RA, and O'Leary DS. Differential arterial baroreflex regulation of renal, lumbar and adrenal sympathetic nerve activity in the rat. Am J Physiol Regul Integr Comp Physiol 275: R995–R1002, 1998.[Abstract/Free Full Text]
  32. 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 Pharmacol Physiol 28: 120–124, 2001.[CrossRef][ISI][Medline]
  33. 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]
  34. 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.[Abstract/Free Full Text]
  35. 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]
  36. 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]
  37. 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]
  38. Scislo TJ and O'Leary DS. NTS adenosine receptors facilitate inhibition of renal sympathetic nerve activity during severe hemorrhage (Abstract). FASEB J 19: A614, 2005.
  39. 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]
  40. 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]
  41. Vallejo M, Carter DA, and Lightman SL. Hemodynamic effects of arginine-vasopressin microinjections into the nucleus tractus solitarius: a comparative study of vasopressin, a selective vasopressin receptor agonist and antagonist, and oxytocin. Neurosci Lett 52: 247–252, 1984.[CrossRef][ISI][Medline]
  42. Van Giersbergen PLM, Palkovits M, and De Jong W. Involvement of neurotransmitters in the nucleus tractus solitarii in cardiovascular regulation. Physiol Rev 72: 789–824, 1992.[Free Full Text]
  43. 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]
  44. 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]
  45. White JD, Krause JE, and McKelvy JF. In vivo biosynthesis and transport of oxytocin, vasopressin, and neurophysins to posterior pituitary and nucleus of the solitary tract. J Neurosci 4: 1262–1270, 1984.[Abstract]
  46. 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]
  47. Zhang X, Abdel-Rahman A, and Wooles WR. Vasopressin receptors in the area postrema differentially modulate baroreceptor responses in rats. Eur J Pharmacol 222: 81–91, 1992.[CrossRef][ISI][Medline]



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
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. J. Scislo and D. S. O'Leary
Adenosine receptors located in the NTS contribute to renal sympathoinhibition during hypotensive phase of severe hemorrhage in anesthetized rats
Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2453 - H2461.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
290/5/H1889    most recent
01030.2005v1