Original Article

Differential Contribution of Afferent and Central Pathways to the Development of Baroreflex Dysfunction in Chronic Kidney DiseaseNovelty and Significance

Ibrahim M. Salman, Cara M. Hildreth, Omar Z. Ameer, Jacqueline K. Phillips
https://doi.org/10.1161/HYPERTENSIONAHA.113.02110
Hypertension. 2014;63:804-810
Originally published March 12, 2014

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Abstract

The effects of chronic kidney disease on baroreflex control of renal sympathetic nerve activity (RSNA) and deficits in afferent and central components of the baroreflex were studied in juvenile and adult male Lewis Polycystic Kidney (LPK) and control Lewis rats under anesthesia (n=35). Blood pressure (BP), heart rate (HR), aortic depressor nerve activity (ADNA), and RSNA were determined after pharmacological manipulation of BP. Responses to ADN stimulation (4.0 V, 2.0 ms, 1–24 Hz) were determined, and the aortic arch was collected for histomorphometry. In juvenile LPK versus age-matched Lewis rats, gain of RSNA (−1.5±0.2 versus −2.8±0.2%/mm Hg; P<0.05) and ADNA (2.5±0.3 versus 5.0±0.6%/mm Hg; P<0.05), but not HR barocurves, were reduced. BP, HR, and RSNA responses to ADN stimulation were normal or enhanced in juvenile LPK. In adult LPK versus age-matched Lewis, the gain and range of RSNA (gain: −1.2±0.1 versus −2.2±0.2%/mm Hg, range: 62±8 versus 98±7%) and HR (gain: −0.7±0.1 versus −3.5±0.7 bpm/mm Hg, range: 44±8 versus 111±19 bpm) barocurves were reduced (P<0.05). The gain and range of the ADNA barocurves were also reduced in adult LPK versus Lewis [1.5±0.4 versus 5.2±1.1 (%/mm Hg) and 133±35 versus 365±61 (%) P<0.05] and correlated with aortic arch vascular remodeling. BP, HR, and RSNA responses to ADN stimulation were significantly reduced in adult LPK. Our data demonstrate a deficit in the afferent component of the baroreflex that precedes the development of impaired central regulation of RSNA and HR in chronic kidney disease, and that progressive impairment of both components is associated with marked dysfunction of the baroreflex pathway.

Introduction

Autonomic dysfunction is a major complication of chronic kidney disease (CKD)1,2 and is likely a key contributor to the high incidence of cardiovascular mortality in this patient population. In addition to sympathetic overdrive, evidenced by increased sympathetic nerve activity (SNA)3–5 and plasma noradrenaline levels,6 baroreflex control of heart rate (HR) is impaired.7–9 Impaired baroreflex control of HR is directly correlated with the severity of CKD10 and is an independent risk factor for sudden cardiac death in people with CKD.11 Whether or not baroreflex control of SNA is impaired in CKD is unclear, with mixed reports of normal12 and impaired9 responses. Moreover, the mechanisms underlying baroreceptor dysfunction in CKD are unknown and could relate to an inability for the baroreceptor afferents, including the aortic depressor nerve (ADN) and carotid sinus nerve,13 to sense changes in blood pressure (BP), influenced by factors such as altered vascular distensibility and mechanotransduction at the receptor level. Alternatively, central relay nuclei such as the nucleus tractus solitarius, nucleus ambiguous, or ventrolateral medullary sites may fail to produce sufficient change in vagal or sympathetic outflow, or the heart and vasculature may inadequately respond to these autonomic inputs.

Previously, we demonstrated that the Lewis Polycystic Kidney (LPK) rat, an animal model of autosomal recessive cystic kidney disease arising from a mutation in the Nek8 gene,14 develops impaired baroreflex control of HR between 10 and 12 weeks of age.15 In the present study, we wished to identify whether a temporal impairment in baroreflex control of renal SNA (RSNA) also occurs in the LPK, and at what point within the baroreflex arc dysfunction occurs. Therefore, we compared the functionality of the afferent and central components of the baroreflex in LPK and control Lewis rats, at 7–8 weeks of age, when the HR reflex is intact, and 12–13 weeks of age, when the HR reflex is impaired,15 and renal function has deteriorated.16 Because progressive remodeling occurs along the thoracic aorta in the LPK between 6 and 12 weeks of age,17 we hypothesized that similar vascular remodeling would occur along the aortic arch, a site of origin of baroreceptors, and be associated with reduced functionality of the afferent component of the baroreflex.

Methods

A detailed description of all experimental methods can be found in the Online Supplement.

Results

Baseline Data

Baseline levels of mean arterial pressure (MAP), systolic blood pressure (SBP), pulse pressure (PP), HR, and RSNA were elevated in the LPK compared with age-matched controls (Table S1 in the online-only Data Supplement). An age-related increase in PP was observed in the LPK. No difference in aortic depressor nerve activity (ADNA) was observed between LPK and age-matched controls but there was an age-related increase in the LPK, despite no concomitant increase in HR. Urinary protein:creatinine ratio was elevated in both juvenile and adult LPK versus age-matched controls and further elevated in adult versus juvenile LPK (Table S1).

Baroreceptor Reflex Control of HR, RSNA, and ADNA

Reflex HR, RSNA, and ADNA responses to pharmacologically evoked increases and decreases in BP after administration of phenylephrine and sodium nitroprusside, respectively, are illustrated in Figure 1. Representative curves showing the sigmoidal fit of the MAP-HR, MAP-RSNA, and MAP-ADNA relationship in adult Lewis and LPK rats are shown in Figure S1, and group data in Figure 2.

Figure 1.
Figure 1.

Representative raw data traces, illustrating responses of aortic depressor nerve activity (ADNA), renal sympathetic nerve activity (RSNA), and heart rate (HR) to evoked changes in arterial pressure (AP) from an (A–C) adult (12–13 weeks old) Lewis and (D–E) adult Lewis Polycystic Kidney (LPK) rats. Bursts of ADNA can be seen in association with each pulse of AP in both Lewis and LPK. In response to phenylephrine (PE, 10–50 μg/kg), RSNA is silenced and HR reduced in the Lewis (B); however, in the LPK (E), reflex sympathoinhibition and bradycardia are reduced. Significant reductions in ADNA and reflex tachycardia are observed when AP is reduced by sodium nitroprusside (SNP, 50–70 μg/kg; C and F). bpm indicates beats per minute.

Figure 2.
Figure 2.

Logistic function curves illustrating the relationship between mean arterial pressure (MAP) and heart rate (HR; A), renal sympathetic nerve activity (RSNA; B), and aortic depressor nerve activity (ADNA; C) in juvenile (7–8 weeks old) and adult (12–13 weeks old) Lewis and Lewis Polycystic Kidney (LPK) rats. Results are expressed as mean±SEM. n values are detailed in Table 1. bpm indicates beats per minute. (HR: R2=0.96±0.1, RSNA: R2=0.95±0.01; and ADNA: R2=0.97±0.01, all groups).

Baroreflex Control of HR

In both juvenile and adult LPK, there was a rightward shift in the HR baroreflex function curve compared with age-matched controls (Figure 2A), as indicated by an increase in the MAP50 (Table 1). In the juvenile LPK, the curve was shifted upward as demonstrated by an increase in the upper plateau of the curve. However, both the lower plateau and the range of the curve were not significantly different between the juvenile LPK and Lewis (Tables 1 and S2). In the adult LPK, the upper plateau of the curve did not differ compared with age-matched controls. However, the lower plateau was higher and, therefore, there was a reduction in the range of the curve in the adult LPK compared with adult Lewis (Tables 1 and S2). The gain of the reflex was comparable in the juvenile LPK and Lewis but was reduced in the adult LPK versus Lewis (Table 1). Consequently, there was an age-related reduction in both the range and the gain of the HR baroreflex in the LPK (Table 1).

View this table:
Table.

Range, Gain, and Midpoint (MAP50) of the Relationship Between MAP, HR, RSNA, and ADNA in Juvenile and Adult Lewis and Lewis Polycystic Kidney Rats

Baroreflex Control of RSNA

RSNA baroreflex function curves were shifted to the right in both the juvenile and adult LPK (Figure 2B). Accordingly, MAP50, MAP threshold (MAPthr) and MAP saturation (MAPsat) were higher in the LPK versus age-matched Lewis (Tables 1 and S2). In juvenile LPK, there was no difference in the upper and lower plateau, and therefore range, of the reflex compared with juvenile Lewis (Tables 1 and S2). In adult LPK, the upper plateau was comparable; however, the lower plateau and therefore RSNA at MAPsat were higher versus Lewis and juvenile LPK rats (Table S2). Consequently, the range of RSNA (%) was reduced in adult LPK versus adult Lewis and juvenile LPK (Table 1). The gain of the RSNA baroreflex was reduced in both juvenile and adult LPK (Table 1).

Because baseline RSNA was elevated in the LPK, baroreflex function curves were also generated using microvolt RSNA (Figure S2). Accordingly, there was an increase of the upper plateau of the reflex and RSNA at MAPthr and MAPsat in the juvenile LPK versus age-matched Lewis (Table S3). Compared to age-matched Lewis, the lower plateau was shifted upward in adult LPK, and this was associated with markedly higher measures of RSNA at MAPsat. The gain and range of the reflex expressed in microvolts was not different between the LPK and Lewis at any age; however, both parameters declined with age in the LPK.

Baroreflex Control of ADNA

Administration of sodium nitroprusside markedly reduced ADNA, whereas phenylephrine resulted in an increase in ADNA (Figure 1).

Baroreflex control of ADNA was shifted to the right in both the juvenile and adult LPK (Figure 2C). Accordingly, MAP50 and MAPsat were higher in the LPK versus Lewis (Tables 1 and S2). The range of the curves was comparable between the juvenile LPK and Lewis; however, in the adult LPK, the upper plateau, range, and ADNA at MAPsat were reduced relative to Lewis and an age-related decrease in the range was evident. The gain of the reflex was also reduced in both juvenile and adult LPK versus Lewis controls, and this reduction tended to be greater (P=0.065) in adult versus juvenile LPK (Table 1).

Central Component of Baroreflex Arc

Electric stimulation of the ADN between 1 and 24 Hz reduced RSNA, HR, and MAP in all groups (Figure 3). In juvenile LPK, the reflex sympathoinhibition was comparable with Lewis controls, consistent with results showing the relationship between ADNA and RSNA was also not different at this age (P=0.13; Figure S3). Reflex bradycardic and depressor responses were however enhanced in juvenile LPK (Figure 3). In adult LPK, reflex responses were reduced compared with Lewis controls and juvenile LPK. This was most noticeable at the higher frequencies.

Figure 3.
Figure 3.

Effect of aortic depressor nerve stimulation on renal sympathetic nerve activity (RSNA; A and B), heart rate (HR; C and D), and mean arterial pressure (MAP; E and F) in juvenile (7–8 weeks old; left) and adult (12–13 weeks old; right) Lewis and Lewis Polycystic Kidney (LPK) rats. A reduction in RSNA, HR, and MAP was observed in all experimental groups. Results are expressed as mean±SEM. aP<0.05 vs age-matched Lewis and bP<0.05 vs strain-matched juvenile rat. cP<0.05; overall 2-way ANOVA strain effect within indicated juvenile or adult age group. n/group: juvenile Lewis=5, juvenile LPK=5, adult Lewis=6, and adult LPK=7. bpm indicates beats per minute.

Sympathoinhibitory responses to ADN stimulation were also analyzed as microvolt data (Figure S4). Results were comparable with those described in terms of percentage change, with no difference between juvenile LPK and Lewis controls, but reduced RSNA reflex responses in the adult LPK, and an age-related reduction evident.

Histomorphometry of the Aortic Arch

Vascular remodeling along the aortic arch was evident in both the juvenile and adult LPK (Figure S5; Table S4). Notably, at both ages, the aortic arch was characterized by an increase in medial wall thickness, reduction in elastin content, elastin-to-collagen ratio, and an increase in the number of elastin lamellae fractures and collagen density in the tunica media. Aortic medial calcium deposition was markedly elevated in adult LPK. These parameters progressively changed with age, indicating an age-related increase in vascular hypertrophy and arteriosclerotic remodeling along the aortic arch.

There was a significant negative correlation between the gain of the ADNA baroreflex function curves and medial wall thickness, number of elastin lamellae fractures, collagen density and nucleus cross-sectional area, and a significant positive correlation with the total elastin density and elastin-to-collagen ratio (Table S5; Figure 4). The range of the ADNA baroreceptor function curve was negatively correlated with aortic medial wall thickness, number of elastin lamellae fractures, and total calcium density, whereas a positive association was seen with total elastin density and elastin-to-collagen ratio (Table S5; Figure 4).

Figure 4.
Figure 4.

Correlation between key histomorphometric variables examined in the aortic arch and afferent baroreceptor function in the juvenile (7–8 weeks old) and adult (12–13 weeks old) Lewis and Lewis Polycystic Kidney (LPK) rats. A, Elastin density vs aortic depressor nerve activity (ADNA) gain. B, Collagen density vs ADNA gain. C, Aortic media thickness vs ADNA range. D, Number of elastin lamellae fractures vs ADNA range. n=21.

Discussion

The major goal of this study was to identify whether any temporal change in baroreflex control of HR and RSNA in CKD is associated with a deficit in the afferent or central component of the baroreflex circuit. The important new findings are the following: (1) there is a temporal decline in baroreflex control of RSNA in the LPK; (2) in juvenile LPK, a deficit in the afferent component of the baroreflex is the primary deficit; (3) in adult LPK, further reduced afferent function and a decrease in central processing are associated with markedly impaired RSNA and HR baroreflexes; (4) a decline in the functionality of the afferent component of the reflex is correlated with vascular remodeling of the aortic arch. Together this shows that in CKD, full expression of baroreflex dysfunction is dependent on both impaired afferent signaling and abnormal central processing.

Afferent Signaling

An early deficit in the afferent component of the baroreflex was observed in the LPK evidenced by a reduction in the gain of the ADNA baroreflex function curves in the juvenile LPK. This impairment worsened with age in the LPK, with the adult animals exhibiting a marked reduction in the range of the reflex. This indicates that in the adult LPK, in response to changes in BP, the ADN does not respond as fast or as effectively in comparison with either juvenile LPK or age-matched Lewis. Dysfunctional baroreceptor afferent function has been previously shown in the spontaneously hypertensive rat18 and Dahl salt-sensitive hypertensive rat.19 To our knowledge, this is the first report of impaired baroreceptor afferent function in CKD.

Hypertension and increased SNA are known to cause vascular hypertrophy and loss of vessel structure, leading to the loss of aortic receptor function.20 Previously, we demonstrated vascular remodeling in the thoracic aorta of the LPK and an associated functional increase in pulse wave velocity, indicating aortic stiffness.17 In CKD patients, impaired baroreflex function directly correlates with a reduction in arterial distensibility, as evidenced by increased pulse wave velocity.21 In patients with polycystic kidney disease, this has been further demonstrated to be apparent before the onset of hypertension or reduced renal function.22 Here, we demonstrate that vascular remodeling occurs along the aortic arch, the site of aortic baroreceptor afferents, correlating with a decline in baroreceptor afferent function. These findings strongly support the hypothesis that in the LPK, hypertrophy and a reduction in elastic properties reduce aortic wall distensibility and hence impair the ability of the aortic baroreceptors to effectively transduce changes in BP.

Central Processing

Altered afferent baroreceptor function preceded any decline in the functionality of the central component of the baroreceptor reflex in the LPK. In juvenile LPK, the central component of the baroreceptor reflex was intact, and greater reductions in HR could be evoked by ADN stimulation when compared with juvenile Lewis. This enhancement may indicate a compensatory mechanism, such that in response to a reduction in afferent input, the HR baroreceptor reflex is able to buffer changes in BP. In adulthood, the LPK demonstrated reduced reflex responses to stimulation of the ADN, indicating a decline in the central component of the reflex. The impairment in central processing seems independent of the afferent fiber type because the reflex responses to both low (<10 Hz) and high (>10 Hz) frequency stimulation were reduced in the LPK, indicating that both A- and C- fiber input are impaired.23 Altered central processing of the baroreceptor reflex is a feature of other models of hypertension, including the spontaneously hypertensive rat,24 renal wrap hypertensive rats,25 and obese Zucker rats,26 and although the exact location of the deficit cannot be elucidated from the present study, it is plausible that key medullary nuclei, such as the rostral ventrolateral medulla, responsible for generating changes in SNA in accordance with the baroreflex, are abnormal in the LPK, as seen in other hypertensive rodent models.27,28

Baroreflex Function

Previously we demonstrated that, under conscious conditions, the LPK develops a temporal decline in the sensitivity of the HR baroreflex between 10 and 12 weeks of age.15 In the present study, we replicate and extend on this finding under anesthesia by showing that there is also a temporal decline in the range of the HR baroreflex in the LPK. Here, we further show that there is a temporal decline in baroreflex control of RSNA in CKD, which is associated with an increase in resting RSNA. This renal sympathetic overactivity was already evident in juvenile LPK but, interestingly, despite a decline in renal function during the same time- frame, RSNA did not further increase. This suggests that, analogous to the human condition, RSNA is increased early in the disease-course and may contribute to the further deterioration in renal function.29

In the juvenile LPK, the RSNA baroreflex gain (%) was reduced; however, the range (% or μV) of the reflex was comparable. This suggests that at this age, the baroreflex is capable of producing a full range of RSNA change, albeit at a slower rate. The decreased gain of the RSNA baroreflex is potentially contributed to by the decreased responsiveness of the ADN that we describe. In contrast, in adult LPK, the gain and range of the RSNA (%) baroreceptor function curves were impaired in comparison with both adult Lewis and juvenile LPK. We think that this change reflects a temporal decline in baroreflex control of RSNA, rendering the reflex impaired in adulthood because (1) there was no further increase in RSNA in the adult LPK that could potentially bias this data; (2) the ability to produce reflex inhibition of RSNA in response to ADN stimulation was reduced when RSNA was expressed in both normalized and absolute units; and (3) there was an age-related reduction in the gain and range of the RSNA (μV) baroreceptor curves in the LPK that was not observed in the Lewis rats. The deficit in baroreflex control of RSNA in the adult LPK observed in this study contrasts with previous findings that baroreflex control of splanchnic sympathetic outflow, while unable to maximally suppress nerve activity, is comparable in the LPK and Lewis in terms of the sensitivity of the reflex.7 Our finding of reduced baroreflex control of RSNA suggests that the reflex control of sympathetic outflow may be differentially regulated and impaired in CKD.

In conclusion, our findings indicate that in the juvenile LPK, a deficit in baroreceptor afferent function is compensated for by the central component of the baroreflex, and consequently HR baroreflex function is preserved and only a minimal impairment in baroreflex control of RSNA is observed. In the adult LPK, however, there is a loss of function in the central component of the baroreflex that, together with a reduction in afferent baroreflex function, results in markedly impaired baroreflex control of both HR and RSNA.

Perspectives and Significance

Cardiovascular autonomic dysfunction is a major cause of morbidity and mortality in patients with CKD1,2; however, the critical underlying mechanisms are not fully understood. Herein, we provide direct evidence of sympathetic overactivity, compounded with impaired baroreflex control of HR and SNA, thus emphasizing the complexity of this pathological condition. The study further highlights key pathways within the baroreflex arc that explain the mechanisms involved and could potentially be targeted for future therapeutics. We suggest that early interventional measures to treat CKD that reduce SNA, lower BP, and limit vascular remodeling may well serve to ameliorate autonomic dysfunction and therefore reduce overall cardiovascular risk in these patients.

Acknowledgments

We acknowledge technical advice and assistance provided by Dr Anita Turner, Dr Willian Korim, Rochelle Boyd (Macquarie University), Debra Birch, and Nicole Vella (The Microscopy Unit, Faculty of Science, Macquarie University).

Sources of Funding

Work in the authors’ laboratory is supported by National Health and Medical Research Council of Australia (GNT1030301, GNT1030297). I. Salman and O.Z. Ameer are recipients of Macquarie University Research Scholarships.

Disclosures

None.

Footnotes

  • Received July 26, 2013.
  • Revision received August 13, 2013.
  • Accepted December 5, 2013.

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Novelty and Significance

What Is New?

This is the first comprehensive investigation to demonstrate mechanisms underlying dysfunctional baroreflex control of heart rate and sympathetic nerve activity (SNA) in chronic kidney disease, and changes associated with disease progression.

What Is Relevant?

The kidney plays a key role in high blood pressure, with a vicious circle whereby hypertension in turn can further damage the kidney. An increase in SNA and impaired autonomic reflex responses is increasingly being recognized as a major cardiovascular risk factor for patients with chronic kidney disease. By identifying dysfunction within the baroreflex arc, future therapeutic targeting to reduce mortality accompanying chronic kidney disease may be developed.

Summary

In the Lewis Polycystic Kidney model of chronic kidney disease, SNA is elevated early in the course of renal dysfunction, whereas reflex control of heart rate and SNA becomes progressively impaired. Our novel data indicate that there is a deficit in the afferent component (aortic depressor nerve) of the baroreflex that precedes the development of impaired central regulation of RSNA and heart rate, and that the progressive impairment of both components is associated with a marked dysfunction of the baroreflex pathway. We also demonstrate that the decline in aortic depressor nerve function correlates with structural remodeling of the aortic arch.

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  • Differential Contribution of Afferent and Central Pathways to the Development of Baroreflex Dysfunction in Chronic Kidney DiseaseNovelty and Significance
    Ibrahim M. Salman, Cara M. Hildreth, Omar Z. Ameer and Jacqueline K. Phillips
    Hypertension. 2014;63:804-810, originally published March 12, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.113.02110
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