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. 2016 Nov 1;594(21):6255-6266.
doi: 10.1113/JP272708. Epub 2016 Sep 23.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats

Wioletta Pijacka  1 , Fiona D McBryde  1   2 , Paul J Marvar  3 , Gisele S Lincevicius  4 , Ana P L Abdala  1 , Lavinia Woodward  5 , Dan Li  5 , David J Paterson  5 , Julian F R Paton  6
Affiliations

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats

Wioletta Pijacka et al. J Physiol. .

Abstract

Key points: Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension.

Abstract: The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n = 9) or sham CSD (n = 9) 5 weeks after renal artery clipping, in comparison with normal Wistar rats (n = 5). After 21 days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98 ± 4 mmHg vs. 2K1C: 147 ± 8 mmHg; P < 0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P < 0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14 ± 2 mmHg by week 3 (P < 0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension.

Keywords: carotid sinus denervation; chemoreceptor reflex; renovascular hypertension.

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Figures

Figure 1
Figure 1. Cardiovascular response to CSD or sham surgery (sham CSD) 5 weeks after induction of 2K1C renovascular hypertension
Top: temporal responses in MAP, respiratory frequency (Resp.), HR and heart rate variability (LF:HF) responses 5 days before and 21 days after CSD or sham CSD surgery (grey dashed vertical line; n = 9 per group). Bottom: average responses of baseline (days −5 to 0) vs. week 3 (days 14–21) in Wistar, 2K1C+sham CSD and 2K1C+CSD rats for LF power of systolic blood pressure (LF of SBP) and spontaneous baroreflex gain (sBRG). Differences were evaluated using one‐way ANOVA with Holm–Sidek post hoc comparisons; # P < 0.05 between‐groups comparison; * P < 0.05 repeated measures within‐subject comparison.
Figure 2
Figure 2. Assessment of chemoreflex and baroreflex sensitivity in 2K1C+sham CSD and 2K1C+CSD rats
A, chemoreflex‐induced increases in SBP by bolus infusion of sodium cyanide (NaCN; 120 μg kg−1, i.v.) were abolished after CSD; P < 0.001. B, cardiac baroreceptor reflex curves produced with i.v. infusions of vasoactive drugs (sodium nitroprusside and phenylephrine) showed an increase in sensitivity during sodium nitroprusside infusion in 2K1C+CSD vs. 2K1C+sham CSD rats (P < 0.05). Note that the responses in the 2K1C+CSD occurred despite a loss of carotid sinus baroreceptor inputs and were mediated by aortic baroreceptors. Data were analysed by one‐way ANOVA with Newman–Keuls multiple comparisons post hoc test (n = 4). * P < 0.05, ** P < 0.01 and *** P < 0.001. Data are presented as the mean ± SEM.
Figure 3
Figure 3. Intracellular free calcium transients in sympathetic neurons from the 2K1C+sham CSD rats, 2K1C+CSD rats and age‐matched controls (Wistar)
A, (i) all neurons imaged were sympathetic as indicated by tyrosine hydroxylase immunopositivity (green) and (ii) were localized in relation to other nuclei stained in blue by 4′,6‐diamidino‐2‐phenylindole. B, pseudocolour‐coded ratio images of Fura‐2‐loaded neurons were obtained by conventional fluorescence microscopy. Ca2+ concentrations were colour‐coded with a basal Ca2+ concentration in blue and a high Ca2+ concentration in red. C, example recording from a stellate neuron exposed to 50 mmol l−1 of KCl (30 s) depolarization, resulting in a rise in intracellular free calcium concentration ([Ca2+]i). Note that CSD attenuated this response. D and E, quantitative data showing the difference in the peak evoked [Ca2+]i between Wistar and Goldblatt hypertensive rats with CSD (2K1C+CSD) or sham CSD (2K1C+sham CSD), obtained from stellate ganglia (D) and mesenteric ganglia (E) neurons collected and cultured from >3 rats per group. Numbers within bars refers to the number of neurons tested, with each response per neuron representing one K exposure. ** P < 0.01 and *** P < 0.001; one‐way ANOVA with Holm–Sidek post hoc comparisons test.
Figure 4
Figure 4. FACS data showing immune cell infiltration of vascular aortic and brainstem tissue in the 2K1C+sham CSD rats, 2K1C+CSD rats and age‐matched control Wistars
CSD reduced macrophage infiltration in the brainstem but had no effect on CD45 and CD3 expressing T cells. One‐way ANOVA with Newman–Keuls multiple comparisons test. * P < 0.05. Data are presented as the mean ± SEM.
Figure 5
Figure 5. Effect of CSD or sham surgery on renal function
Renal function was assessed at 21 days after CSD (n = 10) or sham CSD (n = 14) in 2K1C hypertensive rats, as well as in age‐matched Wistar controls (n = 11). 2K1C hypertension was associated with multiple impairments in renal function compared to Wistar controls. CSD normalized proteinuria and albuminuria (P < 0.05). Data were analysed by one‐way ANOVA with Newman–Keuls multiple comparisons tests. * P < 0.05 and ** P < 0.01. Data are presented as the mean ± SEM.
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