Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats

The carotid body has recently emerged as a promising therapeutic target for treating cardiovascular disease, however the potential impact of carotid bodies removal on the dynamic cardiovascular responses to acute stressors such as exercise, hypoxia and hypercapnia in hypertension is an important safety consideration that has not been studied. We first validated a novel surgical approach to selectively resect the carotid bodies bilaterally (CBR) sparing the carotid sinus baroreflex. Second, we evaluated the impact of CBR on the cardiovascular responses to exercise, hypoxia and hypercapnia in the conscious, chronically instrumented spontaneously hypertensive (SH) rats. Our results confirm that our CBR technique successfully and selectively abolished the chemoreflex, whilst preserving carotid baroreflex function. CBR produced a sustained fall in arterial pressure in the SH rat of ~20 mmHg that persisted across both dark and light phases (P<0.001), with baroreflex function curves resetting around lower arterial pressure levels. The cardiovascular and respiratory responses to moderate forced exercise were similar between CBR and Sham. In contrast, CBR abolished the pressor response to hypoxia seen in Sham animals, although the increases in heart rate and respiration were similar between Sham and CBR groups. Both the pressor and respiratory responses to 7% hypercapnia were augmented after CBR (P<0.05) compared to sham. Our finding that the carotid bodies play a critical role in maintaining arterial pressure during hypoxia has important implications when considering resection therapy of the carotid body in disease states such as hypertension as well as heart failure with sleep apnoea

Carotid sinus denervation (CSD) ameliorates renovascular hypertension in adult Wistar rats

The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (2 kidney 1 clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. Here, we show that CSD ameliorates 2K1C hypertension and reveal potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, then underwent CSD (n = 9) or sham CSD (n = 9) five weeks after renal artery clipping, versus normal Wistar (n = 5). After 21 days renal function was assessed, and tissue collected to assess sympathetic postganglionic intracellular calcium transients ([Ca(2+) ]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 neuro-inflammatory markers and enhanced [Ca(2+) ]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), accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca(2+) ]i evoked responses from stellate neurons, and 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 neurones and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension

The Total Denervation of the Ischemic Kidney Induces Differential Responses in Sodium Transporters’ Expression in the Contralateral Kidney in Goldblatt Rats

The Goldblatt model of hypertension (2K-1C) in rats is characterized by renal sympathetic nerve activity (rSNA). We investigated the effects of unilateral renal denervation of the clipped kidney (DNX) on sodium transporters of the unclipped kidneys and the cardiovascular, autonomic, and renal functions in 2K-1C and control (CTR) rats. The mean arterial pressure (MAP) and rSNA were evaluated in experimental groups. Kidney function and NHE3, NCC, ENaCβ, and ENaCγ protein expressions were assessed. The glomerular filtration rate (GRF) and renal plasma flow were not changed by DNX, but the urinary (CTR: 0.0042 ± 0.001; 2K-1C: 0.014 ± 0.003; DNX: 0.005 ± 0.0013 mL/min/g renal tissue) and filtration fractions (CTR: 0.29 ± 0.02; 2K-1C: 0.51 ± 0.06; DNX: 0.28 ± 0.04 mL/min/g renal tissue) were normalized. The Na+/H+ exchanger (NHE3) was reduced in 2K-1C, and DNX normalized NHE3 (CTR: 100 ± 6; 2K-1C: 44 ± 14, DNX: 84 ± 13%). Conversely, the Na+/Cl− cotransporter (NCC) was increased in 2K-1C and was reduced by DNX (CTR: 94 ± 6; 2K-1C: 144 ± 8; DNX: 60 ± 15%). In conclusion, DNX in Goldblatt rats reduced blood pressure and proteinuria independently of GRF with a distinct regulation of NHE3 and NCC in unclipped kidneys

Total renal denervation reduces sympathoexcitation to different target organs in a model of chronic kidney disease

It is known that increased sympathetic nerve activity in chronic kidney disease (CKD) progressively worsens kidney function and hypertension. We tested the hypothesis that total renal denervation contributes to reduce sympathetic activation to different beds and improves renal function in 5/6 nephrectomy model of CKD in male Wistar rats. After eight weeks of 5/6 nephrectomy surgery there was an increase in mean arterial pressure (CKD 179 +/- 22 mm Hg, n = 6 vs. control animals 108 +/- 9p < 0.05, n = 6) with no changes in heart rate (HR). Sympathetic nerve activity was increased at different levels to the remaining kidney, splanchnic and lumbar beds compared to control (CTL) group (CKD rSNA: 150 +/- 50, n = 9 vs. CTL 96 +/- 15, n = 9CKD sSNA: 129 +/- 51, n = 5 vs. CTL 34 +/- 14, n = 6CKD ISNA: 203 +/- 35, n = 8 vs. CTL 146 +/- 21, spikes/s, n = 7, p < 0.05). Three weeks after total renal denervation (DNX) MAP was normalized in the CKD rats (124 +/- 19 mm Hg, n = 5, p < 0.05), with no change in HR. The ISNA was normalized (151 +/- 40, n = 5, vs. CKD 203 +/- 35 spikes/s, n = 8) and sSNA was decreased in 49% (64 +/- 34, n = 5 vs. CKD 129 +/- 51 spikes/s, n = 5, p < 0.05). Renal function, assessed by creatinine plasma levels was improved after renal denervation (CKD 1.50 +/- 0.64, n = 8vs. CKD + DNX 0.82 +/- 0.22 mg/mL, n = 8, p < 0.05). These findings demonstrate that renal nerves contribute to the maintenance of hypertension in CKD by increasing sympathoexcitation to other beds. (C) 2016 Elsevier B.V. All rights reserved.Sao Paulo Research FoundationCNPq fellowshipsFAPESPCAPES-PNPD Postdoctoral FellowshipsUniv Fed Sao Paulo, Dept Physiol, Cardiovasc Div, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Physiol, Div Renal, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Physiol, Cardiovasc Div, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Physiol, Div Renal, Sao Paulo, BrazilFAPESP: 2013/22522-9FAPESP: 2013/23741-6Web of Scienc