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Am J Physiol Heart Circ Physiol 292: H593-H600, 2007. First published September 1, 2006; doi:10.1152/ajpheart.00181.2006 Free Article
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Baroreflex responses to electrical stimulation of aortic depressor nerve in conscious SHR

Helio C. Salgado,1 Álvaro R. Barale,1 Jaci A. Castania,1 Benedito H. Machado,1 Mark W. Chapleau,2 and Rubens Fazan, Jr.1

1Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; and 2Departments of Internal Medicine and Physiology and Biophysics, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 20 February 2006 ; accepted in final form 31 August 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Baroreflex responses to changes in arterial pressure are impaired in spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances were measured before and during electrical stimulation (5–90 Hz) of the left aortic depressor nerve (ADN) in conscious SHR and normotensive control rats (NCR). The protocol was repeated after beta-adrenergic-receptor blockade with atenolol. SHR exhibited higher basal MAP (150 ± 5 vs. 103 ± 2 mmHg) and HR (393 ± 9 vs. 360 ± 5 beats/min). The frequency-dependent hypotensive response to ADN stimulation was preserved or enhanced in SHR. The greater absolute fall in MAP at higher frequencies (–68 ± 5 vs. –38 ± 3 mmHg at 90-Hz stimulation) in SHR was associated with a preferential decrease in hindquarter (–43 ± 5%) vs. mesenteric (–27 ± 3%) resistance. In contrast, ADN stimulation decreased hindquarter and mesenteric resistances equivalently in NCR (–33 ± 7% and –30 ± 7%). Reflex bradycardia was also preserved in SHR, although its mechanism differed. Atenolol attenuated the bradycardia in SHR (–88 ± 14 vs. –129 ± 18 beats/min at 90-Hz stimulation) but did not alter the bradycardia in NCR (–116 ± 16 vs. –133 ± 13 beats/min). The residual bradycardia under atenolol (parasympathetic component) was reduced in SHR. MAP and HR responses to ADN stimulation were also preserved or enhanced in SHR vs. NCR after deafferentation of carotid sinuses and contralateral right ADN. The results demonstrate distinct differences in central baroreflex control in conscious SHR vs. NCR. Inhibition of cardiac sympathetic tone maintains reflex bradycardia during ADN stimulation in SHR despite impaired parasympathetic activation, and depressor responses to ADN stimulation are equivalent or even greater in SHR due to augmented hindquarter vasodilation.

spontaneously hypertensive rats; arterial pressure; heart rate; atenolol

BARORECEPTOR AFFERENT SENSITIVITY (1, 2, 19, 43) and baroreflex-mediated changes in heart rate (HR) (25, 38) are consistently impaired in spontaneously hypertensive rats (SHR). More controversial is baroreflex control of sympathetic nerve activity, which has been reported to be impaired (8, 10), preserved (22, 33, 46), or augmented (46) in SHR. The inconsistent findings may reflect, in part, differential baroreflex control of sympathetic activity to different regions and use of anesthesia in many of the studies. In the majority of studies, baroreflex responses were measured in response to drug-induced changes in arterial blood pressure (BP), which does not allow assessment of reflex changes in vascular resistance.

The goal of the present study was to compare the magnitude of reflex responses to electrical stimulation of baroreceptor afferents in the aortic depressor nerve (ADN) in conscious normotensive control rats (NCR) and SHR. This approach allowed us to assess not only the fall in HR but also the decrease in BP and regional vascular resistances. Furthermore, we hypothesized that electrical activation of baroreceptor afferents would more effectively inhibit HR and BP in SHR due to bypassing mechanosensory transduction, which is known to be impaired in SHR (1, 2, 19, 43), and the importance of elevated sympathetic activity in mediating the hypertension in this model (8, 26, 27, 39). Impaired baroreflex control of HR in SHR has been attributed primarily to a defect in parasympathetic control (25, 38). To assess the relative roles of parasympathetic activation and sympathetic inhibition to the reflex decreases in BP, we recorded responses to ADN stimulation both before and after administration of the beta1-adrenergic-receptor blocker atenolol.

Reflex responses to electrical stimulation of baroreceptor afferents have been studied in a variety of species, usually under anesthesia because of technical difficulties in implementing the technique in conscious animals (12–14, 16–18, 21, 23, 28, 41, 42, 47). To our knowledge, all of the previous studies that have examined responses to ADN stimulation in SHR have been carried out under anesthesia (21, 23, 41, 47), which can profoundly influence baseline parasympathetic and sympathetic tone, peripheral vascular resistance, and the central mediation of the baroreflex (47).

Recently, there has been a resurgence of interest in using electrical stimulation of baroreceptor afferents as a means to lower BP in conscious dogs and patients with hypertension (31, 32, 44). We recently developed a technique to stimulate the aortic depressor nerve (ADN) in conscious freely moving rats (9, 35) and have employed this methodology in the present study to investigate baroreflex function in SHR.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Male NCR (Wistar) and SHR (18–22 wk of age, 270–340 g) were used in the present study. All procedures were reviewed and approved by the Committee of Ethics in Animal Research at the University of São Paulo, School of Medicine at Ribeirão Preto.

The methodological approaches to stimulate the left ADN and record simultaneously the BP, HR, and regional blood flows have been described elsewhere (9, 24, 35). Briefly, under thiopental sodium anesthesia (40 mg/kg; Sigma, St. Louis, MO), a 4–6 mm length of the left ADN was carefully isolated below its juncture with the superior laryngeal nerve and placed on a bipolar platinum electrode with an interelectrode distance of 2 mm. The correct identification of the nerve was confirmed by its typical pattern of discharge synchronous with arterial pulse pressure. The ADN was covered with silicone impression material (Super-Dent; Carlisle Laboratories, Rockville Center, NY). A 30-min period was allowed for complete polymerization of the silicone impression material, and the activity of the nerve was recorded again to verify the integrity of the signal. Once the integrity of the signal was confirmed, the fine platinum wires of the electrodes were exteriorized on the back of the rats and soldered to a small plug to be connected to the electrical stimulator.

Under the same anesthesia, the femoral artery and vein were catheterized with polyethylene tubing (PE-50 and PE-10, Intramedic; Becton Dickinson, Sparks, MD) for arterial BP recording and intravenous drug administration, respectively. In addition, a laparotomy was performed for the placement of miniaturized Doppler probes (Iowa Doppler Products, Iowa City, IA) around the superior mesenteric artery or inferior abdominal aorta to measure changes in blood flow velocity and calculate mesenteric or hindquarter vascular resistance, respectively (24). Catheters and flow probes were exteriorized on the back of the rats, and surgical incision sites were closed by sutures. Twenty-four hours after the end of the surgery, the rats were connected to the recording system, which consisted of a pressure transducer (P23Gb; Statham Instruments, Hato Hey, Puerto Rico), a pulsed Doppler flowmeter (545C-4; Department of Bioengineering, The University of Iowa, IA), and an electrical stimulator (EMG/EP, N200/A; BioMed, Budapest, Hungary). The signals, i.e., pulsatile arterial pressure, mean arterial pressure (MAP), and regional (mesenteric or hindquarter) blood flow velocity were fed to an IBM personal computer equipped with a 12-bit analog-to-digital interface (CAD 12/36 Lynx Eletrônica, São Paulo, Brazil) and continuously sampled (500 Hz). HR was derived from the BP trace (pulse intervals), and vascular resistances were calculated online as the ratio of MAP to mean blood flow velocity with computer software (Advanced CODAS; Dataq Instruments, Akron, OH).

Cardiovascular variables were recorded for at least 15 min before electrical stimulation of the ADN (1 mA, 2-ms pulse length, for 5 s) at 5, 10, 15, 30, 50, 70, and 90 Hz in a random sequence, before and after the administration of the beta1-adrenergic-receptor blocker atenolol (2 mg/kg iv; Sigma). Each stimulus was applied for 5 s at intervals of at least 5 min. After the administration of atenolol, we waited 15 min before beginning a new series of electrical stimulations. The differences between the prestimulation baseline levels of MAP, HR, and vascular resistances measured over 15–20 s and the maximum changes in these variables elicited by each frequency of peak responses to electrical stimulation (averaged over ~0.5 s) were quantified. Changes in vascular resistance were calculated for mesenteric and hindquarter vascular beds as described by Haywood et al. (24). The protocol was successfully carried out in 18 intact NCR and 18 intact SHR.

Reflex changes in BP evoked by left ADN stimulation may be buffered by the remaining intact baroreceptors. To evaluate this possibility, additional experiments was performed in NCR (n = 7) and SHR (n = 7). At the time of instrumentation, the carotid sinus baroreceptors and right ADN were denervated by a procedure originally described by Krieger (29) with slight modifications. The adventitia and associated connective tissues were stripped from the carotid sinus regions, including the adjacent internal, external, occipital, and common carotid arteries, followed by sectioning of the carotid sinus nerves. Next, the right common carotid artery and right vagal trunk were isolated and retracted, enabling identification of the right ADN. The ADN and the communicating branch of the ADN leading to the superior laryngeal nerve were sectioned. The right superior cervical ganglion and superior laryngeal nerve were excised. The incision was closed, and the rat was allowed to recover for 24 h before the experiment was conducted.

Data are presented as means ± SE. Frequency-response data for ADN stimulation in SHR and NCR were analyzed by repeated-measures two-way ANOVA (group: SHR vs. NCR; repeated measures: stimulus frequency). Within each group of rats, the magnitudes of changes in hindquarter and mesenteric vascular resistances were compared by a separate two-way ANOVA. The effects of atenolol on the frequency-response data in each group were analyzed by repeated-measures two-way ANOVA. When ANOVA was significant, Tukey's multiple comparison post hoc test was used to test for differences between means. Baseline values of MAP, HR, and vascular resistances before and after atenolol were compared by paired t-test. Differences in baseline values in NCR vs. SHR were compared by unpaired t-test. Differences were considered significant when P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Basal MAP and HR before and after atenolol. The basal level of MAP in SHR was higher than in NCR (150 ± 5 vs. 103 ± 2 mmHg). SHR also had a significantly higher HR than NCR (393 ± 9 vs. 360 ± 5 beats/min). Atenolol decreased basal HR to a significantly greater extent in SHR (from 393 ± 9 to 340 ± 4 beats/min, change of 53 ± 8 beats/min) than in NCR (from 360 ± 5 to 349 ± 5 beats/min, change of 11 ± 4 beats/min). Atenolol did not change basal MAP in NCR (103 ± 2 vs. 105 ± 2 mmHg) but did slightly increase MAP in SHR (from 150 ± 5 to 163 ± 3 mmHg).

Hemodynamic responses to electrical stimulation of ADN. Figure 1 illustrates the hypotension, bradycardia, and decrease in hindquarter vascular resistance elicited by electrical stimulation (30 Hz) of the ADN in conscious NCR and SHR. Figure 2 illustrates the responses to ADN stimulation in another pair of rats (NCR and SHR) that depict the fall in mesenteric vascular resistance. The group data for the changes in MAP and HR elicited by electrical stimulation of ADN are summarized in Fig. 3. ADN stimulation caused significant frequency-dependent decreases in MAP and HR (Fig. 3). The absolute decreases in MAP (mmHg) were similar in NCR vs. SHR at low frequencies of ADN stimulation and significantly larger in SHR at higher frequencies of stimulation (Fig. 3). The frequency-dependent reflex decreases in HR in response to ADN stimulation were not significantly different in SHR vs. NCR (Fig. 3).


Figure 1
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  		Fig. 1. Typical tracings from a normotensive control rat (NCR) and a spontaneously hypertensive rat (SHR) showing pulsatile and mean arterial pressure (top), heart rate (middle), and hindquarter vascular resistance (bottom) before, during, and after 5 s of electrical stimulation (ES) of the left aortic depressor nerve (ADN; 1-mA pulses, 2-ms duration, 30 Hz). bpm, Beats/min.

 

Figure 2
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  		Fig. 2. Typical tracings from another NCR and a SHR showing pulsatile and mean arterial pressure (top), heart rate (middle), and mesenteric vascular resistance (bottom) before, during, and after 5 s of electrical stimulation of the left ADN (1-mA pulses, 2-ms duration, 30 Hz).

 

Figure 3
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  		Fig. 3. Baroreflex in NCR and SHR. Shown are frequency-dependent changes in mean arterial pressure ({Delta}MAP) and heart rate ({Delta}HR) in response to electrical stimulation of the left ADN (1-mA pulses, 2-ms duration) in NCR and SHR. Baseline levels of MAP averaged 103 ± 2 and 150 ± 5 mmHg in NCR and SHR, respectively. Baseline HR averaged 360 ± 5 and 393 ± 9 beats/min in NCR and SHR, respectively. Data are means ± SE. *Significant difference in SHR vs. NCR (ANOVA and Tukey's test; P < 0.05).

 
ADN stimulation significantly decreased both hindquarter and mesenteric vascular resistances in both NCR and SHR (Figs. 1, 2, and 4). NCR showed similar decreases in mesenteric and hindquarter vascular resistance. On the other hand, the reflex decrease in hindquarter vascular resistance was significantly greater than the decrease in mesenteric vascular resistance in SHR (Fig. 4). The difference in the magnitude of the reflex vasodilatation in SHR vs. NCR did not reach statistical significance.


Figure 4
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  		Fig. 4. Frequency-dependent changes in hindquarter and mesenteric vascular resistances, in response to electrical stimulation of the left ADN (1-mA pulses, 2-ms duration) in NCR (top) and SHR (bottom). Data are means ± SE. *Significant difference in hindquarter vs. mesenteric vascular resistance (ANOVA and Tukey's test, P < 0.05). Although the reflex fall in hindquarter vascular resistance was significantly greater than the fall in mesenteric resistance in SHR, the difference in the magnitude of the reflex in SHR vs. NCR did not reach statistical significance.

 
Effects of atenolol on responses to electrical stimulation of ADN. The group data for changes in MAP and HR elicited by electrical stimulation of the ADN, before and after blockade of beta1-adrenergic receptors with atenolol, are summarized in Fig. 5. In NCR, stimulation of the ADN produced frequency-dependent decreases in both MAP and HR, neither of which was affected by atenolol (Fig. 5). As observed in NCR, atenolol did not influence baroreflex-mediated decreases in MAP in SHR (Fig. 5). In contrast, atenolol significantly attenuated the reflex decreases in HR in SHR (Fig. 5). The residual parasympathetic-mediated baroreflex bradycardia in the presence of atenolol was significantly reduced in SHR compared with that in NCR (Fig. 5). The magnitude of the reflex decrease in HR evoked by 90-Hz ADN stimulation averaged –116 ± 16 beats/min in NCR and –88 ± 14 beats/min in SHR (P < 0.05). Atenolol did not influence the baroreflex-mediated decreases in hindquarter and mesenteric vascular resistances in either NCR or SHR (data not shown).


Figure 5
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  		Fig. 5. Frequency-dependent {Delta}MAP and {Delta}HR in response to electrical stimulation of left ADN (1-mA pulses, 2-ms duration) before (basal) and after atenolol in NCR (left) and SHR (right). Data are means ± SE. *Significant difference before (basal) vs. after atenolol, P < 0.05.

 
Baroreflex after carotid sinus and contralateral ADN deafferentation. We considered the possibility that the preserved or enhanced baroreflex-mediated decreases in HR and BP in SHR may reflect impaired baroreflex buffering of the BP fall by the remaining intact baroreceptors. To address this possibility, we performed additional experiments in rats with bilateral carotid sinus and contralateral right ADN deafferentation. Similar to what was found in intact rats (Fig. 3), baroreflex-mediated decreases in MAP and HR were preserved at low frequencies of ADN stimulation and significantly enhanced at high frequencies of stimulation in denervated SHR vs. denervated NCR (Fig. 6). The reflex decreases in HR were not significantly different between the groups (Fig. 6). Thus the preserved (or enhanced) baroreflex in intact SHR cannot be attributed to impaired baroreflex buffering.


Figure 6
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  		Fig. 6. Baroreflex in carotid sinus and contralateral ADN-denervated NCR and SHR. Shown are frequency-dependent {Delta}MAP and {Delta}HR in response to electrical stimulation of the left ADN (1-mA pulses, 2-ms duration). Baseline levels of MAP averaged 103 ± 3 and 178 ± 4 mmHg in NCR and SHR, respectively. Baseline HR averaged 308 ± 18 and 369 ± 14 beats/min in NCR and SHR, respectively. Data are means ± SE. *Significant difference in SHR vs. NCR (ANOVA and Tukey's test, P < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results of the present study demonstrate distinct differences in central baroreflex control in conscious SHR vs. NCR. Inhibition of cardiac sympathetic tone maintains reflex bradycardia during ADN stimulation in SHR despite impairment of parasympathetic control, and depressor responses to ADN stimulation are equivalent or even greater in SHR due to augmented hindquarter vasodilation.

Our results are discussed in relation to previous studies of baroreflex function in SHR, use of the ADN stimulation method to study the baroreflex, and the implications of our findings.

Previous studies of baroreflex function in SHR. Baroreceptor afferent sensitivity (1, 2, 19, 30, 43) and baroreflex-mediated changes in HR (25, 38) have been shown to be consistently impaired in SHR. The decreased baroreflex sensitivity for control of HR has been attributed primarily to a defect in parasympathetic control (25, 38). Our finding that the HR response to ADN stimulation in SHR is preserved before beta1-receptor blockade with atenolol but attenuated after beta1-receptor blockade is consistent with the notion of a selective defect in the parasympathetic limb of baroreflex control of HR in SHR.

The lack of effect of atenolol on baroreflex-mediated bradycardia in NCR was expected. The baroreceptor reflex bradycardia during rapid increases in BP is normally mediated by the parasympathetic nervous system in conscious rats (25, 45). Furthermore, in a previous study, we showed that the bradycardia elicited by brief electrical stimulation of the ADN in conscious NCR was abolished by methylatropine (9), confirming the predominant role of the parasympathetic nervous system in mediating rapid bradycardic responses to brief increases in baroreceptor activity. The present results indicate that, in contrast with NCR, withdrawal of sympathetic activity contributes significantly to baroreflex-mediated bradycardia in SHR but not in NCR. This effect may relate, in part, to the higher basal level of cardiac sympathetic tone in SHR, supported in the present study by the significantly greater fall in HR after atenolol administration in SHR vs. NCR. The absence of a sympathetic component of baroreflex bradycardia in NCR may reflect, in part, the low basal sympathetic tone in conscious NCR.

The contribution of the baroreflex-mediated decrease in HR to the fall in BP is likely to be negligible. We have demonstrated that attenuation of the HR response to baroreceptor stimulation by cardiac autonomic blockade does not affect the reflex decreases in BP (Fig. 5) or regional vascular resistance (9). Interestingly, the enhanced depressor response to ADN stimulation in SHR was associated with preferential vasodilation in the hindlimb compared with the mesenteric vascular bed. This result is consistent with previous studies that demonstrated a stronger baroreflex influence on hindlimb vs. mesenteric vascular resistance (9, 15, 34) and a minimal contribution of the mesenteric vasculature to the elevated peripheral vascular resistance in SHR (27).

The baroreflex-mediated vasodilation and fall in BP are determined by both the magnitude of inhibition of sympathetic nerve activity and the vascular response to sympathetic withdrawal. Hypertrophy of arterioles in SHR may alter the extent of vasodilation for a given fall in sympathetic activity and/or the degree of passive vasoconstriction accompanying the fall in BP (40). Because we have not measured sympathetic activity, we cannot distinguish these components. Baroreflex control of renal sympathetic nerve activity has been reported to be attenuated (8, 10), normal (22, 33, 46), and enhanced (46) in SHR. Also, in contrast to our results in conscious SHR, the bradycardic responses to ADN stimulation are blunted and the depressor response to ADN stimulation has been reported to be either attenuated or unchanged in anesthetized SHR compared with NCR (21, 23, 41, 47).

The reasons for conflicting results between studies are not well understood, but multiple factors are likely to play a role, including the presence or absence of anesthesia and the baseline level of sympathetic activity. For example, resting sympathetic tone and HR are elevated in SHR and the magnitude of baroreflex-mediated bradycardia is greater in the awake state than in the anesthetized (25, 38, 41, 47, and present findings). Less well appreciated are the effects of the type of baroreceptor activated and the duration of the period of activation on the reflex response. Electrical activation of baroreceptor afferents provides unique insights into the influence of these factors as discussed below.

Assessment of baroreflex by response to ADN stimulation. Reflex responses to stimulation of the ADN in some species (e.g., cats, dogs) and the carotid sinus nerves are complex because of the presence of both baroreceptor and chemoreceptor afferent fibers (12, 14). Fortunately, the rat ADN contains a relatively pure population of baroreceptor afferents (16–18, 42). Consequently, reflex responses to electrical stimulation of rat ADN can be attributed to baroreceptor activation.

Use of electrical stimulation of baroreceptor afferents provides several advantages in studies of baroreflex function. This approach enables the assessment of baroreflex-mediated changes in vascular resistance and BP, responses that cannot be assessed by often-used pharmacological techniques (e.g., phenylephrine and nitroprusside administration). Furthermore, electrical stimulation of afferent fibers bypasses the site of baroreceptor mechanosensory transduction, which is known to be impaired in SHR (1, 2, 19, 43). The reflex response to ADN stimulation therefore provides information about the central processing of the afferent input and the properties of the central and efferent components of the reflex.

Electrical stimulation enables exquisite control of the afferent signal transmitted to the central nervous system. Increasing the intensity of the applied current or voltage pulses recruits additional nerve fibers with myelinated A fibers activated at lower intensities and nonmyelinated C fibers activated at higher intensities (12–14, 16–18, 42). In the present study, we used a relatively high stimulus intensity (1 mA, 2-ms pulses) in an attempt to activate essentially all fibers in the ADN and varied the frequency of stimulation over a wide range to define the full frequency-response relationship.

The relationship between stimulus frequency and reflex response differs for myelinated A fibers and nonmyelinated C fibers in the rat ADN with the full range of reflex responses occurring between 1 and ~10 Hz for C-fiber stimulation and between 15 and ~100 Hz for A-fiber stimulation (16, 18). Interestingly, the absolute changes in BP and HR evoked by ADN stimulation were similar in SHR and NCR at low frequencies of stimulation but were significantly enhanced in SHR at high frequencies of stimulation (Figs. 3 and 6). These results suggest that the reflex response to activation of C-fiber baroreceptors is similar in SHR and NCR but that the additional input from A-fiber afferents at higher frequencies of stimulation enhances the reflex response to a much greater extent in SHR than in NCR.

Previous studies of anesthetized NCR have demonstrated that HR responses to supramaximal activation of A and C fibers in ADN are additive, whereas BP responses are not (16, 18). Our results confirm a strong additive interaction in regards to HR control in conscious NCR. In conscious SHR, this additive interaction between A- and C-fiber afferents is enhanced and influences not only baroreflex control of HR but also BP. The increased reliance on A-fiber input in SHR is consistent with a preferential reduction in the number of nonmyelinated C fibers in ADN of SHR (19, 20).

Baroreceptor afferents were intact in the majority of our experiments. Convergence of carotid sinus and aortic baroreceptor afferent inputs onto neurons in nucleus tractus solitarius may facilitate or inhibit neurotransmission and baroreflex responses depending on the timing of the inputs (3, 11, 28, 36, 37). In addition, baroreceptor fibers in the contralateral ADN and carotid sinus nerves might buffer the fall in BP during left ADN stimulation. Less effective buffering in SHR might explain the preserved falls in HR and BP during ADN stimulation.

To address this issue, we performed a separate group of experiments in which both carotid sinuses and the contralateral right ADN were denervated beforehand. The preserved (or enhanced) reflex responses in SHR were still apparent after denervation of the remaining three sets of baroreceptor afferents (Fig. 6). Denervation of contralateral ADN and carotid sinuses also did not affect the BP response to ADN stimulation in pentobarbital sodium-anesthetized Sprague-Dawley rats (17). Thus preserved baroreflex responses to ADN stimulation in SHR cannot be attributed to impaired baroreflex buffering by other sets of baroreceptors.

There are limitations to our ADN stimulation protocol that should be considered. The synchronous continuous activation of essentially all afferents in ADN differs from the physiological state where the pattern of action potential firing is pulsatile (in phase with the arterial pressure pulse) and the recruitment pattern of individual baroreceptor fibers varies depending on the BP level, the pressure thresholds of individual fibers, and fiber type (1, 2, 4–7). In addition, we limited the duration of ADN stimulation to 5 s to facilitate testing multiple frequencies of stimulation and to minimize buffering of the reflex change in BP by other baroreceptor afferents in the carotid sinus nerves and contralateral ADN. The results of previous studies suggest that impairment of baroreflex-mediated decreases in sympathetic nerve activity and BP in SHR is most evident during sustained periods of baroreceptor stimulation; the immediate reflex response is relatively normal (21, 47). Future studies are needed to determine whether the augmented depressor responses to high-frequency stimulation of ADN in conscious SHR are maintained throughout more prolonged periods of ADN stimulation.

Perspectives. The concept of decreased baroreflex sensitivity in hypertension is widely accepted and is supported by numerous studies in humans and animal models, including SHR. The evidence for decreased baroreflex sensitivity in SHR comes mostly from studies of baroreflex control of HR and studies of control of sympathetic nerve activity and BP in anesthetized rats. In the present study, we used a novel preparation that enables measurement of responses to electrical stimulation of baroreceptor afferents in the ADN in conscious rats (9, 35).

Our results demonstrate well-preserved or even enhanced baroreflex responses in SHR that reflect alterations in central baroreflex control, high resting sympathetic activity susceptible to inhibition by strong baroreceptor input, and bypassing of impaired mechanosensory transduction by ADN stimulation.

The effective baroreflex-mediated decreases in vascular resistance and BP encourage further investigation into the use of electrical activation of baroreceptor afferents in the treatment of chronic hypertension. In fact, recent studies have demonstrated sustained reductions in BP during chronic electrical activation of carotid sinus baroreceptor afferents in conscious dogs and humans with hypertension (31, 32, 44).


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa de Apoio a Núcleos de Excelência (PRONEX), and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).


   ACKNOWLEDGMENTS
 
The authors thank Mauro Oliveira and Carlos Alberto Aguiar da Silva for excellent technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. C. Salgado, Dept. of Physiology, School of Medicine of Ribeirão Preto, Univ. of São Paulo, Av. Bandeirantes, 3900, 14049–900 Ribeirão Preto, SP, Brazil (e-mail: hcsalgad{at}fmrp.usp.br)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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A. E. Simms, J. F. R. Paton, and A. E. Pickering
Hierarchical recruitment of the sympathetic and parasympathetic limbs of the baroreflex in normotensive and spontaneously hypertensive rats
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