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(Hypertension. 1995;25:278-282.)
© 1995 American Heart Association, Inc.

Articles

Attenuated Cardiovascular Response to Adenosine in the Brain Stem Nuclei of Spontaneously Hypertensive Rats

Ching-Jiunn Tseng; Luo-Ping Ger; Hui-Ching Lin; Che-Se Tung

From the Department of Medical Education and Research (C.-J.T., L.-P.G.), Kaohsiung Veterans General Hospital, Kaohsiung, and the Departments of Pharmacology (C.-J.T., H.-C.L.) and of Physiology and Biophysics (C.-S.T.), National Defense Medical Center, Taipei, Taiwan, Republic of China.

	Abstract

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Abstract We previously reported that adenosine has significant depressor effects in the nucleus tractus solitarii and area postrema of the rat. The purpose of this study was to determine whether the spontaneously hypertensive rat (SHR) has abnormalities in medullary sensitivity to adenosine. Male SHR and Wistar-Kyoto (WKY) rats (aged 12 to 15 weeks) were anesthetized with urethane, and blood pressure was monitored intra-arterially. Stereotaxic microinjection (60 nL) of adenosine was made into the nucleus tractus solitarii and the area postrema and was confirmed histologically. Dose-related decreases in mean blood pressure and heart rate occurred in both strains tested, and this effect was completely abolished by 1,3-dipropyl-8-p-sulfophenylxanthine (0.92 nmol), a potent adenosine receptor antagonist. However, there were significant differences between SHR and WKY rats in the magnitude of blood pressure and heart rate depression. A similar pattern of response was found in the area postrema. Thus, adenosine is a potent depressor agent in the nucleus tractus solitarii and area postrema of rats, and adenosine has significantly fewer depressor effects in SHR. These data suggest that alterations in purinergic mechanisms of central cardiovascular control exist in the SHR model.

Key Words: adenosine • rats, inbred SHR • rats, inbred WKY • brain stem

	Introduction

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Adenosine is a ubiquitous product in the metabolism of adenosine triphosphate.^{1 2} Specific receptors for adenosine have been found in the central nervous system (CNS) and modulate intracellular levels of cyclic AMP.^{3 4 5} CNS tissue levels of adenosine have been shown to increase during hypoxia and seizures.^{6 7} Adenosine inhibits the release of many neurotransmitters, including acetylcholine,^{8 9} norepinephrine,^{10 11} dopamine,¹² -aminobutyric acid, and glutamate,¹³ both in the CNS and in peripheral tissues. This substance also has a marked depressant action on the firing of neurons in virtually all CNS regions tested.^{14 15 16} Previously, we¹⁷ and others^{18 19 20} reported evidence that endogenous adenosine might play a role as a central modulator in cardiovascular regulation. Adenosine decreased blood pressure (BP) and heart rate (HR) in the brain stem of normotensive rats.^{17 20 21 22}

The presence of hypertension selectively modifies the responsiveness to different substances. Spontaneously hypertensive rats (SHR) are more sensitive to the central cardiovascular effects of catecholamines, opioids, and angiotensin II than are Wistar-Kyoto (WKY) rats.²³ On the other hand, the effects of neuropeptide Y or bradykinin are the same in both SHR and WKY rats. However, the sensitivity of SHR to the central effects of microinjected adenosine has not been explored.

In the present experiment, we compared the effects of adenosine injected in the area postrema (AP) and the nucleus tractus solitarii (NTS) of anesthetized SHR and WKY rats.

	Methods

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Male SHR and WKY rats (12 to 15 weeks old) were obtained from Charles River (Tokyo, Japan) and housed in the animal room of the National Defense Medical Center (Taipei, Taiwan, Republic of China). The rats were kept in individual cages in a room where the lighting was controlled (12 hours on, 12 hours off) and the room temperature was kept between 23° and 24°C. The animals were given Purina Laboratory Chow and tap water ad libitum.

A total of 30 SHR (n=15 for the NTS and n=15 for the AP study groups) and 30 WKY rats (n=15 for the NTS and n=15 for the AP study groups) were used in this study. Rats were anesthetized with urethane (1.0 g/kg IP supplemented with 300 mg/kg IV if necessary). A polyethylene cannula was placed in the femoral vein for administration of drugs. BP was measured directly through a cannula placed into the femoral artery and connected to a pressure transducer (P23 ID, Gould) and a polygraph (RS3800, Gould). HR was monitored continuously by a tachograph preamplifier (13-4615-65, Gould). Tracheostomy was performed to maintain airway patency during the experiment.

The rats were placed in a stereotaxic instrument (Kopf) with the head flexed downward at a 45° angle. The dorsal surface of the medulla was exposed by limited craniotomy, and the rats rested for at least 1 hour before experiments. For microinjections into the brain stem nuclei, single-barreled glass cannulas (0.031-inch outer diameter, 0.006-inch inner diameter; Richland Glass Co) with an external tip diameter of 40 µm were prepared. Each cannula was connected to a Hamilton microsyringe by polyvinyl tubing and was filled with L-glutamate (2.3 nmol per 60 nL to functionally identify the NTS, see below), sterile saline, or different doses of adenosine and adenosine antagonists. The cannula was lowered into the NTS with these coordinates: anteroposterior, 0.0 mm; mediolateral, 0.5 mm; and vertical, 0.4 mm, with the calamus scriptorius as reference. The coordinates for the AP were anteroposterior, +0.5 mm; mediolateral, 0.0 mm; and vertical, 0.2 mm.

During the experiment, the injection sites in the NTS area were confirmed by responsiveness to L-glutamate administration. A specific decrease in BP and HR has been demonstrated after microinjection of 2.3 nmol L-glutamate in the NTS.^{24 25} The response is restricted to the subpostremal NTS region,²⁶ and administration of the same dose of L-glutamate in areas adjacent to the NTS fails to elicit the response. To determine the cardiovascular effects of adenosine in different brain stem nuclei, increasing doses of adenosine were microinjected into either the NTS or AP of SHR and WKY rats at 30-minute intervals.¹⁷ Our previous experiences have indicated the lack of significant tachyphylaxis to repeated administration of adenosine at these time intervals. In agreement with our previous study^{27 28} and another report,²⁴ we did not observe significant effects on BP or HR after the administration of 60 nL sterile saline in either the NTS or AP; therefore, we used saline for the control experiments in this study.

After completion of the experiment, ink was injected through the cannula and the animals were perfused with saline followed by a solution of 4% formaldehyde and finally with a 30% sucrose solution. Sections (40 µm) of the brain stem were stained with cresyl violet, and proper placement of the pipette tip in the AP and NTS was verified by microscopic examination of the sections. A diagrammatic representation of some individual injection sites in the SHR is presented in Fig 1.

View larger version (23K): [in this window] [in a new window]   Figure 1. Diagrammatic representations of some individual injection sites in the brain stem nuclei of spontaneously hypertensive rats. A, Coronal section 14.08 caudal to the bregma. B, Coronal section 13.68 caudal to the bregma. Arrowheads indicate sites of injections into nucleus tractus solitarii or area postrema. Maps and coordinates (from bregma) are taken from the atlas of Paxinos and Watson.29 Gr indicates gracile nucleus; Sol, nucleus tractus solitarius; 12, hypoglossal nucleus; Sp5, spinal trigeminal tract; LRN, lateral reticular nucleus; ION, inferior olive nucleus; Cu, cuneate nucleus; AP, area postrema; and 12n, root of hypoglossal nerve.

Drugs for microinjection were dissolved so that the desired amount of drug was contained in 60 nL. The following drugs were used: urethane (Aldrich Chemical Co), L-glutamic acid, adenosine (Sigma Chemical Co), and 1,3-dipropyl-8-p-sulfophenylxanthine ([DPSPX] RBI).

For statistical analysis, the difference in mean BP (MBP) or HR after administration of different doses of adenosine in the SHR group (or in the WKY rat group) was tested by repeated-measures ANOVA. When the repeated-measures ANOVA revealed a statistical difference, the residual mean square was applied in Dunnett's test to characterize which values were statistically different from the vehicle control (saline). Group differences between SHR and WKY rats were analyzed by unpaired t test, and group differences between administration of adenosine and prior administration of DPSPX in the same group were analyzed by paired t test. All null hypotheses were two tailed, and a value of P<.05 was considered significant. All data are presented as mean±SEM.

	Results

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SHR were hypertensive at the time of the experiment. Basal systolic and diastolic BP and MBP of the SHR differed from BP values in WKY rats. In the SHR group, systolic BP was 172±9 mm Hg, diastolic BP was 82±8 mm Hg, and MBP was 112±8 mm Hg, with an HR of 326±14 beats per minute (n=15). In the WKY rat group, values of 123±5 mm Hg, 57±4 mm Hg, 79±4 mm Hg, and 332±12 beats per minute were observed for systolic and diastolic BP, MBP, and HR, respectively (n=15).

Similar to results in our previous experiments, microinjection (60 nL) of adenosine (0, 0.07, 0.23, 0.7, and 2.3 nmol) in the NTS produced a dose-related decrease in MBP (F_4,56=7.62 for SHR and F_4,56=9.83 for WKY rats; P<.01) and HR (F_4,56=8.24 for SHR and F_4,56=12.42 for WKY rats; P<.01) in both the SHR and WKY rats (Fig 2). Maximal changes occurred 90 seconds after injection. However, there was a significant difference in the cardiovascular effects of adenosine between these two strains of rat. The depressor and bradycardic effects observed in the SHR were significantly less pronounced than in the WKY rats. Similarly, microinjection of adenosine in the AP in both SHR and WKY rats produced dose-related depressor (F_4,56=5.67 for SHR and F_4,56=7.94 for WKY rats; P<.01) and bradycardic (F_4,56=8.22 for SHR and F_4,56=10.64 for WKY rats; P<.01) effects (Fig 3), and the responses in SHR were significantly less pronounced than in WKY rats.

View larger version (15K): [in this window] [in a new window]   Figure 2. Line graphs show comparative effects of increasing doses of adenosine on mean blood pressure (MBP) and heart rate (HR) after unilateral injection into the nucleus tractus solitarii in both anesthetized spontaneously hypertensive rats (SHR, n=15) and Wistar-Kyoto (WKY) rats (n=15). *P<.01 by unpaired two-tailed t test.

View larger version (16K): [in this window] [in a new window]   Figure 3. Line graphs show comparative effects of increasing doses of adenosine on mean blood pressure (MBP) and heart rate (HR) after unilateral injection into the area postrema in both anesthetized spontaneously hypertensive rats (SHR, n=15) and Wistar-Kyoto (WKY) rats (n=15). *P<.01 by unpaired two-tailed t test.

The Table compares the cardiovascular effects of microinjection of adenosine unilaterally into the NTS of SHR and WKY rats. Microinjection of 0.7 nmol adenosine into the NTS elicited a significantly different response in MBP and HR for SHR compared with WKY rats (n=15, P<.01).

View this table: [in this window] [in a new window]   Table 1. Cardiovascular Effects of Adenosine Unilaterally Microinjected Into the NTS of SHR and WKY Rats

To determine the specific effect of adenosine, we used a potent and specific adenosine receptor antagonist, DPSPX (0.92 nmol). The injection of the antagonist itself into the NTS had no effect on BP or HR. However, the antagonist abolished the effect of further injections of adenosine into the NTS (Figs 4 and 5). Similar effects of DPSPX on the depressor and bradycardic effects of adenosine in the AP were noted (Fig 6).

View larger version (14K): [in this window] [in a new window]   Figure 4. Representative tracings of cardiovascular effects of unilateral injection of adenosine (ADO, 2.3 nmol) into the nucleus tractus solitarii before and after 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX, 0.92 nmol) in both anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. ADO and DPSPX were injected at the indicated time points. Blood pressure (B.P.) and heart rate (H.R.) recordings were made at a paper speed of 5 mm/min. Horizontal bar represents recording during 2 minutes.

View larger version (17K): [in this window] [in a new window]   Figure 5. Bar graphs show comparative mean blood pressure (MBP) and heart rate (HR) effects of adenosine (ADO, 2.3 nmol) injected into the nucleus tractus solitarii before and after administration of 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX, 0.92 nmol) in both spontaneously hypertensive rats (SHR, n=15) and Wistar-Kyoto (WKY) rats (n=15). *Significant difference (P<.001 by paired t test) before and after administration of DPSPX. Significant change (P<.01 by unpaired t test), SHR vs WKY rats.

View larger version (19K): [in this window] [in a new window]   Figure 6. Bar graphs show comparative mean blood pressure (MBP) and heart rate (HR) effects of adenosine (ADO, 2.3 nmol) injected into the area postrema before and after administration of 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX, 0.92 nmol) in both spontaneously hypertensive rats (SHR, n=15) and Wistar-Kyoto (WKY) rats (n=15). *Significant (P<.001 by paired t test) difference before and after administration of DPSPX. Significant change (P<.01 by unpaired t test), SHR vs WKY rats.

	Discussion

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SHR have been used as a model of human essential hypertension for many years.²⁴ Although much has been learned about the etiology of the BP abnormality in these rats, no definitive cause has been identified. It is therefore of interest to study differences in BP control in response to various interventions.

We and others^{17 20 21 22 30} have been interested in purinergic mechanisms of BP regulation and have shown that substantial effects are exerted by adenosine on the brain stem in the afferent fibers impinging on cardiovascular regulatory sites^{22 31} and on sympathetic outflow.³² The effect of centrally administered adenosine on BP control in SHR compared with WKY rats remains to be explored.

The development of hypertension in SHR has been shown to alter the response to a number of centrally administered substances.^{23 30} As reported thus far, the alteration has usually been an increased response to either pressor or depressor substances in hypertensive rats compared with normotensive rats. This may be because SHR have a higher pressure, and hence a given fractional fall in BP is larger in absolute terms. Therefore, the administration of adenosine, a potent depressor and bradycardic substance, into the NTS of SHR might have been expected to cause increased depressor effects, indicating an important role for adenosine in the regulation of basal tone.

In our experimental model, however, the fall in BP after stereotaxic administration of adenosine into the NTS was less in SHR than in WKY rats, no matter whether the BP change was seen in terms of either absolute or relative alteration. This decreased response to adenosine compared with normotensive rats may suggest an alteration in adenosine receptor sensitivity and is consistent with the findings of Matias et al,³³ who showed a decreased response on the basis of saturation and competition studies with brain membranes from SHR and WKY rats. They provided biochemical evidence for alterations in the adenosine A₁ receptor in hypertensive animals, possibly induced by a defective G protein or altered coupling between G protein and adenosine A₁ receptors. The adenosine depressor system may thus play a lesser role in the tonal regulation of BP in SHR compared with the normotensive WKY rats. An alternative explanation, based on the findings of Barraco and Phillis,³⁴ is that adenosine pressor A₁ and depressor A₂ receptors might exist in different ratios in SHR.

Another possible explanation for these findings may be a desensitization effect. If there is already a large amount of adenosine present in the NTS, this would cause downregulation of the receptors. Indeed, a recent report suggests that this may be the case. Conscious SHR with established hypertension had significantly higher levels of plasma adenosine compared with normotensive WKY rats, possibly as a compensation mechanism against hypertension.³⁵ Although the source of the increased adenosine is unknown, the investigators speculate that its origin is the vascular endothelium. Therefore, the experimental addition of more adenosine might have a reduced effect if baseline levels were raised to begin with.

The findings in this and the other studies mentioned lend support to the view that adenosine mechanisms are altered in SHR. Whether this effect is primary or in some way secondary to other changes in SHR remains unknown.

	Acknowledgments

 
This work was supported by NSC 81-0412-B-016-142 and NSC 81-0420-B-016-583 to Ching-Jiunn Tseng and Che-Se Tung. We thank Drs David Robertson and Chok-Yung Chai for valuable discussion of this manuscript.

	Footnotes

 
Reprint requests to Ching-Jiunn Tseng, MD, PhD, Department of Medical Education and Research, Veterans General Hospital–Kaohsiung, 386, Ta-Chung 1st Rd, Kaohsiung, Taiwan, Republic of China.

Received October 28, 1993; first decision November 3, 1993; accepted October 4, 1994.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tseng, C.-J. Articles by Tung, C.-S. Search for Related Content PubMed PubMed Citation Articles by Tseng, C.-J. Articles by Tung, C.-S.