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