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1 Department of Physiology, Kagawa Medical University, Kagawa, Japan; 2 Department of Physiology, Gifu University School of Medicine, Gifu, Japan; and 3 Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha, Nebraska 68198-4575
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In previous studies we used NG-nitro-L-arginine (L-NNA) to investigate the role of nitric oxide (NO) in baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). L-NNA increased resting mean arterial pressure (MAP), decreased HR, and did not change or slightly decreased RSNA. These changes complicated the assessment of the central effects of NO on the baroreflex control of HR and RSNA. Therefore, in the present study the effects of the relatively selective neuronal NO synthase inhibitor 7-nitroindazole (7-NI) on the baroreflex control of HR and RSNA were investigated in rabbits. Intraperitoneal injection of 7-NI (50 mg/kg) had no effect on resting HR, MAP, or RSNA. 7-NI significantly reduced the lower plateau of the HR-MAP baroreflex curve from 140 ± 4 to 125 ± 4 and from 177 ± 10 to 120 ± 9 beats/min in conscious and anesthetized preparations, respectively (P < 0.05). In contrast, there was no significant difference in the RSNA-MAP curves before and after 7-NI administration in conscious or anesthetized preparations. These data suggest that blockade of neuronal NO synthase influences baroreflex control of HR but not of RSNA in rabbits.
sympathetic nerve activity; vagus; arterial pressure
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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NITRIC OXIDE (NO) is synthesized from L-arginine via the enzyme NO synthase (NOS) (24). At least three isoforms of NOS exist: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (1, 3). eNOS mainly exists in endothelial cells and plays an important role in vasodilation (25). nNOS exists in large quantities in brain, spinal cord, sympathetic ganglia (28), and kidney. Therefore, it is conceivable that the majority of NO in the brain is synthesized by the action of nNOS. Because NO was identified as the endothelium-derived relaxing factor, there has been a vast amount of evidence suggesting that NO modulates the autonomic nervous system via central sites such as the nucleus tractus solitarius (10, 19, 29), the area postrema, the rostroventrolateral medulla (14, 32), and the caudal ventrolateral medulla (13, 30). In a previous study we demonstrated that inhibition of NO synthesis by NG-nitro-L-arginine (L-NNA) enhances the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). Clear evidence was provided for a central locus of action in this study (18). Systemic administration of L-NNA resulted in a significant and profound decrease in resting HR. L-NNA is a nonspecific inhibitor of NOS; 7-nitroindazole (7-NI) is a relatively selective nNOS inhibitor (22, 23). It has been shown that 7-NI administered at 50 mg/kg decreased NOS activity within the forebrain to 45% after 30 min (33). 7-NI allowed us to provide further evidence for a role of nNOS in the control of baroreflex function and thereby the control of sympathetic nerve activity.
Therefore, the aim of present study was to determine whether blockade of nNOS by 7-NI affects the baroreflex control of HR and RSNA. These experiments were carried out in conscious and anesthetized rabbits.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Twenty-five New Zealand White rabbits (2.5-3.5 kg) were divided into groups: a normal unblocked group, an atropine-pretreated group, and a metoprolol-pretreated group. The experiments in these three groups were carried out under general anesthesia (see below). A fourth group was examined in the conscious state. All rabbits were fed and housed according to guidelines of the University of Nebraska Medical Center and at Kagawa Medical University. The studies were approved by the University of Nebraska Medical Center Institutional Animal Care and Use Committee and conform to the "Guiding Principles for the Use and Care of Laboratory Animals" of the American Physiological Society and National Institutes of Health guidelines.
Surgical Procedures
Rabbits were anesthetized with
-chloralose (70 mg/kg iv) and urethan
(700 mg/kg iv). An arterial catheter was inserted into the aorta via a
femoral artery to record arterial pressure and measure blood gases, and
a venous catheter was inserted into the inferior vena cava via a
femoral vein to inject drugs during the experiment. A 5-Fr Tygon
catheter was introduced into the abdomen to infuse 7-NI
intraperitoneally. A left renal sympathetic nerve was isolated through
a left flank incision, and RSNA was recorded. For conscious
experiments, an anesthetic cocktail consisting of ketamine
hydrochloride (Ketaset, Fort Dodge Laboratories, Fort Dodge, IA; 58.8 mg/kg), acepromazine maleate (Fermenta Animal Health, Kansas City, MO;
1.2 mg/kg), and xylazine (Rompun, Miles, Shawnee Mission, KS; 5.9 mg/kg) in lactated Ringer solution was given by intramuscular injection
(1 ml/kg), then the rabbits were chronically instrumented for recording
of RSNA. For supplemental anesthesia, pentobarbital sodium (Abbott
Laboratories, North Chicago, IL; 0.3-0.35 mg/kg) was injected
intravenously via a marginal ear vein. The left renal sympathetic
nerves were exposed through a flank incision using a retroperitoneal
approach. The renal nerves were dissected from the surrounding tissue
and renal artery. A pair of Teflon-coated stainless steel wire
electrodes (A-M Systems, Everett, WA; 0.125 mm OD) were placed around
the dissected renal nerves. To insulate the electrodes and the nerve
from the surrounding tissue and to prevent the nerves from desiccation,
the electrodes and the nerve assembly were covered with a two-component
silicone gel (Wacker Sil-Gel, Munich, Germany). The electrodes were
tunneled beneath the skin to the back and fixed between the shoulder
blades. The flank incision was closed. Postoperatively, the rabbits
were placed on an antibiotic regimen for 3 days (tylosin, Elano Animal Health, Indianapolis, IN; 5 mg/kg im). In addition, a chronic intraperitoneal catheter was implanted for administration of 7-NI. An
arterial and a venous catheter were inserted at the time of the
experiment, as described below.
Data Acquisition
The arterial catheter was connected to a pressure transducer (Hewlett-Packard) to measure mean arterial pressure (MAP). HR was determined using a Honeywell cardiotachometer that was triggered by the arterial pressure pulse. RSNA was recorded by preamplifying the signal using a Grass P16 preamplifier with the band-pass filters set between 100 Hz and 1 kHz. The amplified signal was displayed on a storage oscilloscope and passed through an audio amplifier and loudspeaker. The raw nerve activity was full-wave rectified and integrated using a voltage integrator (model 1801, Buxco Electronic, Sharon, CT). The signals were led to a Mac Lab data acquisition system (model 8s, AD Instruments, Milford, MA) and sampled at 100 Hz/channel. All sympathetic nerve recordings had a signal-to-noise ratio of at least 3.Experimental Protocols
To investigate the effects of nNOS inhibition on baroreflex control of HR and RSNA, baroreflex curves were compared before and after intraperitoneal injection of 7-NI (50 mg/kg). Thirty minutes were allowed to elapse before the postblockade curve was constructed. 7-NI was dissolved in warm peanut oil (5 mg/ml). Baroreflex curves were generated by measuring the RSNA response to increases and decreases in arterial pressure by intravenous administration of phenylephrine or sodium nitroprusside. Phenylephrine (American Reagent Laboratories, Shirley, NY; 30 µg/kg) or sodium nitroprusside (Hoffmann-La Roche, Nutley, NJ; 100 µg/kg) was administered in random order. MAP was altered at a rate of 1-2 mmHg/s. Experiments were repeated after administration of L-arginine (600 mg/kg iv). To examine the parasympathetic components of the interaction between NO and the autonomic innervation of the sinoatrial (SA) node, metoprolol bitartrate (2 mg/kg) was injected intravenously, and a baroreflex curve was generated before and after 7-NI administration. Supplemental doses of metoprolol (0.2 mg/kg) were injected every 30 min. To examine the sympathetic components of the interaction between NO and the autonomic innervation of the SA node, atropine methylbromide (0.2 mg/kg) was injected intravenously, and a baroreflex curve was generated before and after 7-NI administration. Supplemental doses of atropine (0.02 mg/kg) were injected every 30 min.To determine the effects of anesthesia, the experiments were repeated in the conscious state. The surgical procedure was performed at least 3 days before the experiment, as described above. On the day of the experiment the rabbit was placed in the experimental box and allowed to rest calmly. A central ear artery was cannulated to measure the arterial pressure and HR. A marginal ear vein was cannulated to administer drugs. The renal nerve electrodes were connected to the preamplifier to record RSNA. Baroreflex curves were compared before and after intraperitoneal infusion of 7-NI. As described above, 30 min were allowed to elapse before the postblockade curve was constructed. Baroreflex curves were generated as described above by measuring the HR and the RSNA response to increases and decreases in arterial pressure during intravenous administration of phenylephrine and sodium nitroprusside.
Measurement of NOS Activity
In two other groups the medulla oblongata was taken 40 min after administration of 7-NI (n = 5) or vehicle (n = 5). The tissues were rapidly frozen and stored at
80°C until analysis. Tissue was
homogenized in 3.5 ml/g of 50 mM
tris(hydroxymethyl)aminomethane · HCl buffer (pH 7.4)
containing 1 mM EDTA, 1 mM ethylene glycol-bis(
-aminoethyl ether)-N,N,N',N'-tetraacetic
acid, 1 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, 15 µM pepstatin A, and 20 µM leupeptin. The homogenate was centrifuged
at 20,000 g for 45 min, and the supernatants were passed over a column of Dowex 50W-X8
(Na+ form) to remove the
endogenous arginine. The eluates were used for the measurements of NOS
activity and protein concentration. All procedures described above were
performed at 4°C. The conversion of
L-[14C]arginine
to
L-[14C]citrulline
by NOS was measured in the supernatants of the tissues as described by
Salter et al. (27). Briefly, 10 µl of tissue supernatant were
incubated with 90 µl of assay buffer solution containing 0.5 µCi/ml
L-[14C]arginine,
50 mmol/l
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4, 50 mmol/l valine, 2 mmol/l NADPH, 1 mmol/l CaCl2, 1 mmol/l
L-citrulline, 3 µmol/l
tetrahydrobiopterin, 3 µmol/l flavin mononucleotide, and 3 µmol/l
flavin adenine dinucleotide for 15 min at 37°C. The reaction was
stopped by addition of 200 µl of 0.1 M HEPES (pH 5.3) containing 10 mmol/l EDTA. To remove L-[14C]arginine,
samples were applied to Dowex 50W-X8
(Na+ form). Columns were then
washed with 1 ml of 100 mmol/l HEPES (pH 5.3) containing 10 mmol/l
EDTA, and the level of
L-[14C]citrulline
was determined with a liquid scintillation counter. NOS activity
was expressed as picomoles of
L-[14C]citrulline
formed per gram of protein per minute.
Data Analysis
The HR and MAP data were acquired every two 2 s from the threshold to the saturation points. A sigmoidal logistic function was fit to the data using a nonlinear regression program (Sigma Plot version 4.16, Jandel) run on a Macintosh computer. Four parameters were derived from the following equation
![HR or RSNA = <IT>A</IT>/{1 + exp [<IT>B</IT>(MAP − <IT>C</IT>)]} + <IT>D</IT>](/content/vol274/issue1/fulltext/R181/img001.gif)
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(1) |
![slope = {<IT>A</IT> × <IT>B</IT> × exp [<IT>B</IT>(MAP − <IT>C</IT>)]}](/content/vol274/issue1/fulltext/R181/img002.gif)
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![/({1 + exp [<IT>B</IT>(MAP − <IT>C</IT>)]}<SUP>2</SUP>)](/content/vol274/issue1/fulltext/R181/img003.gif)
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(2) |
Values are means ± SE. RSNA is expressed as percentage of maximal activity. Data were analyzed using a one-way analysis of variance for repeated measures comparing more than two sets of mean data. When the F ratio exceeded the critical value, Fisher's protected least-significant difference test was applied to test the significance of the differences among the values of each group. To evaluate the baseline parameters before and after 7-NI alone, a paired t-test was used. P < 0.05 was considered statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effects of 7-NI on the Baroreflex Control of HR in Anesthetized Rabbits
Table 1 shows the effects of 7-NI on baseline hemodynamics, RSNA, and curve parameters in the control state and after atropine or metoprolol. There was no significant effect of 7-NI on baseline arterial pressure, HR, or RSNA. Composite baroreflex curves generated during control and after 7-NI are shown in Fig. 1. 7-NI decreased minimum HR from 177 ± 10 to 120 ± 9 beats/min (P < 0.05). In the control state the HR range was 121 ± 8 beats/min. After 7-NI, HR range was significantly increased to 160 ± 13 beats/min (Fig. 1, Table 1; P < 0.05). There were no significant differences in any other parameter before and after administration of 7-NI. These results indicate that blockade of nNOS increased the range mainly because of a reduction of the minimum HR. There was a slight increase in the maximum gain, but this parameter did not reach statistical significance. All changes were completely reversed after L-arginine administration (Table 1). In fact, L-arginine reduced the maximum gain below the control level.
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Effects of 7-NI on the Baroreflex Control of HR in Anesthetized Rabbits After Autonomic Blockade
Pretreatment with atropine. Composite baroreflex curves generated during control, after pretreatment with atropine, and after 7-NI are shown in Fig. 2. Pretreatment with atropine increased the minimum HR from 178 ± 8 to 248 ± 3 beats/min (Table 1; P < 0.05). Intraperitoneal administration of 7-NI evoked a decrease in the minimum HR after atropine to 229 ± 3 beats/min (P < 0.05; Table 1). The maximum gain after atropine was significantly reduced and was restored toward control by 7-NI (Table 1).
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Pretreatment with metoprolol. Composite baroreflex curves generated during control, after pretreatment with metoprolol, and after 7-NI are shown in Fig. 3. Pretreatment with metoprolol reduced minimum HR from 202 ± 7 to 181 ± 8 beats/min (P < 0.05). Intraperitoneal injection of 7-NI caused a further and significant reduction in minimum HR to 158 ± 5 beats/min (P < 0.05; Table 1). 7-NI increased the maximum gain toward the control level (Table 1).
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Effects of 7-NI on the Baroreflex Control of RSNA in Anesthetized Rabbits
Composite baroreflex curves of RSNA generated before and after intraperitoneal administration of 7-NI in anesthetized rabbits are shown in Fig. 4. Although there was some shift of the curve to the left and a slight reduction in maximum gain, 7-NI had little effect on the baroreflex control of RSNA in this group of rabbits.
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Effects of 7-NI on the Baroreflex Control of HR and RSNA in Conscious Rabbits
Composite baroreflex curves relating HR to MAP generated before and after intraperitoneal administration of 7-NI in conscious rabbits are shown in Fig. 5. The only difference observed in this group of rabbits after 7-NI was a significant decrease in minimum HR from 140 ± 4 to 125 ± 4 mmHg (P < 0.05). Composite baroreflex curves relating RSNA to MAP before and after intraperitoneal administration of 7-NI in conscious rabbits are shown in Fig. 6. 7-NI had no effects on the baroreflex control of RSNA in this group of rabbits.
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Effects of 7-NI on the NOS Activity of Medulla Oblongata
NOS activity in the medulla was significantly lower in the 7-NI-treated than in the vehicle-treated group: 202 ± 21 vs. 334 ± 18 pmol · min
1 · mg
protein1
(P < 0.05).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In the present study we investigated the effects of nNOS inhibition on
the baroreflex control of HR and RSNA in anesthetized and conscious
rabbits with the use of the relatively selective nNOS inhibitor 7-NI.
The new findings of the present study are as follows.
1) Blockade of nNOS decreased the
minimum HR of the baroreflex in conscious and anesthetized rabbits
without changing the resting MAP and HR.
2) The mechanisms of the decrease in
minimum HR involve sympathetic and parasympathetic pathways. The
effects of 7-NI on minimum HR are not likely to be due to a direct SA nodal effect, since we previously showed that inhibition of NO synthesis with L-NNA had no
effect on resting or baroreflex-mediated HR changes after combined
cholinergic and -blockade (18).
3) Blockade of nNOS had no effect on
baroreflex control of RSNA in conscious or anesthetized rabbits.
The central pathways involved in the modulation of the baroreflex are
complex. In addition to the nucleus tractus solitarius, the
rostroventrolateral medulla, the nucleus ambiguus, and the dorsal motor
nucleus of the vagus and several other important areas of the brain
stem and hypothalamus can modulate baroreflex function. According to
recent studies, NO can influence baroreflex function at several of
these sites in the baroreflex pathway (8, 9). In most in vivo studies,
nonspecific NOS inhibitors such as
NG-monomethyl-L-arginine
and
N
-nitro-L-arginine
methyl ester cause changes in resting HR and MAP (6, 7, 15, 21, 31),
making assessment of baroreflex modulation separately from the effects
of acute changes in arterial pressure difficult (5). Therefore, in the
present study we used the relatively selective nNOS inhibitor 7-NI.
After intraperitoneal administration of 7-NI, there was no effect on
resting HR and MAP in anesthetized or conscious animals. The fact that
7-NI had no influence on resting HR and MAP is in good agreement with
the results obtained by Yoshida et al. (33). Although it has been reported that 7-NI is not totally effective in inhibiting nNOS, there
was still a higher degree of selectivity for nNOS than for eNOS (34).
The differences between our results and those of Zagvazdin et al. (34)
may reflect species differences. It is not likely that the effects of
7-NI are due to a time phenomenon, since our previous study (18) showed
no effect of D-NNA on baroreflex function compared with the control curve over the same time course used
in the present study.
Several studies have assessed the effects of anesthesia on baroreflex function (4, 20). To determine the effects of anesthesia, we repeated these experiments in conscious rabbits. There was no significant effect on resting MAP or HR after intraperitoneal administration of 7-NI. Although the magnitude of the change in minimum HR was smaller in the conscious state than in the anesthetized state, the results were qualitatively similar in conscious and anesthetized conditions. The finding that 7-NI affects the baroreflex control of HR but not of RSNA is surprising and suggests that the central modulation of baroreflex function by NO is targeted primarily to those structures that regulate autonomic outflow to the heart rather than to the kidney. NO may have heterogenous effects on sympathetic outflow to different beds, such as may be exhibited here. Recently, Hirai et al. (11, 12) clearly showed that NO inhibition increased RSNA but had the opposite effect on lumbar sympathetic nerve activity in anesthetized rats. The lack of effect of nNOS inhibition on RSNA in this study is in good agreement with the results of our previous study carried out in conscious rabbits (18). In that study we also found a greater effect of NO inhibition on baroreflex control of HR than of RSNA. The lack of an effect on resting RSNA in this study as in the previous one may reflect specificity of the sites in the brain that are modulated by NO or may reflect the lack of an endogenous excitatory pathway that is permissive for sympathoexcitation after NO inhibition. We recently provided evidence for such an effect (17). When arterial pressure was kept constant in conscious rabbits, N-nitro-L-arginine methyl ester failed to increase RSNA unless plasma levels of angiotensin II (ANG II) were elevated. ANG II can act as a central sympathoexcitatory agent (2, 26). ANG II levels may not be sufficiently high in normal animals to facilitate the sympathoexcitation when NO synthesis is blocked. It is possible that the inhibition of NOS activity was not sufficient to affect the baroreflex control of RSNA in the present study. The inhibition of NOS activity after 7-NI was ~40% in the present study, significantly less than in the vehicle-treated rabbits.
In summary, the present study indicates that endogenous brain NO decreases the baroreflex control of HR but not of RSNA. Cardiac sympathetic and parasympathetic components are involved in the HR effects.
Perspectives
The present study was designed to elucidate the central effects of NO on the baroreflex control of HR and RSNA. The conclusion of our study indicated that NO had small but significant effects on the baroreflex control of HR. The importance of these findings is that NO has central effects on regulation of the circulation. In some pathological situations, NO is decreased or increased. It appears that clarification of the central effects of NO in such a pathophysiological state is more important and should be examined in the future.| |
ACKNOWLEDGEMENTS |
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The authors thank Johnnie F. Hackley and Pamela Curry for expert technical assistance.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-38690 and Postdoctoral Fellowship 95-04613 from the American Heart Association, Nebraska Affiliate.
Address for reprint requests: H. Murakami, Dept. of Physiology, Kagawa Medical University, 1750-1, Ikenobe, Miki, Kagawa 761-07, Japan.
Received 1 May 1997; accepted in final form 10 September 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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, Control; 
, 7-NI; 
and 
, mean resting values for control and 7-NI,
respectively. MAP, mean arterial pressure; bpm,
beats/min.
, atropine + 7-NI; 
, mean resting values for control, atropine, and
atropine + 7-NI, respectively.
