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(Hypertension. 1997;29:808-814.)
© 1997 American Heart Association, Inc.
Articles |
Differential Central Modulation of the Baroreflex by Salt Loading in Normotensive and Spontaneously Hypertensive Rats
the Fourth Department of Internal Medicine (A.O., T.F.) and Department of Physiology (T.K., M.K.), The University of Tokyo (Japan).
Correspondence to Ayumu Ono, MD, Fourth Department of Internal Medicine, The University of Tokyo School of Medicine, 3-28-6 Mejirodai, Bunkyo-ku, Tokyo 112, Japan.
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Abstract |
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In salt-sensitive hypertensive animal models and human subjects compared with their salt-resistant counterparts, sympathetic activity is abnormally enhanced during a high salt diet. We examined whether salt loading differentially modulates the arterial baroreceptor reflex (ABR), a major control mechanism of arterial pressure and sympathetic vasomotor activity, in young normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Six-week-old WKY and SHR were fed a normal (0.66%) or high (8.00%) salt diet for 4 weeks. After the diet regimen, baseline levels of mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and the overall and central properties of the ABR were compared among the four groups of rats under halothane anesthesia. In WKY, a high salt diet did not affect baseline arterial pressure and RSNA but potentiated the ABR, as evidenced by an increase in the maximal slope of MAP-RSNA and MAP–heart rate relationships. In SHR, by contrast, salt loading accelerated hypertension and sympathetic overactivity and impaired the ABR. Salt-induced modulation of the ABR was associated with that of the central property, since reflex inhibition of RSNA by stimulation of the aortic depressor nerve was augmented in WKY and attenuated in SHR. These results suggest that differential modulation of the central mechanism subserving the baroreflex control of sympathetic activity at least partly accounts for the difference in salt sensitivity between WKY and SHR.
Key Words: sodium, dietary • rats, inbred WKY • rats, inbred SHR • pressoreceptors • central nervous system • sympathetic nervous system
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Introduction |
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Much evidence supports the hypothesis that abnormal modulation of the sympathetic nervous system is involved in salt-induced hypertension. Salt loading has been shown to augment sympathetic activity in salt-sensitive rats but not in their normotensive counterparts.1 2 3 4 5 6 7 8 9 Furthermore, a high salt diet decreases plasma concentrations of norepinephrine in normotensive subjects and salt-resistant individuals with hypertension but not in their salt-sensitive counterparts.10 11 12 13 14 The abnormal sympathetic response to high salt intake in salt-sensitive rats and human subjects suggests impairment of the sympathetic control mechanism in salt-induced hypertension.
The ABR is a major control mechanism of arterial pressure and sympathetic vasomotor activity.15 Salt loading impairs the ABR in certain salt-sensitive hypertensive animals but occasionally potentiates it in normotensive or salt-resistant hypertensive animals.16 17 18 We have previously demonstrated that salt loading accelerated hypertension with central impairment of the ABR in salt-loaded young SHR.19 We thus hypothesized that the difference in the salt-induced modulation of the ABR between salt-sensitive animal models and their salt-resistant counterparts is produced at the central site and underlies the different sympathetic responses. In normotensive or salt-resistant hypertensive animals, however, salt-induced central modulation of the ABR remains to be determined.
The aim of the present study was to compare the effect of salt loading on the ABR in young normotensive WKY and SHR, with special attention paid to its central property. The overall property of the ABR was assessed by the relationship between MAP and RSNA or HR when changes in MAP were induced pharmacologically. RSNA was used as a reflex sympathetic response because it reflects the activity of sympathetic vasomotor fibers.20 The central property of the ABR was assessed by reflex inhibition of RSNA or HR elicited by electrical stimulation of the ADN because the ADN in the rat consists exclusively of baroreceptor afferents.21
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Methods |
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The present study was conducted in 19 male normotensive WKY and 18 male SHR purchased from Charles River Japan (Atsugi, Japan) at 6 weeks of age. The rats were randomly placed on a normal (0.66%) or high (8.00%) salt diet (Oriental Yeast) and were maintained at a constant humidity (60±5%), constant temperature (23±1°C), and regular light/dark cycle (light from 6 AM to 6 PM) for 4 weeks. The number of rats in each group was as follows: normal salt WKY, n=10; high salt WKY, n=9; normal salt SHR, n=8; and high salt SHR, n=10. Food and tap water were supplied ad libitum.
At 10 weeks of age, the rats were prepared for assessment of their ABR function. The rats were anesthetized initially with ether for insertion of tracheal, arterial, and venous cannulas; immobilized by d-tubocurarine chloride (initially, 0.1 mg per rat IV; thereafter, 0.1 mg/h IV); and then artificially ventilated with halothane (1.0% to 1.5% during surgery and 0.6% to 0.8% during the recording period) in oxygen-enriched room air. Arterial pressure was recorded from the abdominal aorta by a polyethylene catheter (0.5 mm ID) inserted through the femoral artery and connected to a transducer (TP-200T, Nihon Kohden). MAP was recorded by passing the arterial pressure signal through a low-pass filter (corner frequency, 0.2 Hz). HR was computed from the arterial pressure pulse by a tachometer (AT-600G, Nihon Kohden).
The left renal nerve was approached retroperitoneally through a left flank incision and prepared for recording from near the renal artery. For recording of efferent discharges of the renal nerve, the central cut end of the nerve was placed on bipolar silver hook electrodes connected to an amplifier (AVB-8, Nihon Kohden) and displaced on an oscilloscope (Tektronix 5113). The lower and higher cutoff frequencies of the recording system were 100 and 3000 Hz, respectively. RSNA were obtained as multifiber discharges, full-wave rectified, and integrated over a 10-second interval. The instrumental noise level was recorded after the cut of the renal nerve at the end of the experiment and was subtracted from all the experimental values of renal nerve discharge. The integrated RSNA was used in those experiments in which the overall property of the ABR was determined as the relation between MAP and RSNA. Renal nerve discharges were also converted into standard pulses by a window discriminator (ET-612J, Nihon Kohden). The threshold was set just above the noise level which was recorded after the cut of the renal nerve at the end of the experiment. This method was used in those experiments in which the central property of the ABR was evaluated by the reflex inhibition of RSNA in response to electrical stimulation of the ADN.
Throughout the experiment, the adequacy of anesthesia was occasionally checked by the absence of increases in arterial pressure, HR, and RSNA to hindlimb toe pinch. All experimental procedures were in accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences Recommended by the Physiological Society of Japan.
Overall Property: MAP-RSNA and MAP-HR Relations
MAP-RSNA and MAP-HR relations were obtained as follows. MAP was altered between approximately 50 and 230 mm Hg by an intravenous bolus injection of sodium nitroprusside (1 to 30 µg/100 µL) or phenylephrine (1 to 30 µg/100 µL). The peak values of RSNA and HR were correlated with that of MAP. The data obtained from a single rat were fitted to the logistic curve with a graphic-assisted fitting program (Kaleida Graph, Synergy Software) to obtain MAP-RSNA and MAP-HR relations (Fig 1
).22 RSNA was expressed as a percentage of the maximum19 23 or baseline23 value and HR as the absolute value (beats per minute). The curve was expressed as y=p4+p1/{1+exp[p2(x-p3)]}, where y is RSNA or HR, and x is MAP (millimeters of mercury). The four parameters in the equation are defined as follows: p1 indicates the range of y (ie, maximum minus minimum values of y); p2, a coefficient related to the maximum gain (see below); p3, median MAP (MAP50), or MAP corresponding to the midpoint over the range of y; and p4, the minimum value of y. The maximum gain (Gmax) was obtained as the absolute value of the slope of the curve at MAP50 and was equal to (-p1·p2/4). These parameters were used for reconstruction of a single logistic curve representing each group and also compared among the groups for evaluation of the effect of salt loading on the ABR.
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Central Property: Reflex Inhibition of RSNA and HR by Electrical Stimulation of the ADN
The central property of the ABR can be assessed by reflex changes in RSNA when the ADN is electrically stimulated.19 21 24 25 26 The left aortic nerve was identified along the vagal nerve at the neck and then dissected free of the surrounding connective tissue and transsected. The distal end of the nerve was placed on a bipolar platinum electrode for stimulation so that impulses went to the brain. After completion of surgery, at least 30 minutes was allowed for stabilization.
The aortic nerve consists of A and C fibers, which are distinct with respect to their reflex action.15 On the basis of previous systematic studies on the aortic nerve reflex in the rat, the stimulus frequency of 100 Hz with intensities less than 2 V would be expected to selectively activate the aortic nerve A fibers.21 On the other hand, selective activation of aortic nerve C fibers would be expected at 25 Hz with intensities higher than 5 V.21
In the present study, electrical stimuli were square-wave pulses 0.2 millisecond long delivered to the rat from a pulse generator (SEN 7103, Nihon-Kohden) through an isolation unit. The stimulus frequencies were 100 or 25 Hz to preferentially activate aortic A and C fibers, respectively. The stimulus intensity ranged from 0.5 to 10 V. The stimulation period was set at 1 second to minimize changes in arterial pressure that could secondarily affect RSNA and HR.
Stimulation was repeated 32 times, each with an interval of 20 seconds or longer, and the peristimulus time histogram (PSTH) of RSNA or HR was constructed at each stimulus intensity. The reflex response recorded as the PSTH was measured21 25 with the aid of a computer (PC-9801RX, NEC) as follows. The area above or below the prestimulus control level of RSNA was calculated by integrating the PSTH between the onset and the end of the evoked response. The area calculated was normalized and expressed as a percentage by dividing it by the prestimulus control level integrated over the 1-second period. A negative sign was attached to indicate that the response decreased below the control level. The evoked response of RSNA thus normalized was termed the normalized response magnitude. As to the reflex HR response to ADN stimulation, maximum decreases from the prestimulus control level averaged for 1 second were expressed in beats per minute.
Statistical Analysis
Data are presented as mean±SE. Comparisons of data were performed by two-way ANOVA. When there was a significant interaction between the two factors (strain and treatment), the four groups were compared with one-way ANOVA followed by Duncan's method for multiple comparisons among individual means.27 Differences in data were considered to be statistically significant at a value of P<.05.
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Results |
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Basal levels of MAP, HR, RSNA, and body weight in young WKY and SHR fed either a normal or high salt diet for 4 weeks are shown in Table 1
. During a normal salt diet, MAP, RSNA, and HR were significantly greater in SHR than WKY. In SHR, MAP and RSNA were significantly greater in rats on a high salt diet than those on a normal salt diet. By contrast, in WKY, MAP and RSNA did not differ significantly between the diet groups. Thus, a high salt diet for 4 weeks accelerated the development of hypertension, with renal sympathetic overactivity in young SHR, whereas it did not alter arterial pressure and renal sympathetic activity in young WKY. Body weight in WKY fed a high salt diet was slightly less than in those fed a normal diet, whereas it did not differ significantly between the two diet groups in SHR.
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Overall Property of the ABR
MAP-RSNA Relation
Intravenous injections of sodium nitroprusside and phenylephrine altered MAP and elicited reflex changes in RSNA. By means of logistic analysis, we correlated changes in RSNA with those in MAP in individual rats to determine the parameters of the logistic curve (see "Methods"). The two methods, ie, calculation of RSNA data as a percentage of maximum and as a percentage of baseline, yielded similar results (Table 2). In SHR fed a high salt diet, Gmax was significantly lower and MAP50 significantly higher than in SHR fed a normal salt diet. Consequently, in SHR fed a high salt diet, the curve was blunted and shifted toward the higher pressure range (Fig 2). By contrast, in WKY fed a high salt diet, Gmax was significantly higher than in WKY fed a normal salt diet. MAP50 was not significantly different between the diet groups of WKY. Consequently, in WKY fed a high salt diet, the curve was steepened without a shift along the MAP axis (Fig 2). Salt loading did not significantly affect the other parameters in either WKY or SHR (Table 2). Between WKY and SHR on a normal salt diet, none of the parameters differed significantly.
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MAP-HR Relation
Gmax and MAP50 values of the MAP-HR relation in the four groups were determined in the same manner as for the MAP-RSNA relation (Table 3). In SHR fed a high salt diet, Gmax was significantly lower and MAP50 significantly higher than in SHR fed a normal salt diet. Consequently, in SHR fed a high salt diet, the MAP-HR relation was blunted and shifted toward the higher pressure range (Fig 3). In contrast, in WKY fed a high salt diet, Gmax was significantly higher than in WKY fed a normal salt diet. MAP50 was not significantly different between the diet groups of WKY. Maximum HR, minimum HR, and HR range did not differ significantly among the four groups.
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On the basis of results on MAP-RSNA and MAP-HR relations, we conclude that salt loading impairs the overall property of the ABR in young SHR but potentiates it in young WKY.
Central Property of the ABR
Since ADN stimulation activates the reflex pathway without involving arterial baroreceptors, the central property of the arterial baroreceptor–RSNA and –HR reflexes is characterized by evoked responses of RSNA and HR to ADN stimulation. Thus, the effect of salt loading on the central property of the ABR was assessed by the magnitude of reflex inhibition in the PSTH of RSNA (Fig 4) and HR caused by electrical stimulation of the ADN. At a stimulus frequency of 100 Hz and intensity of 0.5 to 10 V, intended to elicit the ABR originating from myelinated baroreceptor afferents, the normalized response magnitude of RSNA was significantly attenuated at all stimulus intensities in SHR fed a high salt diet compared with SHR fed a normal salt diet (marked by a dagger in Fig 5A). By contrast, in WKY fed a high salt diet, the normalized response magnitude of RSNA was significantly greater at all stimulus intensities than in WKY fed a normal salt diet (marked by an asterisk in Fig 5A). These results indicate that salt loading centrally attenuates the ABR mediated by myelinated ADN fibers in young SHR but potentiates it in young WKY.
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P<.05,
At a stimulus frequency of 25 Hz, intended to elicit the ABR originating from unmyelinated baroreceptor afferents, the normalized response magnitude of RSNA did not differ significantly among the four groups (Fig 5B
). Salt loading in young WKY and SHR did not appear to have significant central modulatory effects on the ABR originating from unmyelinated ADN fibers.
With respect to the reflex HR response, there were no significant differences among the four groups at a stimulus frequency of either 25 or 100 Hz (Fig 6). We conclude that salt loading impairs the central property of the arterial baroreceptor–renal sympathetic reflex in young SHR but potentiates it in young WKY and that the reflex pathway activated by myelinated fibers of the ADN is involved in this salt-induced reflex modulation.
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Discussion |
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We compared the effect of salt loading on baseline arterial pressure and RSNA as well as the overall and central properties of the ABR between young WKY and SHR. In agreement with our previous study,19 salt loading in young SHR resulted in accelerated hypertension, an increase in RSNA, and impairment of both overall and central properties of the arterial baroreceptor–renal sympathetic reflex arising from myelinated baroreceptor afferents. In young WKY, on the other hand, the same salt loading induced facilitation of both overall and central properties of the ABR arising from myelinated baroreceptor afferents, without significant changes in baseline arterial pressure and RSNA. Thus, a high salt diet differentially modulated the arterial baroreceptor–renal sympathetic reflex in young WKY and SHR, and modification of the central reflex mechanism was involved in this process.
Impairment of ABR in SHR
In the present study, 10-week-old SHR fed a normal salt diet did not develop impairment of the overall property of the ABR despite significant elevation of baseline arterial pressure and RSNA. In keeping with this result, Judy and Farrell28 demonstrated that impairment of the arterial baroreceptor–renal sympathetic reflex in SHR on a normal salt diet was not apparent until establishment of hypertension at about 15 weeks of age or later.
A report by Calhoun et al,29 however, showed a conflicting result that the sensitivity of arterial baroreflex control of lumbar sympathetic nerve activity (LSNA) in 9-week-old salt-sensitive SHR was blunted compared with age-matched normotensive WKY on a normal salt diet. We suspect that the apparent discrepancy between their results and ours depends on the difference in the parameter measured. We selected RSNA rather than LSNA to monitor the reflex response. As previously discussed,19 although RSNA reflects sympathetic vasomotor fiber activity, LSNA can be considered to reflect various modalities, such as vasomotor, sudomotor, and piloerector fibers. For this reason, these two sympathetic nerves may respond differently to baroreceptor stimulation in normotensive and/or hypertensive animals.
As to impairment of the central property of the ABR, Gonzalez et al30 reported that in 19-week-old SHR on a normal salt diet with established hypertension, reflex inhibition of RSNA by electrical stimulation of the ADN was attenuated compared with age-matched normotensive WKY. In 10-week-old SHR on a normal salt diet in the present study, the central property of the ABR was preserved despite elevation of baseline arterial pressure and RSNA. It thus seems likely that in SHR fed a normal salt diet, the overall and central impairment of the arterial baroreceptor–renal sympathetic reflex is not responsible for the spontaneously developed hypertension but is secondary to prolonged hypertension.
In salt-loaded young SHR, impairment of the overall and central properties of the ABR was associated with increases in arterial pressure and RSNA. This result also conflicts with the report by Calhoun et al29 that salt loading in salt-sensitive SHR enhanced rather than attenuated the response of LSNA to stimulation of arterial baroreceptors in the conscious, unrestrained condition. We speculate that the discrepancy is due to the selected parameters, ie, LSNA versus RSNA, as discussed above. The effect of halothane anesthesia could not account for the discrepancy because in our experiments, the ABR was obtained under 0.6% to 0.8% halothane, the level at which the reflex response of sympathetic fibers should be comparable to that obtained in the conscious state.31 Actually, the sensitivity of the arterial baroreceptor–renal sympathetic reflex was similar to that in conscious SHR reported by Kumagai et al.23
Although the mechanism by which dietary salt intake centrally impairs the ABR is unknown, some possibilities include the following. An increase in sodium concentration in cerebrospinal fluid may cause the abnormality, because intracerebroventricular infusion of hypertonic NaCl in rats has been shown to attenuate the reflex HR response in the ABR and elevate arterial pressure.32 33 34 However, a chronic increase in sodium concentration in cerebrospinal fluid in SHR fed a high salt diet is controversial.35 36 An abnormal increase in a ouabainlike substance in cerebrospinal fluid may also deteriorate the central mechanism of the ABR, as supported by a recent finding in salt-loaded SHR that immunological blockade of a central ouabainlike substance by its antibody Fab fragments sensitized rather than suppressed the baroreceptor-induced changes in RSNA.37 The possibility remains, however, that salt-induced hypertension secondarily impairs the central reflex.
Potentiation of ABR in WKY
In agreement with salt-induced potentiation of the ABR in WKY, salt loading facilitates the ABR in other salt-resistant animal models.16 17 Moreover, Huang and Leenan18 demonstrated in young WKY differential modulatory action of salt loading on ABR gain, ie, augmentation of the RSNA response, and attenuation of the HR response. This result suggests that salt-induced modulation in WKY occurred within the central nervous system but not at peripheral receptors, because resetting of arterial baroreceptors is expected to modulate RSNA and HR reflexes in a similar manner. We therefore directly examined whether the central property of the ABR was altered in salt-loaded WKY and found that the renal sympathetic reflex was centrally potentiated. In addition, as in SHR, the central mechanism of the ABR by myelinated afferents in WKY seems to be more sensitive to high salt intake compared with that by nonmyelinated afferents. The absence of an alteration in the central property of the HR baroreflex, as discussed in our previous study,19 does not automatically imply that this reflex is not affected centrally because of the short duration (1 second) of electrical stimulation of the ADN.
The mechanism responsible for salt-induced central potentiation of the ABR in WKY is not clear. It was not secondary to hypertension, since baseline arterial pressure did not significantly change after salt loading. A likely mechanism would be involvement of the renin-angiotensin system. There is a well-documented inverse relation between salt intake or subsequent expansion of plasma volume and plasma renin activity.38 Because angiotensin II is known to depress the ABR by its central action through the area postrema,39 expected depression of plasma renin activity by salt loading would potentiate the ABR through diminishing the angiotensin II action. Consistent with this hypothesis is a finding that in salt-resistant rabbits with impaired control of HR by the ABR, salt loading diminished plasma renin activity and simultaneously restored the reflex HR response.17
Summary and Perspectives
In summary, salt loading in young WKY centrally potentiated the arterial baroreceptor–renal sympathetic reflex without changing baseline arterial pressure and renal sympathetic activity, whereas in young SHR, it caused central impairment of the reflex, with exaggerated hypertension and sympathetic overactivity. An opposite mode of the central modulation may account at least partly for the difference in salt sensitivity of arterial pressure and renal sympathetic activity between SHR and WKY.
Although salt loading potentiates the ABR without alterations in arterial pressure in intact WKY and Sprague-Dawley rats, subsequent removal of the ABR by sinoaortic denervation leads to a sustained increase in arterial pressure during salt loading.18 40 41 It is thus likely that impairment of the ABR may play a crucial role in salt-induced hypertension and that potentiation protects against it.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Part of this work was supported by a Grant-in-Aid (07457576, 06670047) for Scientific Research.
Received July 31, 1996; first decision September 11, 1996; accepted September 11, 1996.
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 M. Fujita, K. Ando, A. Nagae, and T. Fujita Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension Hypertension, August 1, 2007; 50(2): 360 - 367. [Abstract] [Full Text] [PDF]
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M. Fujita, T. Kuwaki, K. Ando, and T. Fujita Sympatho-Inhibitory Action of Endogenous Adrenomedullin Through Inhibition of Oxidative Stress in the Brain Hypertension, June 1, 2005; 45(6): 1165 - 1172. [Abstract] [Full Text] [PDF]
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 T. Sato, T. Kawada, M. Inagaki, T. Shishido, M. Sugimachi, and K. Sunagawa Dynamics of sympathetic baroreflex control of arterial pressure in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R262 - R270. [Abstract] [Full Text] [PDF]
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J. Y.H. Chan, L.-L. Wang, H.-Y. Lee, and S. H.H. Chan Augmented Upregulation by c-fos of Angiotensin Subtype 1 Receptor in Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats Hypertension, September 1, 2002; 40(3): 335 - 341. [Abstract] [Full Text] [PDF]
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U. C. Kopp, M. Z. Cicha, and L. A. Smith Endogenous angiotensin modulates PGE2-mediated release of substance P from renal mechanosensory nerve fibers Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R19 - R30. [Abstract] [Full Text] [PDF]
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A. Ergul Hypertension in Black Patients : An Emerging Role of the Endothelin System in Salt-Sensitive Hypertension Hypertension, July 1, 2000; 36(1): 62 - 67. [Abstract] [Full Text] [PDF]
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 T. Sato, T. Kawada, T. Shishido, M. Sugimachi, J. Alexander Jr, and K. Sunagawa Novel Therapeutic Strategy Against Central Baroreflex Failure : A Bionic Baroreflex System Circulation, July 20, 1999; 100(3): 299 - 304. [Abstract] [Full Text] [PDF]
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T. Sato, T. Kawada, M. Inagaki, T. Shishido, H. Takaki, M. Sugimachi, and K. Sunagawa New analytic framework for understanding sympathetic baroreflex control of arterial pressure Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2251 - H2261. [Abstract] [Full Text] [PDF]
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T. Sato, T. Kawada, H. Miyano, T. Shishido, M. Inagaki, R. Yoshimura, T. Tatewaki, M. Sugimachi, J. Alexander Jr., and K. Sunagawa New simple methods for isolating baroreceptor regions of carotid sinus and aortic depressor nerves in rats Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H326 - H332. [Abstract] [Full Text] [PDF]
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 M. LO, K. L. LIU, J.-R. CLEMITSON, J. SASSARD, and N. J. SAMANI Chromosome 1 blood pressure QTL region influences renal function curve and salt sensitivity in SHR Physiol Genomics, February 11, 2002; 8(1): 15 - 21. [Abstract] [Full Text] [PDF]
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