(Hypertension. 1996;27:297-302.)
© 1996 American Heart Association, Inc.
Articles |
Atrial Natriuretic Peptide Blunts Arterial Baroreflex in Spontaneously Hypertensive Rats
From the Vascular Biology and Hypertension Program, Departments of Medicine (S.-T.Z., Y.-F.C., S.O., D.A.C.) and Cell Biology (J.M.W.), University of Alabama at Birmingham, and the Second Division, Department of Medicine, Kyoto University School of Medicine, Japan (K.N., H.I.).
Correspondence to David A. Calhoun, MD, Vascular Biology and Hypertension Program, 520 ZRB, University of Alabama at Birmingham, Birmingham, AL 35294-0007.
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Abstract |
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Abstract We and other laboratories have reported that arterial baroreflex–mediated control of heart rate is blunted in spontaneously hypertensive rats (SHR) compared with normotensive controls. Recently, we reported that atrial natriuretic peptide (ANP) microinjected into the caudal nucleus tractus solitarii of SHR further blunts this defect. The present study tested the hypothesis that ANP modulates arterial baroreflex–mediated control of sympathetic nervous system activity. Nine-week-old, male SHR (n=29) and normotensive Wistar-Kyoto control rats (n=24) were instrumented for microinjection into the caudal nucleus tractus solitarii and for direct measurement of arterial blood pressure, heart rate, and lumbar sympathetic nervous system activity. After urethane- and
-chloralose–induced anesthesia,
arterial baroreflex–mediated control of heart rate and
lumbar sympathetic nerve activity was assessed during
phenylephrine- (5 to 40
µg·kg-1·min-1)
induced increases and sodium nitroprusside– (15 to 300
µg·kg-1·min-1)
induced decreases in mean blood pressure before and after
microinjection of ANP (50 ng) or monoclonal antibody to ANP (0.55 µg)
into the caudal nucleus tractus solitarii. ANP reduced and the antibody
enhanced the sensitivity of baroreflex-mediated control of both
heart rate and lumbar sympathetic nerve activity in SHR but not in
Wistar-Kyoto controls (P<.05). Arterial
baroreflex sensitivity was unchanged with control microinjections of
vehicle or mouse IgG in SHR. These data suggest that
endogenous ANP in the caudal nucleus tractus solitarii may
contribute to the development and/or maintenance of
hypertension in SHR by blunting baroreflex-mediated control of
sympathetic nervous system activity.
Key Words: baroreceptor • solitary nucleus • rats, inbred WKY
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Our laboratory has reported that microinjection of ANP into the caudal NTS reduces the sensitivity of arterial baroreflex control of HR in SHR.1 Microinjection of mAb to ANP into the caudal NTS had the opposite effect, enhancing baroreflex control of HR in SHR. In contrast, microinjection of ANP or mAb to ANP had no effect on baroreflex control of HR in normotensive WKY control rats. These changes in arterial baroreflex control of HR induced by introduction of exogenous ANP and blocking of endogenous ANP with mAb suggest that endogenous ANP contributes to the development of hypertension in SHR through modulation of sympathetic nervous system activity.
Studies from other laboratories also suggest that ANP within the brain lowers blood pressure through alterations in sympathetic activity. Injection of ANP into the third ventricle decreases nerve traffic in renal and lessor splanchnic sympathetic nerves and lowers blood pressure in sinoaortic-denervated, chloralose-urethane–anesthetized Sprague-Dawley rats.2 Microinjection of exogenous ANP into the caudal NTS increases the firing rates of NTS neurons, facilitating a reduction in blood pressure in anesthetized Wistar rats.3 In addition, single neuronal units excited by microinjection of ANP into the caudal NTS are also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading, providing evidence of a direct link between ANP and baroreflex function.4
The present study was designed to test the hypothesis that endogenous ANP within the NTS reduces the sensitivity of arterial baroreflex control of both HR and sympathetic nervous system activity by directly measuring changes in HR and LSNA during phenylephrine-induced increases and nitroprusside-induced decreases in blood pressure. Alteration of baroreflex control of HR, as reported in our earlier study, suggests but does not unequivocally establish alteration of baroreflex-mediated control of sympathetic nervous system activity. Autonomic control of HR in rats is predominantly parasympathetic, so that changes in baroreflex control of HR do not necessarily involve changes in control of sympathetic nervous activity.5 The present study was designed to determine whether the effects of exogenous and endogenous ANP in the caudal NTS on arterial baroreflex–mediated control of HR and LSNA are concordant.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Eight-week-old, male SHR (IBU-3 colony) and WKY control rats were obtained from Taconic Farms, Germantown, NY. All rats were housed four per cage and allowed free access to water and standard rat chow containing 1% NaCl (Ralston-Purina). A constant 12-hour light/dark cycle was maintained throughout the experimental protocol. These studies were conducted in accordance with University of Alabama at Birmingham Institutional Animal Care and Use Committee guidelines.
At 9 weeks of age and after anesthetization with sodium pentobarbital (50 mg/kg IP) and ketamine (8 mg/kg IP), each rat was placed into a stereotaxic apparatus. The skin overlying the middle of the skull was incised, and a small hole was drilled through the appropriate portion of the skull. A guide cannula (26-gauge stainless steel tubing) was lowered to a position 2.0 mm dorsal to the caudal NTS (anteroposterior, -4.3 to 5.1 mm from the interaural line; mediolateral, 0.2 to 1.0 mm; dorsoventral, 7.5 to 8.6 mm; degree of lowered angle, 26°) as previously described.6 All cannulas were placed in the right side of the brain; thus, all injections were made unilaterally. The guide cannula was fixed to the skull with stainless steel screws and fast polymerized cannula cement. A 32-gauge obdurator (stainless steel wire) was inserted into the guide cannula after implantation.
Two days after surgery, each animal was anesthetized with
methohexital (70 mg/kg IP), and cannulas (PE-10 fused with PE-50) were
implanted into the abdominal aorta via the right femoral artery for
measurement of arterial pressure and into the right femoral
vein for intravenous infusion of phenylephrine
and sodium nitroprusside. After catheter placement, further
anesthesia was obtained with intravenous bolus
injection of urethane (25 mg/kg) and -chloralose (50 mg/kg).
Subsequent boluses of -chloralose (10 to 25 mg/kg) were given as
needed to maintain a constant level of anesthesia. This
combination of anesthetics was chosen to provide adequate
anesthesia and analgesia with minimal effect on
cardiovascular and baroreflex function.7 8
After laparotomy, the left lumbar sympathetic nerve was isolated and
freed of fat and connective tissue. Bipolar-stranded stainless
steel electrodes (Medwire) were placed around the nerve for multifiber
nerve recording. The electrodes were connected by a
high-gain impedance probe (model P511, Grass Instrument Co) to a
Grass P511 preamplifier, where the signal was amplified (x20 000) and
filtered (low frequency, >30 Hz; high frequency, <1000 Hz). The
modified signal was fed into an oscilloscope (model 5113, Tektronix)
and a Grass AM8 audio monitor for evaluation. When an optimal signal
was achieved, the electrodes were fixed in place with silicone cement
(Wacker Sil Gel 604, Wacker-Chemie Gimble). The abdominal incision was
then closed, with externalization of the recording lumbar
electrodes.
The femoral artery cannula was connected to a CP-02 pressure transducer (Century Technology) for recording of arterial pressure on a Grass model 7 polygraph. HR was monitored by a cardiotachometer (Grass 7P44C) triggered by the systolic pressure rise. The signal from the lumbar recording electrodes was amplified and filtered as above and then rectified and integrated over 1-second intervals (Grass 7P10) before being recorded on the polygraph. The quality of the nerve signal was assessed with an intravenous injection of norepinephrine (5 µg). Significant inhibition of nerve activity indicated a good signal. MAP, HR, and LSNA were recorded continuously throughout each experiment. After a 15-minute control period, incremental doses of phenylephrine (5, 10, 20, 30, and 40 µg/min) were infused through the femoral vein catheter to achieve a ramp increase in MAP of 40 mm Hg over a period of 5 minutes. MAP and HR were allowed to return to baseline during a 15-minute stabilization period. Nitroprusside was then infused in incremental doses (15, 30, 60, 150, and 300 µg·kg-1·min-1) to produce a ramp decrease in MAP of 40 mm Hg over 5 minutes. MAP, HR, and LSNA were allowed to return to baseline during a second 30-minute stabilization period.
The obdurator was removed from the guide cannula and replaced with an inner cannula (32-gauge stainless steel tubing) filled with the agent to be administered. The tip of the inner cannula extended 1.0 mm beyond the guide cannula. The inner cannula was attached to a 0.5-µL Hamilton syringe through tubing (PE-20) filled with heparin (5 U/mL saline). A small air bubble was placed between the heparin and the injection solution. After insertion of the inner cannula and the return of vital signs to baseline, ANP (50 ng) (Sigma Chemical Co) in 50 nL of ACSF or ACSF vehicle was microinjected into the caudal NTS. Ten minutes later, the phenylephrine and nitroprusside infusions were repeated as above.
In parallel experiments, the effects on baroreceptor function of blocking endogenous ANP within the caudal NTS by microinjection of mAb to ANP were examined. Surgery, arterial and venous cannulation, brain cannula implantation, and phenylephrine and nitroprusside infusion were performed as above, except that mAb to ANP (mAb KY-ANP-II, 0.55 µg in a volume of 50 nL) purified from ascites fluid or control mouse IgG (Sigma Immuno Chemicals, 0.55 µg) in a volume of 50 nL was microinjected into the caudal NTS.
At the conclusion of each experiment, 1% pontamine sky-blue solution in ACSF (80 nL) was injected through the brain cannula. Each rat was then killed by intravenous pentobarbital overdose, and postmortem nerve activity was recorded for 30 minutes. Thirty-minute postmortem nerve activity was subtracted from all measured LSNA values. Then, the brain was removed from the skull and sectioned at 30 µm on a freezing microtome (Slee Medical Equipment Ltd). Sections were mounted for verification of the microinjection site and for measurement of extent of spread of the dye. In two SHR and two WKY rats, 50 nL of radioactive ANP (125I-ANP) (Amersham) solution (1500 cpm/nL) was microinjected into the NTS. Thirty minutes later, the animals were killed by pentobarbital overdose. The brains were removed, sectioned (30 µm) on a freezing microtome, and then placed on photographic film. After 3 days of exposure, the film was developed and the exposed area of the film corresponding to the spread of the 125I-ANP solution was measured.
The mAb used in these studies was the high-affinity antibody against the 28–amino acid form of rat ANP (99-126) [ANP-(99-126)], produced by Mukoyama et al9 and named mAb KY-ANP-II. mAb KY-ANP-II has been shown to produce significant reductions in plasma cGMP levels in stroke-prone SHR and deoxycorticosterone acetate–salt rats, indicating that the antibody can block the activity of rat ANF-(99-126) in the intact rat.10 We purified IgG containing mAb KY-ANP-II from mouse ascites fluid (1 mL) with a protein A agarose column.11 Retained IgG with mAb KY-ANP-II was eluted from the protein A column with 3 mol/L MgCl and dialyzed against 0.9% saline overnight. We demonstrated that the purified IgG (1.1 mg/mL) fraction containing mAb KY-ANP-II bound 50% of 125I-ANP (17 000 cpm) at 1:100 000 final dilution in a total volume of 500 µL.12 In addition, we observed that intravenous injection of a 100-µg dose of purified mAb KY-ANP-II inhibited the increase in plasma cGMP induced by administration of exogenous ANP (20 µg/kg IV) to the intact rat, confirming the previous characterization by Itoh et al10 and Jin et al.1 The dose of mAb KY-ANP-II (0.55 µg) used in the present experiment is equivalent to the anti-ANP antibody contained in 0.55 µL of mouse ascites fluid. This is 0.5% of the intravenous dose (100 µL of ascites fluid) of this mAb used in previous studies by Itoh et al.10
Statistical Analysis
All values are expressed as
mean±SEM. LSNA is expressed as
percent change from baseline nerve activity. The linear portion of the
curve relating LSNA to change in MAP and relating the change in HR to
change in MAP was analyzed by linear regression and correlation
analysis for each rat during phenylephrine- and
nitroprusside-induced changes in MAP. A mean slope and an average
correlation coefficient were calculated for each relation for each
group. The slopes of these regression lines were used as an index of
baroreceptor reflex sensitivity. Baroreflex sensitivity at baseline and
the change in baroreflex sensitivity after microinjection of ANP, mAb
KY-ANP-II, or vehicle into the caudal NTS were compared by one-way
ANOVA. Body weight and pre- and post-ANP, mAb KY-ANP-II, and vehicle
MAP and HR values were also compared by ANOVA followed by
Student-Newman-Keuls post hoc analysis. Statistical
significance was obtained at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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SHR (n=29) and WKY rats (n=24) receiving ANP, mAb KY-ANP-II, or ACSF or IgG vehicle microinjection in which histological examination confirmed that cannulas were properly placed in the caudal NTS were studied. Neurons near the injection tip had normal morphology in Nissel-stained sections, indicating minimal damage at this site. In the four animals injected with 125I-ANP, the largest dimension of spread was limited to 690±88 µm.
Baseline body weights were similar for the three experimental groups (SHR-ANP, n=7; SHR-vehicle, n=6; and WKY-ANP, n=7) microinjected with ANP (249±2 versus 247±3 versus 250±6 g, SHR-ANP versus SHR-vehicle versus WKY-ANP). Baseline MAP was significantly higher in SHR than WKY rats (127±2 versus 127±2 versus 102±1 mm Hg, SHR-ANP versus SHR-vehicle versus WKY-ANP; P<.01). HR tended to be lower in SHR than WKY rats, but the difference was not statistically significant (435±12 versus 439±18 versus 483±15 beats per minute, SHR-ANP versus SHR-vehicle versus WKY-ANP). Microinjection of ANP or ACSF vehicle into the caudal NTS did not significantly alter MAP, HR, or LSNA in SHR or WKY rats.
Phenylephrine-induced increases and
nitroprusside-induced decreases in MAP were associated with
significant decreases and increases, respectively, in HR and LSNA in
SHR and WKY rats. The phenylephrine- and
nitroprusside-induced changes in MAP were not significantly altered
by microinjection of ANP into the caudal NTS. The slopes of the
HR/MAP and LSNA/MAP relations were significantly
diminished
in SHR treated with either ANP or vehicle compared with WKY rats,
indicating blunting of arterial baroreflex control of HR
and LSNA in SHR (Tables 1
and 2, Fig
1). The average correlation coefficient for both
relationships was >.90 for all experimental groups, indicating a high
degree of linearity between the change in HR and LSNA and the change in
MAP.
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Microinjection of ANP into the caudal NTS did not alter pretreatment
MAP or HR in either SHR or WKY rats but did produce significant
reductions in the slopes of the HR/MAP and the LSNA/MAP
relationships during phenylephrine-induced
decreases and nitroprusside-induced decreases in MAP in SHR but not
in WKY rats (Tables 1
and 2, Fig
1). Thus, microinjection of ANP into
the caudal NTS further blunted baroreflex-mediated control of HR
and LSNA in SHR. In contrast, microinjection of ACSF into the caudal
NTS did not alter the slopes of the HR/MAP or the LSNA/MAP
relationships in SHR (Tables 1 and 2).
In four animals, the ANP injection site was outside the caudal NTS (three in the rostral NTS and one in the dorsal ventricle). ANP injection did not alter baroreflex sensitivity in these animals, suggesting that the ANP effect was specific for the target area, ie, the caudal NTS.
Baseline body weights were similar for the three experimental groups
(SHR-ANP-Ab, n=8; SHR-IgG, n=6; and WKY-ANP-Ab, n=7)
microinjected with
ANP-Ab (248±2 versus 243±2 versus 253±6 g, SHR-ANP-Ab
versus SHR-IgG
versus WKY-ANP-Ab). Baseline MAP was significantly higher in SHR than
in WKY rats (139±4 versus 132±4 versus 99±4 mm Hg,
SHR-ANP-Ab versus
SHR-IgG versus WKY-ANP-Ab; P<.05). Baseline HR was
significantly lower in SHR than in WKY rats (415±8 versus 394±16
versus 456±9 beats per minute, SHR-ANP-Ab versus SHR-IgG versus
WKY-ANP-Ab; P<.01). Microinjection of mAb KY-ANP-II into
the caudal NTS did not significantly alter MAP, HR, or LSNA in SHR or
WKY rats. The phenylephrine- and nitroprusside-induced
changes in MAP were not significantly altered by ANP-Ab microinjection.
The slopes of the HR/MAP and LSNA/MAP relationships during
phenylephrine and nitroprusside infusions were
significantly increased in SHR (P<.05) but not WKY rats
treated with mAb KY-ANP-II, indicating that blockade of
endogenous ANP in the caudal NTS increased the gain of
baroreceptor reflex control of HR and LSNA in SHR but not in WKY rats
(Tables 3 and 4, Fig 2).
In contrast, microinjection of the same amount of IgG into the NTS did
not alter baroreflex sensitivity in SHR (Tables 3 and
4) or WKY rats
(n=2).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The principal finding of the present study was that microinjection of ANP into the caudal NTS of SHR blunted and microinjection of mAb to ANP enhanced arterial baroreflex control of both HR and LSNA during phenylephrine-induced increases and nitroprusside-induced decreases in MAP. In contrast, microinjection of ANP or mAb KY-ANP-II had no effect on baroreflex control of HR or LSNA in WKY rats, suggesting that endogenous ANP in the caudal NTS modulates baroreflex control of HR and LSNA in SHR but not in WKY rats. In addition, the present study confirms the earlier observation from this and other laboratories that baseline baroreflex-mediated control of HR and LSNA is blunted in SHR compared with WKY rats.14 15 16 17 18 19
An increasing number of studies demonstrate that ANP, both peripherally and centrally, modulates sympathetic nervous system activity. In anesthetized normotensive rats, systemic administration of ANP reduces sympathetic tone through a mechanism involving a vagal afferent pathway.20 Intravenous administration of ANP to anesthetized normotensive rats reduces blood pressure and HR in conjunction with decreases in sympathetic outflow.21 Sinoaortic denervation exaggerates these responses to intravenous ANP, while vagal cooling reversibly abolishes the sympathoinhibitory effect of intravenous ANP, indicating that this reflexively mediated action is dependent on afferent C-fiber activity in the vagus nerves.22 Other recent studies demonstrate that circulating ANP in doses that do not significantly alter blood pressure or HR exerts a complex modulatory effect on arterial baroreceptor reflexes in conscious normotensive rats. ANP potentiates reflex bradycardia but attenuates reflex tachycardia in response to intravenous boluses of phenylephrine and nitroprusside, respectively; it does not alter the pressor response to carotid occlusion.23 Mechanisms that have been hypothesized to account for these effects of ANP include sensitization of afferent vagal pathways and sensitization of baroreceptor afferents, resulting in an increase in their responsiveness during stimulation, a maintenance of their discharge during deactivation, and direct excitation of neurons in the NTS.24 25
In the present study, ANP microinjected into the NTS blunted baroreflex sensitivity in SHR but not WKY rats. We hypothesize that ANP receptors within the NTS are upregulated in SHR compared with WKY rats, thus rendering SHR more sensitive to ANP stimulation. In a previous study, we found that ANP content within the NTS was reduced in SHR compared with WKY rats, regardless of dietary NaCl ingestion.26 We hypothesize that reduced levels of ANP promote an upregulation of ANP receptors, thus making the SHR more sensitive to exogenous ANP injected into the NTS.
It has been reported that at high doses, phenylephrine may stimulate both the arterial and cardiopulmonary baroreceptors, in which case, its use, as in this experiment, would not be selective for the arterial baroreflex.27 However, we have previously shown that phenylephrine in the doses used in this study does not significantly stimulate cardiopulmonary baroreceptors. In a previously published study, we demonstrated that in SHR with the arterial baroreflex deactivated via sinoaortic denervation, phenylephrine infusion, in doses identical to those used in the present experiment, did not alter LSNA or HR, indicating that cardiopulmonary receptors were not activated.28 This argues against significant contamination of the results by stimulation of the cardiopulmonary component of the baroreflex.
Our laboratory previously reported that ANP microinjected into the caudal NTS blunts, whereas mAb to ANP enhances, arterial baroreflex control of HR in SHR.1 The present study extends these observations by demonstrating that endogenous ANP within the caudal NTS modulates arterial baroreflex–mediated control of both HR and sympathetic nervous system activity. Since HR control is predominantly vagal, changes in baroreflex sensitivity relating to HR control might not be reflected in concomitant changes in baroreflex-mediated control of sympathetic activity.5 The results of the present study argue against such a divergent effect.
In total, recent and present results suggest that endogenous ANP within the caudal NTS contributes to the development and/or maintenance of hypertension in SHR by further blunting of baroreflex-mediated control of sympathetic nervous system activity. A reduction in gain of baroreflex control would be expected to produce increases in sympathetic outflow, with consequent increases in peripheral vascular resistance and blood pressure.
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute grants HL-22544 and HL-47081 and by Grants-in-Aid from the American Heart Association National Center and Alabama Affiliate. Dr Calhoun is a recipient of a Physician-Scientist Award (HL-02568) from the National Heart, Lung, and Blood Institute.
Received March 27, 1995; first decision April 13, 1995; accepted November 14, 1995.
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