| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1996;27:939-948.)
© 1996 American Heart Association, Inc.
Articles |
Differential Alteration of Neuronal and Cardiovascular Responses to Adenosine Microinjected Into the Nucleus Tractus Solitarius of Spontaneously Hypertensive Rats
From the Department of Pharmacology, East Carolina University, School of Medicine, Greenville, NC.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract We previously reported that adenosine elicited site-dependent neuronal and cardiovascular responses in two subareas of the nucleus tractus solitarius (NTS) of normotensive rats. Pressor and tachycardic responses were obtained from the rostral NTS (adenosine pressor system), and depressor and bradycardic responses were obtained from the caudal NTS (adenosine depressor system). In both areas, adenosine inhibited the firing rate of barosensitive neurons. The present study investigated whether spontaneously hypertensive rats (SHR) exhibit abnormal neuronal and cardiovascular responses mediated by the adenosine pressor and depressor systems within the NTS. Male SHR and Wistar-Kyoto rats (WKY) were anesthetized with urethane and prepared for blood pressure and heart rate recording, stereotaxic microinjection of adenosine into the NTS, and extracellular recording of single-unit neuronal activity of NTS neurons. Chemical identification of the targeted neuronal pool was made by L-glutamate (5 nmol) and confirmed by histology. SHR exhibited significantly higher mean arterial pressure and firing rate of caudal NTS neurons (45.0±4.5 versus 27.3±4.7 spikes per 2.5 seconds, P<.05) but similar heart rate and neuronal firing rate of rostral NTS neurons compared with WKY. Adenosine (0.1, 1, and 10 nmol) elicited dose-related neuronal and cardiovascular responses in both strains. However, SHR exhibited differential alterations in both adenosine systems. Compared with WKY, SHR exhibited attenuated pressor, tachycardic, and neuronal responses mediated by the adenosine pressor system and exaggerated depressor, bradycardic, and neuronal responses mediated by the adenosine depressor system. In both strains, the responses elicited by adenosine were virtually abolished by theophylline (10 mg/kg IV), suggesting that these responses were mediated by adenosine receptors in the NTS. Furthermore, the theophylline-evoked increase in blood pressure was twofold higher in SHR (15.0±1.7 versus 6.9±1.5 mm Hg, P<.05); larger but nonsignificant increases in heart rate and neuronal firing rate also were evident in SHR compared with WKY. These findings suggest differential alterations in adenosine pressor and depressor systems in the NTS of SHR, which may be implicated in the pathophysiology of this model of hypertension.
Key Words: adenosine • nucleus tractus solitarius • rats, inbred, SHR
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The NTS exhibits the highest density of adenosine uptake sites in the central nervous system1 2 and represents the primary site for first-order neuronal input from baroreceptor afferents.3 4 5 6 Previous studies including our own have shown that adenosine microinjected into the NTS elicits hypotensive and bradycardic responses.7 8 9 10 11 These responses involved an inhibitory action of adenosine on barosensitive neurons in the NTS.11 Interestingly, both neuronal and cardiovascular responses elicited by adenosine mimicked (caudal) or contrasted (rostral) those elicited by L-glutamate depending on the targeted neuronal pool within the NTS.11 In virtually all central areas studied, adenosine has been shown to inhibit neuronal firing rate.12 13
Hypertension modifies the responsiveness to vasoactive agents. The SHR exhibits significantly greater hypotensive responses to centrally acting drugs and opioids compared with the WKY.14 Surprisingly, a recent study by Tseng et al15 has shown that adenosine microinjected into brain stem nuclei elicited attenuated hypotensive and bradycardic responses in SHR compared with WKY. No consideration was given in that study15 to potential differences in pressor responses to adenosine between the two strains. More importantly, the neuronal responses that precede the cardiovascular responses elicited by adenosine microinjected into these subareas of the NTS have not been studied in the SHR.
The present study compared the neuronal and cardiovascular responses elicited by adenosine microinjected into the pressor (rostral) and depressor (caudal) areas of the NTS of SHR and WKY. Whether these responses were blocked by the adenosine receptor blocker theophylline was also investigated. Finally, the neuronal and cardiovascular changes that followed blockade of adenosine receptors are indicative of the magnitude of involvement of central adenosine receptors in the tonic control of BP.11 This study also investigated whether these mechanisms are altered in SHR.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
General Procedure
A total of 14 male SHR and 12 WKY (Charles River, Raleigh, NC) at 12 weeks old were used in the study. The rats were anesthetized with urethane (1.25 to 1.5 g/kg IP, Sigma Chemical Co). The trachea and left femoral artery and vein were cannulated. The arterial catheter was connected to a pressure transducer (Gould Instruments), and phasic arterial pressure was displayed on a polygraph (Grass model 7D). HR was computed from the BP pulse by a Grass tachograph and displayed on another channel of the polygraph. Rectal temperature was maintained between 37°C and 38°C. The rats were placed in a stereotaxic frame (David Kopf Instruments) in a prone position. A limited occipital craniotomy was conducted to expose the posterior atlanto-occipital membrane and caudal medulla, and the region of the obex was then revealed by delicate dissection. Methods used were in accordance with institutional guidelines. All protocols were approved by the Institutional Animal Care and Use Committee.
Microinjection and Single-Unit Recording
Procedure
For microinjection and single-unit recording, a
probe, modified from that described by other
researchers,16 17 was fabricated as in our previous
study.11 The probe consisted of a three-barreled glass
micropipette (World Precision Instruments Inc) with a tip diameter of
40 to 60 µm and a metal microelectrode. The platinum or stainless
steel microelectrode (Fred Haer Co) with a 5-µm exposed fine tip was
glued to the glass micropipette. A similar probe that consisted of a
microinjector of a similar tip size glued to a recording
micropipette has been described.17 After stabilization of
arterial pressure and HR at basal levels, the probe was
introduced unilaterally into the NTS according to the atlas of
Pellegrino et al18 as in our previous
study.11 With the calamus scriptorius as the reference and
the bite bar at 20 mm below the interaural line, the following
coordinates were used: mediolateral, 0.6 mm; anteroposterior, 0.6 mm;
and dorsoventral, 0.5 to 0.8 mm, as described by other
researchers.19 The pipettes were filled with a test dose
of L-glutamate and varying concentrations of
adenosine freshly prepared in ACSF, with the final pH adjusted
to between 7.2 and 7.3. ACSF of the following composition (mmol/L) was
used: NaCl 123, CaCl2 0.86, KCl 3, MgCl2 0.89,
NaHCO3 25, NaH2PO4 0.50, and
Na2HPO4 0.25, aerated with 95%
O2/5% CO2, pH 7.4, as described
by Tseng et al.20 Drug solutions injected
intravenously were dissolved in 0.9% NaCl solution. All
drugs and chemicals were purchased from Sigma Chemical Co.
Action potentials were amplified by a preamplifier (A-M Systems), with low and high filters set at 100 and 5 kHz, respectively. The amplified signals were displayed continuously on a Tektronix storage oscilloscope and also monitored with a loudspeaker. Neuronal action potentials were discriminated and counted (every 2.5 seconds) by a spike processor (D 130, Digitimer, Medical Systems Corp). The output of the spike processor was displayed as a time histogram on a third channel of the polygraph, along with arterial pressure and HR as in our previous study.11
Site Identification and Histology
The sites of microinjection and recording were
chemically identified at the beginning and in most cases at the end of
the experiment by microinjection of a test dose (5 nmol) of
L-glutamate. After a responsive site was identified by
observation of depressor and bradycardic responses to
L-glutamate, the probe remained in this site throughout the
experiment. Three-barreled micropipettes were used for
microinjection of drugs or dye (fast green) into the NTS. For the lower
doses of adenosine or the test dose of glutamate, the volume
injected was approximately 50 nL delivered over 15 seconds. The maximal
volume injected for delivery of the high dose of adenosine was
120 nL. Accordingly, the site of microinjection for postmortem
histological verification was marked by microinjection
of 120 nL of the dye. Equal volumes of ACSF microinjected into the NTS
had no significant effects on neuronal and hemodynamic
variables.11 At the conclusion of an experiment, the
rat was killed by an overdose of pentobarbital; the brain was removed,
frozen, and cut on a freezing microtome. Sections of 40 µm of the
brain stem were stained with cresyl violet, and verification of the
injection site was made by histology as in our previous
study11 and as shown in Fig 1
.
|
Protocol and Experimental Groups
In all experiments, the measured
variables—arterial pressure, HR, and NTS
single-unit firing rate—were allowed to stabilize at baseline
levels. Responses were expressed as change from basal levels in
absolute units for arterial pressure (millimeters of
mercury) and HR (beats per minute) and as percentage of control for NTS
neuronal firing rate. For
electrophysiological measurements, a
control value of at least 30 seconds was considered 100%. The window
discriminator was set to display the number of action potentials every
2.5 seconds; ie, a minimum of 15 readouts was taken before drug
administration as in our previous study.11
Neuronal and Hemodynamic Responses Before and After
Adenosine Receptor Blockade
Dose-response curves depicting neuronal and
cardiovascular responses elicited by adenosine
were generated by microinjection of adenosine (0.1, 1, 10 nmol)
after chemical identification of the injection site in both rat
strains. Because L-glutamate elicits depressor and
bradycardic responses when microinjected into the rostral and caudal
NTS,10 11 15 it was not possible to determine whether the
tip of the probe was located in the rostral or caudal NTS at the
beginning of the experiment. However, the location of the tip can be
ascertained by observation of the neuronal responses elicited by
L-glutamate that consist of increases (rostral) and
decreases (caudal) as in our previous findings.11
Increases and decreases in neuronal firing rate elicited by
L-glutamate indicated location of the probe tip in the
rostral and caudal NTS, respectively, as later verified by
histology.11 On the basis of these criteria, the three
adenosine doses were microinjected into the rostral (6 SHR and
6 WKY) or caudal (8 SHR and 6 WKY) NTS; adequate time was allowed
between doses for recovery. The ability of theophylline to block
neuronal and hemodynamic responses to adenosine
microinjected into the two NTS subareas of SHR and WKY was
investigated. The dose-response curves depicting the neuronal and
cardiovascular responses elicited by adenosine
were generated in the same rats after administration of 10 mg/kg
theophylline IV. Our previous findings demonstrated that the neuronal
and cardiovascular responses elicited by
adenosine were not influenced by time.11
Therefore, we performed no control experiments in the present
study. Because of the difficulty of dissolving theophylline in ACSF at
a concentration that would yield an adequate dose of the
antagonist when microinjected into the NTS, the drug was
injected intravenously at a dose of 10 mg/kg. This
theophylline dose adequately blocked adenosine receptors in our
previous study.11 At least 10 minutes were allowed before
the second dose-response curve for adenosine was
constructed. During this period, the neuronal and
hemodynamic changes reflected the contribution of
central adenosine receptors to tonic control of BP and HR. In
our previous study,11 we conducted a control experiment
for theophylline in which a water-soluble adenosine
receptor blocker, 8-(p-sulfophenyl)theophylline (2.5
mg/kg), that does not cross the blood-brain
barrier21 22 did not cause significant neuronal or
cardiovascular responses.
Statistical Analyses
Data are presented as mean±SE change from basal
values. Absolute units for changes in mean arterial
pressure (millimeters of mercury) and HR (beats per minute) and
percentage of basal control values for neuronal firing rate determined
before drug administration for each rat are presented. Mean
arterial pressure (MAP) was calculated as
MAP=DBP+(SBP-DBP)/3, where DBP is diastolic BP and
SBP is systolic BP. Group differences between SHR and WKY were
analyzed by unpaired t test. This applied to
differences in baseline BP, HR, and neuronal firing rate as well as
neuronal and cardiovascular responses elicited by
theophylline. Repeated-measures ANOVA was used for factorial
experiments (dose-response curves) as well as Dunnett's procedure
for post hoc multiple comparisons among means.23
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Data and Cardiovascular and Neuronal Responses to L-Glutamate
Pretreatment values for mean arterial pressure, HR, and NTS single-unit firing rate for SHR and WKY are presented in Table 1
. Mean arterial
pressure of SHR was significantly higher than that of WKY, but baseline
HR did not differ for the groups used for microinjection studies in
both areas of the NTS (Table 1). Furthermore, the caudal NTS neuronal
firing rate was significantly (P<.05) higher in SHR than in
WKY (Table 1). On the other hand, the rostral NTS neuronal firing rate
was similar in SHR and WKY (Table 1). A test dose (5 nmol) of
L-glutamate was routinely microinjected at the beginning of
the experiment for chemical identification of the injection site. In
both strains, chemical stimulation by L-glutamate (5 nmol)
elicited depressor and bradycardic responses that were preceded by
either excitatory or inhibitory neuronal responses.
Histological verification of the microinjection sites
revealed that excitatory and inhibitory neuronal responses
to L-glutamate occurred as a result of microinjection into
the rostral and caudal NTS, respectively (Fig 1
).
|
Dose-Related Cardiovascular and Neuronal Responses
Elicited by Adenosine Microinjected Into Rostral and Caudal NTS
of SHR and WKY
In WKY, adenosine (0.1, 1, 10 nmol) elicited
dose-related neuroinhibitory responses when
microinjected into the rostral (n=6) and caudal (n=6) NTS (Fig 2A). As shown in Fig 2, these neuronal responses were
associated with dose-related pressor and tachycardic versus
depressor and bradycardic responses when adenosine was
microinjected into the rostral and caudal NTS, respectively. By
contrast, SHR exhibited significantly (P<.05) greater
neuronal responses when adenosine was microinjected into the
caudal compared with the rostral NTS (Fig 3A).
Nonetheless, similar to WKY, SHR exhibited site-dependent
cardiovascular responses when adenosine was
microinjected into the two NTS subareas (Fig 3), ie, increases
(rostral) and decreases (caudal) in BP and HR (Fig 3B and 3C).
|
) and caudal
(
) NTS of WKY. Data are mean±SE; n is number of rats. FR
indicates firing rate; MAP, mean arterial pressure.
*P<.05.
|
) and caudal
(
) NTS of SHR. Data are mean±SE; n is number of rats.
Abbreviations are as in Fig 2
Figs 4 and 5 compare the neuronal and
cardiovascular responses elicited by adenosine
(0.1, 1, 10 nmol) microinjected into the rostral and caudal NTS,
respectively, of SHR and WKY. Compared with WKY, SHR exhibited
attenuated neuronal (Fig 4A), tachycardic (Fig 4B), and pressor
(particularly with the higher dose; Fig 4C) responses elicited by
adenosine microinjected into the rostral NTS. By contrast, the
dose-related neuronal (Fig 5A), bradycardic (Fig 5B), and depressor
(Fig 5C) responses elicited by adenosine microinjected into the
caudal NTS were significantly (P<.05) greater in SHR than
in WKY.
|
|
Neuronal and Cardiovascular Effects of Theophylline
in SHR and WKY
In both strains, regardless of the NTS subarea studied, systemic
administration of theophylline (10 mg/kg) virtually abolished the
neuronal and cardiovascular responses elicited by
adenosine. As shown in Figs 6 and 7, a significant attenuation of the
dose-related responses elicited by adenosine microinjected
into the rostral and caudal NTS, respectively, of SHR occurred after
theophylline. Similar results were obtained with theophylline in WKY
(Figs 8 and 9). It is notable that
theophylline elicited in both strains excitatory neuronal and
cardiovascular responses, as illustrated in Fig 10
(middle panels). The neuronal responses that preceded
the cardiovascular responses consisted of increases in
neuronal firing rates when recordings were made from rostral or
caudal NTS. These neuronal and cardiovascular responses
elicited by theophylline tended to be greater in SHR (Fig 10, middle
panels). However, because variations existed in these responses, the
differences between the neuronal and HR responses obtained in both
strains were not significant (Table 2). Nonetheless, the
pressor response elicited by intravenous theophylline was
significantly (P<.05) greater in SHR than in WKY (Table 2).
These findings indicate that adenosine receptors exert a
greater tonic inhibitory influence on BP in SHR than in
WKY.
|
|
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study investigated the neuronal and cardiovascular responses elicited by adenosine microinjected into the pressor (rostral) and depressor (caudal) areas of the NTS of SHR and WKY. In addition to confirming reported cardiovascular7 8 9 10 11 15 and neuronal11 responses observed in normotensive rats, results of the current study demonstrate for the first time the neuronal and cardiovascular responses elicited by adenosine microinjected into the two subareas of the NTS in SHR.
Microinjection of adenosine into the NTS elicited site-dependent cardiovascular responses. Increases and decreases in BP and HR followed microinjection of adenosine into the rostral and caudal NTS, respectively. Nonetheless, adenosine inhibited the firing rate of both neuronal pools. These findings in WKY confirm and extend our previous findings in another strain of normotensive rats, the Sprague-Dawley rat.11 Results from the present study and our previous study11 showed that the neuronal responses preceded the cardiovascular ones. In our previous study,11 only the middle dose (1 nmol) of adenosine was microinjected into the rostral NTS of Sprague-Dawley rats. Microinjection of a lower and a higher dose allowed the conclusion that the neuronal and cardiovascular responses elicited by adenosine in this area (adenosine pressor system) are dose related.
It is prudent to note that measurement of neuronal responses in the present study and in our previous study11 has strengthened our knowledge of the role of two distinct neuronal pools of the NTS in BP and HR regulation. Reliance on observation of the cardiovascular responses elicited by L-glutamate as a chemical marker as in other studies, including our own,10 11 15 may not lead to a precise definition of which neuronal pool of the NTS has been targeted. The present study and others10 11 15 have shown that L-glutamate microinjected as a chemical marker elicits hypotensive and bradycardic responses regardless of whether the site was the rostral or caudal NTS. Furthermore, this study, in agreement with our previous study,11 shows that the neuronal responses that preceded the similar cardiovascular responses elicited by L-glutamate consisted of increases and decreases in firing rates when microinjections were made into the rostral and caudal NTS, respectively. The current study was not intended to investigate the neuronal and cardiovascular effects of L-glutamate. Nonetheless, it is important to comment on these responses because the type of cardiovascular response elicited by adenosine, excitatory or inhibitory, seems to be determined at least partially by the type of targeted neuronal pool. More importantly, these neurons have been considered barosensitive because they responded to baroreceptor activation and unloading in our previous study.11 The rostral NTS neurons are excited, whereas those of the caudal NTS are inhibited, by L-glutamate. Adenosine elicited dose-related inhibition of both neuronal pools. However, the subsequent cardiovascular responses were opposite (rostral) and similar (caudal) to those elicited by L-glutamate. Other researchers have shown that adenosine may inhibit12 24 25 or enhance10 the release of L-glutamate. The current findings suggest that within the two NTS subareas studied, adenosine-glutamate interaction leads to opposite (rostral) or similar (caudal) cardiovascular responses.
It is well accepted that hypertension alters the cardiovascular responses to centrally administered agents.14 15 26 27 28 Consistent with this view, results of the present study demonstrate that the hypotensive and bradycardic responses elicited by adenosine microinjected into the caudal NTS are exaggerated in SHR. More importantly, we demonstrate for the first time that the neuroinhibitory responses recorded at the injection site are also enhanced in SHR. This finding may suggest an alteration in adenosine receptor sensitivity in SHR. Notably, the enhanced neuroinhibitory and depressor responses accompanied significantly higher baseline BP and neuronal firing rate in SHR. However, whether the enhanced responses are a cause of or result from hypertension cannot be ascertained from our findings.
Our findings do not agree with those recently reported by Tseng et al.15 These authors reported attenuated hypotensive and bradycardic responses elicited by adenosine microinjected into the NTS of SHR compared with WKY. The reasons for this apparent discrepancy are not known. It is notable, however, that in the study by Tseng et al,15 the rats referred to as SHR were in effect normotensive based on their baseline mean arterial pressure level (112±8 versus 156±6 mm Hg in our study). No matter what the reason or reasons for an apparent "normotensive" level of BP for their SHR might be (strain, depth of anesthesia, etc), the main feature of SHR, the higher BP, was not evident in their rats. As discussed earlier, the higher level of BP in SHR is a major contributor to the enhanced hypotensive responses to centrally acting substances.14 Therefore, it is plausible to explain the contradictory findings of the present study and that of Tseng et al15 at least partially on the basis of the significant difference in baseline BP values.
It is interesting to note that the responsiveness of the two neuronal pools of the NTS and the consequent cardiovascular responses are differentially altered in SHR. Results of the present study show that the pressor response, expressed as a percentage of baseline, and tachycardic response elicited by adenosine microinjected into the rostral NTS were attenuated in SHR compared with WKY. That these cardiovascular responses were preceded by smaller decreases in the firing rate of the rostral NTS neurons suggests a subsensitivity of these neurons to adenosine in SHR. These findings may implicate adenosine receptors in the NTS in the pathophysiology of hypertension in SHR. A hypoactive adenosine pressor system (rostral neurons) and hyperactive adenosine depressor system (caudal neurons) in the NTS of SHR are expected to guard against further exacerbation of hypertension in this animal model. Our functional findings on the adenosine pressor system are indicative of reduced affinity or number of adenosine receptors in the rostral NTS. In agreement with this view is the finding that the affinity of central adenosine A1 receptors is decreased in SHR.29 It must be remembered that the pressor response elicited by adenosine is mediated by A1 receptors.30 Interestingly, Matias et al29 attempted to explain the attenuated depressor response elicited by adenosine microinjected into the NTS of SHR on the basis of the decreased affinity of the adenosine A1 receptor in the central nervous system of SHR. Such an alteration in A1 receptors in SHR29 cannot explain the attenuated hypotensive responses obtained in SHR reported recently15 because adenosine-evoked decreases in BP and HR are mediated by A2 receptors in the NTS.30 Indeed, these enhanced responses shown in the present study in SHR may suggest increased affinity or number of A2 receptors in the NTS. However, it is also possible that the higher baseline BP in SHR influenced the responses to adenosine.
Although no binding studies have investigated this possibility, two findings of the present study may support this hypothesis. First, the electrophysiological responses of the rostral NTS neurons involved in the A1 receptor–mediated pressor and tachycardic responses30 agree with the biochemical evidence that showed a decreased affinity of central A1 receptors in SHR.29 With this in mind, one can see that it is possible the enhanced adenosine-mediated electrophysiological responses obtained in the caudal NTS (adenosine depressor system) are indicative of a higher affinity or upregulation of A2 receptors and may explain the enhanced cardiovascular responses in SHR. Second, the greater pressor and tachycardic responses elicited by the nonselective adenosine receptor blocker theophylline in SHR compared with WKY are consistent with this view.
It is possible that the theophylline-evoked pressor response was peripherally mediated because it was administered systemically and that the neuronal responses were secondary to increases in BP. In support of the latter possibility was the finding that a greater increase in BP evoked by theophylline in SHR was associated with a larger increase in neuronal firing rate. Nonetheless, it is also likely that the neuronal responses occurred first as a result of blockade of central adenosine receptors and triggered the cardiovascular responses. The following findings support the view that theophylline-evoked cardiovascular responses are mediated at least in part as a consequence of blockade of central adenosine receptors: (1) As in our previous study,11 the increases in neuronal firing rate preceded the increases in BP and HR; (2) An increase in sympathetic neural activity preceded the increases in BP and HR.11 If the neural and neuronal responses were secondary to peripherally mediated increases in BP, a decrease instead of increase in neuronal firing rate would be expected.11 Furthermore, two lines of evidence support the view that the neuronal and cardiovascular responses elicited by theophylline were mediated centrally. First, theophylline-evoked increases in neuronal firing rate, BP, and HR obtained in this study and in our previous study11 were absent after blockade of peripheral adenosine receptors by 8-(p-sulfophenyl)theophylline,11 a polar adenosine receptor blocker that does not cross the blood-brain barrier.21 Other researchers31 32 have shown that acute administration of another water-soluble adenosine receptor blocker, 1,3-dipropyl-8-sulfophenylxanthine, also failed to increase BP. Second, systemic theophylline, but not the water-soluble analogue,11 blocked the neuronal and cardiovascular responses elicited by adenosine microinjected into the caudal NTS. Finally, microinjection of the water-soluble analogue into the caudal NTS virtually abolished the neuronal and cardiovascular responses elicited by adenosine in the same area.11 Taken together, these findings support the view that blockade of central adenosine receptors contributed at least partially to the neuronal and cardiovascular responses elicited by theophylline. The possibility still exists, however, that the greater responses obtained in SHR may be due to the higher baseline BP in this strain.
Reported findings including our own have implicated adenosine in the modulation of baroreceptor function. The evidence is based on the ability of adenosine receptor blockers to attenuate the baroreceptor HR response in experimental animals9 33 and humans.34 Furthermore, our previous study has yielded direct electrophysiological evidence that showed a neuromodulatory action of adenosine on barosensitive neurons in the NTS.11 The use of nonselective adenosine receptor blockers in reported studies9 34 precludes a conclusion about whether A1 or A2 receptors in the NTS mediate the action of adenosine on baroreflexes. It is tempting to speculate, on the basis of findings of the present and reported studies, that this role is played by A1 receptors. Results of the present study demonstrated that SHR exhibit a hypofunctional adenosine pressor system that is modulated by A1 receptors in the NTS.30 This finding coincides with an approximately 50% attenuation of baroreceptor HR response in SHR compared with age-matched WKY.35 Further support for this notion is based on our recent finding which demonstrated that an oligodeoxynucleotide targeting the A1 receptors microinjected into the NTS of conscious normotensive rats attenuated their baroreceptor HR response by approximately 50%.36
In conclusion, findings of the present study support the view that differential alterations in the adenosine pressor and depressor systems exist in SHR. Whereas the rostral NTS neurons involved in the A1-mediated pressor and tachycardic responses are hypofunctional, those located in the caudal NTS and involved in A2-mediated depressor and bradycardic responses are hyperfunctional in SHR compared with WKY. Whether these neuronal and subsequent cardiovascular alterations are the cause of or result from hypertension is not known. Nonetheless, in established hypertension these alterations in both adenosine pressor and depressor systems seem to function as a safeguard against the further exacerbation of hypertension.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by Public Health Service grant AA07839 from the National Institute on Alcohol Abuse and Alcoholism.
|
Footnotes |
|---|
Reprint requests to Abdel A. Abdel-Rahman, PhD, Department of Pharmacology, East Carolina University, School of Medicine, Greenville, NC 27858.
Received September 20, 1995; first decision October 31, 1995; accepted December 11, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bisserbe JC, Patel J, Marangos PJ. Autoradiographic localization of adenosine uptake sites in rat brain using [3H]nitrobenzyl-thioinosine. J Neurosci. 1985;5:544-550. [Abstract]
2. Deckers J, Bisserbe JC, Marangos PJ. Quantitative [3H]dipyridamole autoradiography: evidence for adenosine transporter heterogeneity in guinea pig brain. Naunyn Schmiedebergs Arch Pharmacol. 1987;335:660-666. [Medline] [Order article via Infotrieve]
3. Bystrzycka EK, Nail BS. Brainstem nuclei associated with respiratory cardiovascular and other autonomic functions. In: Paxinos D, ed. The Rat Nervous System. New York, NY: Academic Press; 1985:95-110.
4. Jordon D, Spyer KM. Brainstem integration of cardiovascular and pulmonary afferent activity. In: Cavero F, Morrison JFB, eds. Progress in Brain Research. New York, NY: Elsevier Science Publishers; 1986;67:295-314.
5. Riche D, Pommery JD, Menetrey D. Neuropeptides and catecholamines in efferent projections of the nuclei of the solitary tract in the rat. J Comp Neurol. 1990;293:399-424. [Medline] [Order article via Infotrieve]
6. Simon JR, Dimicco SK, Aprison MH. Neurochemical studies of the nucleus of the solitary tract, dorsal motor nucleus of the vagus and the hypoglossal nucleus in the rat: topographical distribution of glutamate uptake, GABA uptake and glutamic acid decarboxylase activity. Brain Res Bull. 1985;14:49-53. [Medline] [Order article via Infotrieve]
7.
Tseng CJ, Biaggioni I, Appalsamy M, Robertson
D. Purinergic receptors in the brainstem mediate hypotension and
bradycardia. Hypertension. 1988;11:191-197.
8. Barraco RA, Janusz CJ, Polasek PM, Parizon M, Roberts PA. Cardiovascular effects of microinjection of adenosine into the nucleus tractus solitarius. Brain Res Bull. 1988;20:129-132. [Medline] [Order article via Infotrieve]
9. Mosqueda-Garcia R, Tseng CJ, Appalsamy M, Robertson D. Modulatory effects of adenosine on baroreflex activation in the brainstem of normotensive rats. Eur J Pharmacol. 1989;174:119-122. [Medline] [Order article via Infotrieve]
10.
Mosqueda-Garcia R, Tseng CJ, Appalsamy M, Beck C,
Robertson D. Cardiovascular excitatory effects
of adenosine in the nucleus of the solitary tract.
Hypertension. 1991;18:494-502.
11. Tao S, Abdel-Rahman AA. Neuronal and cardiovascular responses to adenosine microinjection into the nucleus tractus solitarius. Brain Res Bull. 1993;32:407-417. [Medline] [Order article via Infotrieve]
12. Dolphin AC, Archer ER. An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus. Neurosci Lett. 1983;43:49-54. [Medline] [Order article via Infotrieve]
13. Phillis JW, Kostopoulos GK, Limacher JJ. Depression of corticospinal cells by various purines and pyrimidines. Can J Pharmacol. 1974;52:1226-1229.
14. Yamori Y. Physiopathology of the various strains of spontaneously hypertensive rats. In: Genest J, Kuchel O, Hamet P, Cantin M, eds. Hypertension: Physiopathology and Treatment. St Louis, Mo: McGraw-Hill Book Publishing Co Inc; 1983:556-581.
15.
Tseng CJ, Ger LP, Lin HC, Tung CS. Attenuated
cardiovascular response to adenosine in the
brain stem nuclei of spontaneously hypertensive rats.
Hypertension. 1995;25:278-282.
16. Adams LM, Foote SL. Effects of locally infused pharmacological agents on spontaneous and sensory-evoked activity of locus coeruleus neurons. Brain Res Bull. 1988;21:395-400. [Medline] [Order article via Infotrieve]
17. Shiekhattar R, Aston-Jones G. Local application of bicuculline potentiates NMDA-receptor mediated sensory responses of brain noradrenergic neurons. Synapse. 1992;10:54-61. [Medline] [Order article via Infotrieve]
18. Pellegrino LJ, Pellegrino AS, Cushman AJ. A Stereotaxic Atlas of the Rat Brain. 2nd ed. New York, NY: Plenum Press; 1979.
19. Kubo T, Kihara M. Evidence of N-methyl-D-aspartate receptor-mediated modulation of the aortic baroreceptor reflex in the rat nucleus tractus solitarii. Neurosci Lett. 1988;87:69-74. [Medline] [Order article via Infotrieve]
20.
Tseng CJ, Mosqueda-Garcia R, Appalsamy M, Robertson
D. Cardiovascular effects of neuropeptide Y in
rat brainstem nuclei. Circ Res. 1989;64:55-61.
21.
Martin SE, Tidmore WC, Patterson RE.
Adenosine receptor blockade with
8-p-sulfophenyltheophylline aggravates coronary
constriction. Am J Physiol. 1991;260:H1753-H1759.
22. Daly JW, Padgett W, Shamin MT, Butts-Lamb P, Waters J. 1,3-Dialkyl-8-(p-sulfophenyl) xanthines potent water-soluble antagonists for A1- and A2-adenosine receptors. J Med Chem. 1985;28:487-492. [Medline] [Order article via Infotrieve]
23. Kirk RE. Experimental Design: Procedures for the Behavioral Sciences. Belmont, Calif: Brooks/Cole Publishing Co; 1968.
24.
Ginsborg BL, Hirst GDS. The effect of
adenosine on the release of the transmitter from the phrenic
nerve of the rat. J Physiol (Lond). 1972;224:629-645.
25. Nishimura S, Mohri M, Okada Y, Mori M. Excitatory and inhibitory effects of adenosine on the neurotransmission in the hippocampal slices of guinea pig. Brain Res. 1990;525:165-169. [Medline] [Order article via Infotrieve]
26.
Tseng CJ, Chou LL, Ger LP, Tung CS.
Cardiovascular effects of angiotensin III
in brainstem nuclei of normotensive and hypertensive rats.
J Pharmacol Exp Ther. 1994;268:558-564.
27.
Mosqueda-Garcia R, Tseng CJ, Appalsamy M, Robertson
D. Cardiovascular effects of microinjection of
angiotensin II in the brainstem of renal hypertensive
rats. J Pharmacol Exp Ther. 1990;255:374-381.
28.
Tsuchihashi T, Abe I, Fujishima M. Role of
metabotropic glutamate receptors in ventrolateral medulla of
hypertensive rats. Hypertension. 1994;24:648-652.
29. Matias A, Zimmer FJ, Lorenzen A, Keil R, Schwabe U. Affinity of central adenosine A1 receptors is decreased in spontaneously hypertensive rats. Eur J Pharmacol. 1993;244:223-230. [Medline] [Order article via Infotrieve]
30. Barraco RA, Phillis JW. Subtypes of adenosine receptors in the brainstem mediate opposite blood pressure responses. Neuropharmacology. 1991;30:403-407. [Medline] [Order article via Infotrieve]
31. Albino-Teixeira A, Matias A, Polonia J, Azevedo I. Blockade of adenosine receptors causes hypertension and cardiovascular structural changes in the rat. J Hypertens. 1991;9:S196-S197.
32. Matias A, Albino-Teixeira A, Polonia J, Azevedo I. Long-term administration of 1,3-dipropyl-8-sulfophenylxanthine causes arterial hypertension. Eur J Pharmacol. 1991;193:101-104. [Medline] [Order article via Infotrieve]
33. Mosqueda-Garcia R, Tseng CJ, Beck CJ, McCormick M, Robertson D. Adenosine in central cardiovascular control. In: Kunos G, Ciriello J, eds. Central Neural Mechanisms in Cardiovascular Regulation. New York, NY: Springer Verlag; 1991:165-180.
34. Mosqueda-Garcia R, Tseng CJ, Biaggioni I, Robertson RM, Robertson D. Effects of caffeine on baroreflex activity in man. Clin Pharmacol Ther. 1990;48:568-574. [Medline] [Order article via Infotrieve]
35. Abdel-Rahman ARA. Differential effects of ethanol on baroreceptor heart rate responses of conscious spontaneously hypertensive and normotensive rats. Alcohol Clin Exp Res. 1994;18:1515-1522. [Medline] [Order article via Infotrieve]
36. Mao L, Nyce J, Abdel-Rahman ARA. Adenosine A1 receptor antisense oligodeoxynucleotide microinjected into the nucleus tractus solitarius attenuates baroreceptors in conscious rats. Circulation. 1994;90(suppl I):I-474. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  N. Nassar and A. A. Abdel-Rahman Brainstem Adenosine A1 Receptor Signaling Masks Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Dependent Hypotensive Action of Clonidine in Conscious Normotensive Rats J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 83 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nassar and A. A. Abdel-Rahman Central Adenosine Signaling Plays a Key Role in Centrally Mediated Hypotension in Conscious Aortic Barodenervated Rats J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 255 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ito, Y. Hirooka, N. Hori, Y. Kimura, Y. Sagara, H. Shimokawa, A. Takeshita, and K. Sunagawa Inhibition of Rho-Kinase in the Nucleus Tractus Solitarius Enhances Glutamate Sensitivity in Rats Hypertension, August 1, 2005; 46(2): 360 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Kitchen, T. J. Scislo, and D. S. O'Leary NTS A2a purinoceptor activation elicits hindlimb vasodilation primarily via a beta -adrenergic mechanism Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1775 - H1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Scislo and D. S. O'Leary Differential role of ionotropic glutamatergic mechanisms in responses to NTS P2x and A2a receptor stimulation Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2057 - H2068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Scislo and D. S. O'Leary Differential control of renal vs. adrenal sympathetic nerve activity by NTS A2a and P2x purinoceptors Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2130 - H2139. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||