ORIGINAL ARTICLE
Altered nitroxidergic and NMDA receptor-mediated
modulation of baroreflex-mediated heart rate in
obese Zucker rats
Jwo-Sheng Chen
1, Hui-Ju Wang
1, Weng-Cheng Chang
2, Chin-Ci Jao
3, Bor-Tsang Wu
4,7, Woei-Cherng Shyu
5,7and Shin-Da Lee
4,6,7Arterial baroreflex, an important physiological regulatory system for buffering systemic blood pressure, is impaired in obesity. This study investigated whether the blunted baroreflex function in obesity is attributed to the altered nitroxidergic or N-methyl-D
-aspartate (NMDA) mechanism. Baroreflex bradycardia responses, blood pressure and heart rate in 30 lean and 30 obese anesthetized Zucker rats (8–12 weeks of age) were assessed after injecting phenylephrine with intravenous preadministration of saline (control), dextromethorphan (DXM, NMDA receptor antagonist, 10 mg kg1) or N(G)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 100 mg kg1). Compared with lean rats (2.00±0.29 b.p.m. mm Hg1), the baroreflex sensitivity (BRS) in obese rats (–0.43±0.05 b.p.m. mm Hg1) was significantly blunted. The BRS was significantly suppressed by DXM in
lean rats but not in obese rats. After administration ofL-NAME, BRS was significantly suppressed in lean Zucker rats but not in
obese Zucker rats. The normal BRS was significantly suppressed in lean rats after administration of both DXM andL-NAME, and
the blunted BRS in obesity was significantly blocked to nearly no BRS after administration of both DXM andL-NAME. This study
suggests that BRS is blunted in obese rats and that blunted baroreflex is, at least in part, attributed to altered nitroxidergic or NMDA receptor-mediated modulation.
Hypertension Research (2010) 33, 932–936; doi:10.1038/hr.2010.109; published online 17 June 2010 Keywords: baroreceptor; blood pressure; glutamate; heart rate; nitric oxide
INTRODUCTION
Baroreflex has an important role in maintaining cardiovascular home-ostasis through a negative feedback loop that regulates blood pressure levels and heart rate (HR).1–2 The baroreflex response is typically initiated by changes in blood pressure or volume that stimulate arterial baroreceptors located in the carotid sinus and aortic arch.1 The impulses triggered by arterial baroreceptors are propagated through the glossopharyngeal and vagus nerves to the nucleus tractus solitarii of the medulla, resulting in inhibition of the sympathetic system and activation of the parasympathetic system.3–4
Baroreflex sensitivity (BRS) has often been reported to be impaired or reduced in normotensive obese subjects,5hypertensive patients with
central obesity,6 obese women,7 young and older obese men,8 and obese patients with metabolic syndrome.9The underlying mechanism
of baroreflex attenuation in obesity is not yet well known; however, there is increasing evidence that it is at least partly related to autonomic nervous system dysfunction and particularly to the sympathetic overactivity that accompanies obesity.10The obese Zucker
rat, a genetic model of morbid obesity, presents many of the same deficits as those noted in obese humans, including hypertension,11
cardiac remodeling,12 impaired baroreflex,13 impaired
chemo-response14–16and poor exercise capacity.17–18Enhanced central sympa-thetic discharge, abnormal hemodynamics and attenuated BRS were found in obese Zucker rats.19–20Even normotensive, obese Zucker rats have impaired chronotropic baroreflexes.20 The blunted baroreflex
may contribute to initial blood pressure elevation and further cause hypertension in obesity.20–21 It is important to note that reduced
baroreflex sensitivity, which is common in obesity, may contribute to the increased risk of cardiovascular disease and represents a negative prognostic factor in cardiovascular diseases.7,9
Neurotransmission or neuromodulation has a crucial role in the processing of neural signals for coordinating arterial baroreflex control.22The neuromodulatory effect of nitroxidergic and glutama-tergic transmission has been reported to be involved in baroreflex regulation.23–24 The N-methyl-D-aspartate (NMDA)-mediated
mec-hanism has an important role in the mecmec-hanism of baroreflex.23
Received 27 September 2009; revised 13 April 2010; accepted 25 April 2010; published online 17 June 2010
1Department of Sports Medicine, China Medical University, Taichung, Taiwan;2Graduate Institute of Medical Science, Chang Jung Christian University, Tainan, Taiwan;3Graduate
Institute of Medical Science, China Medical University, Taichung, Taiwan;4Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University,
Taichung, Taiwan;5Department of Neurology and Graduate Institute of Immunology, Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan and 6Department of Healthcare Administration, Asia University, Taichung, Taiwan
7These authors contributed equally to this work.
Correspondence: Professor, S-D Lee, Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, 91 Hsueh-Shih Road, Taichung 40202, Taiwan.
The gain of baroreflex bradycardia is reduced by the microinjection of NMDA receptor antagonists.25A previous study suggested that nitric oxide (NO) has a physiologically significant neuromodulatory role in baroreflex regulation.24
Adult obese Zucker rats have elevated sympathetic vasomotor tone and arterial pressure and blunted sympathetic baroreceptor reflexes compared with adult lean Zucker rats.13Our previous studies indicate
that altered glutamatergic mechanisms exerting an effect on NMDA receptors, as well as nitroxidergic mechanisms, are partially respon-sible for blunted chemoresponses in obese Zucker rats.15,26
Whether the abnormal BRS observed in obese Zucker rats is associated with altered NMDA receptor-mediated modulation and/or nitroxidergic modulation has not been previously studied. We hypothesized that the altered BRS in obese Zucker rats is mediated by altered glutamatergic NMDA and nitroxidergic modulation. We used dextromethorphan (DXM), a noncompetitive NMDA receptor antagonist, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric
oxide synthase inhibitor, to investigate whether downregulated endogenous glutamate and NO modulate BRS in obese Zucker rats. A parallel study design was used, with age-matched wild-type lean Zucker rats serving as controls.
METHODS Animals
The studies were conducted on 30 obese (fa/fa) and 30 age-matched lean wild-type (Fa/Fa or Fa/fa) male Zucker rats. Animals were bred using female (Fa/fa) and male (Fa/fa) breeders purchased from the Charles River Lab in France (Charles River Lab, L’Arbresle, France). One lean and one obese rat were studied at the same age (approximately 8–12 weeks old) and on the same day. Ambient temperature was maintained at 25 1C and the animals were kept on an artificial 12-h light–dark cycle. The light period began at 0700 hours. Rats were provided with standard laboratory chow (Lab Diet 5001; PMI Nutrition International, Brentwood, MO, USA) and water ad libitum. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, Taichung, Taiwan.
Surgical preparation
All rats were anesthetized with a-chloralose–urethane (initial dose 50 mg kg1 a-chloralose and 500 mg kg1urethane, Sigma Chemical, St Louis, MO, USA) dissolved in distilled water and injected intraperitoneally. Adequate anesthesia was administered by infusion of 10 mg kg1 a-chloralose and 100 mg kg1
urethane (intravenously), when needed. The disappearance of pedal reflexes indicated adequate anesthesia. The rat was placed supine on a small table and secured by tying its four limbs. A middle incision was made in the neck region. The pretracheal muscle was retracted to expose the trachea and a transverse incision was made between two rings. A cannula was introduced into the opening to allow free breathing without obstruction. The temperature of the rat’s hot pad was maintained at 35–36 1C. The left femoral artery was exposed and a polyethylene catheter (PE50, Becton Dickinson, Sparks, MA, USA) filled with heparin solution (500 IU ml1, v/v) was inserted into the artery through a
small incision to record arterial blood pressure. The catheters were attached to a 23-gauge needle connected by a three-way stopcock to a pressure transducer. Femoral veins of both limbs were cannulated to inject drugs.
Arterial blood pressure and HR recording
Before recording arterial blood pressure, the catheter was flushed with heparinized saline solution (500 IU ml1, v/v) to prevent the formation of
blood clots, which might interfere with the normal recording of arterial blood pressure. The blood pressure recording system was calibrated with the help of a mercury manometer before each experiment. Arterial blood pressure was monitored continuously using a cannula inserted into the femoral artery and connected by a pressure transducer (model P23-ID, Gould Instruments, Cleveland, OH, USA). The signals recorded from the pressure transducer were amplified with a pressure processor amplifier (Gould 20-4615-52). The
amplified signals were recorded on a PowerLab acquisition system (AD Instruments, Colorado Springs, CO, USA). Blood gases and pH were moni-tored for the arterial blood sample, which was analyzed using a blood gas analyzer (Rapidlab 348, Bayer, Medfield, MA, USA) in the beginning and after the final recording, and were within normal limits. Arterial blood pressure was measured after a 20-min stabilization period. Systolic, diastolic, mean arterial pressure and HR were recorded on the PowerLab data acquisition system (4SP, AD Instruments, Castle Hill, Australia) with a computerized analysis program.
Measurement of BRS
BRS was measured by administering vasoconstrictor phenylephrine (750–1500 ng salt per 100 g body weight per min) for 1 min through a venous catheter. The resultant changes in HR at the corresponding rise in systolic blood pressure of approximately 30–40 mm Hg were measured continuously. The relationship between the increase in systolic blood pressure evoked by phenylephrine and associated bradycardia was assessed by the ratio of peak change in HR to peak change in mean blood pressure (MBP) for the individual animal. BRS regression (several points of MBP and HR) was carried out for most of the lean and obese Zucker rats for the purpose of calibration before or after the experimental protocol. We plotted BRS regression to confirm the ratio of peak change in HR to peak change in MBP when given a single phenyl-ephrine administration.
Experimental protocol
After surgical preparation and calibration, one lean and one obese Zucker rat on the same day using BRS as the baseline at 10 min after the infusion of saline (control). After the complete recovery of blood pressure and HR in 30 min, the BRS of rats was determined again 10 min after the infusion of DXM (10 mg kg1) or L-NAME (10 mg kg1) through the vein. After complete recovery of blood pressure and HR in another 30 min, baroreflex sensitivities in rats were reassessed 10 min after the infusion ofL-NAME (10 mg kg1) or DXM (10 mg kg1) through the vein to observe the effect of DXM plus L-NAME. All solutions were prepared daily. To minimize potential differences,
each rat was tested at approximately the same time during the day. The experimental protocol for BRS with the infusion of DXM (n¼20) and then with the addition ofL-NAME is as follows:
BRS DXM BRS (DXM)+L-NAME BRS Saline
10min 30min 10min 30min 10min
The experimental protocol for BRS with the infusion ofL-NAME (n¼10)
and then with the addition of DXM is as follows:
BRS L-NAME BRS (L-NAME)+DXM BRS
Saline
10min 30min 10min 30min 10min
Statistical analysis
The body weights of lean and obese Zucker rats were averaged in all experiments, and differences between the two groups were tested by unpaired Student’s t-test. The other parameters (MBP, HR, body temperature, DHR/DMBP) were analyzed by analysis of variance using the general linear model in a one-between (lean and obese) and one-within (saline and drug) design. Differences in BRS-related parameters among saline (control), DXM,L-NAME and DXM plusL-NAME
were subsequently tested as single-group repeated measures with contrast transformation against control in lean or obese Zucker rats, separately. The contrast transformation is useful when one level of the repeated measures is a control level (saline) against the other level (DXM,L-NAME or DXM plus L-NAME). In all cases, Po0.05 was considered statistically significant. All data
presented in the text, tables and figures are means±s.e.m.
RESULTS
Body weights in obese Zucker rats were significantly higher than those in lean rats (Table 1). Body temperature, MBP and HR of the lean and
obese groups did not differ (Table 1). Body temperature, MBP and HR did not change after DXM infusion for either the lean or the obese Zucker rats (Table 2). Body temperature and HR did not change after
L-NAME or DXM plusL-NAME infusion for either the lean or the
obese Zucker rats. MBP in obese Zucker rats was significantly increased after L-NAME or DXM plus L-NAME infusion, but this
change was not found in lean rats (Table 2).
BRS stimulated by phenylephrine in obese Zucker rats was sig-nificantly reduced compared with lean rats (Figure 1). BRS was significantly reduced after DXM infusion in lean but not in obese Zucker rats (Figure 2). BRS was significantly reduced afterL-NAME infusion in lean but not in obese Zucker rats (Figure 3). BRS was significantly suppressed in lean rats after infusing both DXM and
L-NAME. The blunted BRS in obesity was significantly blocked to
nearly no BRS after administration of both DXM and L-NAME
(Figure 4). Representative changes in BRS in lean and obese Zucker rats after vehicle (control), DXM infusion, L-NAME infusion and
coexistent DXM andL-NAME infusion were shown in Figure 5. DISCUSSION
Our findings can be summarized as follows: (1) The phenylephrine-induced BRS-mediated HR reduction in obese Zucker rats was significantly blunted compared with that in lean rats. (2) BRS was significantly suppressed by DXM in lean rats but not in obese Zucker rats. (3) After infusion ofL-NAME, the BRS was significantly
sup-pressed in lean but not in obese Zucker rats. (4) BRS was significantly suppressed in lean rats after infusion of both DXM and L-NAME, whereas the blunted BRS in obese Zucker rats was suppressed to nearly no BRS after infusion of both DXM andL-NAME. Our findings imply
that the blunted BRS in obesity is, at least in part, attributed to altered nitroxidergic or NMDA receptor-mediated modulation.
Glutamate, an excitatory neurotransmitter, has an important role in the central mechanisms of baroreflex sensitivity.27–28Glutamate
acti-vates ionotropic NMDA (N-methyl-D-aspartate) and non-NMDA
Table 2 Basic characteristics, blood pressure, and heart rate in lean and obese Zucker rats before and after DXM,L-NAME and DXM plus L-NAME administration
DXM
Lean (n¼20) Obese (n¼20)
n Before After Before After
BW (g) 160±9 240±15* BT (1C) 35.6±0.6 35.4±0.3 35.8±0.6 35.7±0.5 MBP (mm Hg) 107±2 102±4 103±5 102±6 HR (b.p.m.) 358±9 333±22 326±16 319±19 L-NAME Lean (n¼10) Obese (n¼10)
n Before After Before After
BW (g) 170±8 230±12* BT (1C) 36.3±0.5 36.2±0.4 36.8±0.6 36.9±0.5 MBP (mm Hg) 114±8 127±11 110±5 145±3# HR (b.p.m.) 280±17 248±11 272±7 268±15 L-NAME+DXM or DXM+L-NAME Lean (n¼30) Obese (n¼30)
n Before After Before After
BW (g) 163±8 236±14*
BT (1C) 35.5±0.6 35.4±0.8 35.6±0.8 35.6±0.6 MBP (mm Hg) 114±7 120±10 112±5 125±4#
HR (b.p.m.) 340±15 314±13 302±10 278±11 Abbreviations: BT, body temperature; BW, body weight; DXM, dextromethorphan;L-NAME, N(G)-nitro-L-arginine methyl ester; HR, heart rate, n, number of subjects; MBP, mean blood pressure. Data presented as mean±s.e.
*Po0.05, significant difference between lean rats and obese Zucker rats.
#Po0.05, significant difference between the values before (that is, vehicle) and after drug (that
is, DXM,L-NAME, or DXM plusL-NAME) infusion.
-3 -2 -1 0 Lean Obese BRS (bpm /mmHg) ∗∗ b a 175 150 125 100 75 MABP (mmHg) 350 300 250 200 150 HR (bpm) PE PE Obese Lean
Figure 1 (a) Representative changes in MBP and HR in lean and obese Zucker rats after phenylephrine (PE) injection. (b) Average BRS in lean and obese Zucker rats (n¼30, 30, respectively). **Po0.01; significant difference between lean rats and obese Zucker rats.
Table 1 Basic characteristics, blood pressure and heart rate in lean and obese Zucker rats
Lean (n¼30) Obese (n¼30)
BW (g) 162±6 225±11**
BT (1C) 35.3±0.4 35.4±0.3
MBP (mm Hg) 108±2 105±4
HR (b.p.m.) 350±14 323±12
Abbreviations: BT, body temperature; BW, body weight; HR, heart rate; MBP, mean blood presure; n, number of the participants.
Data presented as mean±s.e.
(a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate) receptors, as well as metabotropic receptors, all of which have been shown to be involved in the modulation of BRS.27–29 Studies have
found that the NMDA and NO modulation processes of chemore-ceptor reflexes are impaired in obese Zucker rats15,26and the
chemor-eceptor reflex control interacts with baroreflex.30 A previous study
showed that the gain of the baroreflex-mediated bradycardia is reduced by the microinjection of NMDA receptor antagonists into the nucleus tractus solitarii.25In this study, the baroreflex-mediated
bradycardia was remarkably reduced by the intravenous infusion of DXM in lean rats but not in obese Zucker rats. The present finding that NMDA-mediated modulation of baroreflex was blunted in obese but not in lean Zucker rats implies that this altered NMDA-mediated modulation of baroreflex might, at least in part, be attributed to obesity in these animals.
A previous study indicated that the inhibition of nitric oxide synthase within the nucleus tractus solitarii attenuated baroreflex, suggesting that NO might have a physiologically significant neuro-modulatory role in baroreflex regulation.24In this study, the
baro-reflex-mediated bradycardia was remarkably reduced by intravenous infusion of L-NAME in lean rats but not in obese Zucker rats.
The findings based on the effects of nitric oxide synthase inhibitor in lean and obese Zucker rats implied that NO-mediated baroreflex bradycardia was normally modulated by endogenous NO in lean rats,
-3 -2 -1 0 Lean Obese BRS (bpm /mmHg) Control DXM ∗∗∗
Figure 2 Average BRS in lean and obese Zucker rats (n¼10, 10, respectively) after vehicle (control) or DXM infusion. ***Po0.001; significant difference between vehicle (control) and DXM.
-3 -2 -1 0 Lean Obese BRS (bpm /mmHg) Control L-NAME ∗∗∗
Figure 3 Average BRS in lean and obese Zucker rats (n¼20, 20, respectively) after vehicle (control) or L-NAME infusion. ***Po0.001; significant difference between vehicle (control) andL-NAME.
Figure 5 Representative changes in MBP and HR in lean and obese Zucker rats after phenylephrine (PE) injection after vehicle (control), DXM infusion,
L-NAME infusion and coexistent DXM andL-NAME infusion.
-3 -2 -1 0 Lean Obese BRS (bpm /mmHg) Control DXM+L-NAME ∗ ∗∗∗
Figure 4 Average BRS in lean and obese Zucker rats (n¼30, 30, respectively) after vehicle (control) or coexistent DXM andL-NAME infusion. *Po0.05, ***Po0.001; significant difference between vehicle (control) and DXM plusL-NAME.
whereas nitroxidergic modulation of baroreflex in obesity was blunted. The altered nitroxidergic modulation might, at least in part, be attributed to the blunted BRS in obesity.
The activation of glutamatergic receptors in the brain or NTS elicits the production and release of NO and other neurotransmitters or neuromodulators.31 The release of NO facilitates glutamatergic
transmission in the brain or NTS and induces NMDA receptor activation.24,31 The interaction of glutamatergic and nitroxidergic
modulation regulates baroreflex-mediated heart rate.24,31 In this study, the blunted BRS in obesity was significantly blocked to nearly no BRS after administration of both DXM andL-NAME. The findings suggest that the blunted BRS in obesity was mediated by the coeffects of NO and NMDA.
Furthermore, potential interactions among obesity, anesthetic agents and experimental drugs, and potential interactions between chemo-reflexes and barochemo-reflexes, may affect our results. Although there are interactions between peripheral chemoreflexes and baroreflexes in animals and humans,32–33to our knowledge, the interactions between chemoreceptor reflexes and baroreflexes in obese Zucker rats remain
unknown. Thus, any effect noted herein after DXM or L-NAME
infusion may be caused by indirect factors and could not be localized to a specific location or system. The purpose of this study, however, was to determine whether downregulated glutamatergic or nitroxidergic modulation is generally responsible for the blunted BRS in obesity. Significance
Arterial baroreceptors have important roles in the short-term regula-tion of arterial pressure through reflex chronotropic effects on the heart and in the reflex regulation of sympathetic outflow to the vessels.10Blunted BRS in obese animals and humans also represents a
negative prognostic factor in cardiovascular diseases and may lead to long-term cardiovascular mortality.7,34The development of blunted
BRS in obesity is insidious and may often be overlooked because patients are typically free of complaints. Our current finding that the blunted BRS in obese Zucker rats is, at least in part, attributed to altered nitroxidergic or NMDA receptor-mediated modulation provides a possible explanation for the development of blunted BRS in obesity. Clinically, when considering possible therapeutic agents to control or prevent the development of blunted BRS in obesity, special attention should be paid to the actions of glutamatergic and nitrox-dergic modulation on baroreflex responses in morbidly obese humans. ACKNOWLEDGEMENTS
This study is supported in part by the Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH99-TD-B-111-004), by the National Science Council (NSC98-2314-B-039-002) and by China Medical University (CMU98-CT-23).
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