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In the spontaneously hypertensive (SH) rat, hyperoxic inactivation of the carotid body (CB) produces a rapid and pronounced fall in both arterial pressure and renal sympathetic nerve

activity (RSA). Here we show that CB de-afferentation through carotid sinus nerve denervation (CSD) reduces the overactive sympathetic activity in SH rats, providing an effective

antihypertensive treatment. We demonstrate that CSD lowers RSA chronically and that this is accompanied by a depressor response in SH but not normotensive rats. The drop in blood pressure is

not dependent on renal nerve integrity but mechanistically accompanied by a resetting of the RSA–baroreflex function curve, sensitization of the cardiac baroreflex, changes in renal

excretory function and reduced T-lymphocyte infiltration. We further show that combined with renal denervation, CSD remains effective, producing a summative response indicative of an

independent mechanism. Our findings indicate that CB de-afferentation is an effective means for robust and sustained sympathoinhibition, which could translate to patients with neurogenic

hypertension.

The causes of human essential hypertension remain unknown. It is established that in many patients, sympathetic nerve activity increases proportionately as hypertension develops and this may

be a causative factor1,2,3,4,5, but it is unclear what triggers heightened sympathetic traffic (reviewed in ref. 6). Despite good pharmacological control of arterial pressure in most

patients with essential hypertension, a significant proportion remain drug resistant or intolerant to medication7,8, and this has been highlighted as a growing problem9,10. This presents a

significant clinical challenge and provides the motivation to discover novel ways to control arterial pressure.

Recently, the role of the carotid body (CB) chemoreceptors in the pathophysiology of cardiovascular disease is gaining considerable interest11,12,13,14,15. The sympathoexcitation in both

sleep apnoea and heart failure may originate from enhanced activity of the CB chemoreceptors16,17,18,19,20. In both human patients and animal models of hypertension, the CB

chemoreflex-evoked sympathoexcitatory responses are enhanced15,21,22,23. However, the hypothesis that CB chemoreceptor drive has an important role in the pathogenesis and/or maintenance of

high arterial pressure was undetermined until most recently. We found that in spontaneously hypertensive (SH) rats, carotid sinus nerve denervation (CSD) lowered arterial pressure by ~17 mm 

Hg, and that this was well maintained and tolerated11. These data are comparable to those in human hypertensive patients where inactivation of the CB with 100% oxygen reduced both arterial

pressure and sympathetic activity24, supporting a causal role for peripheral chemoreceptors in the aetiology of neurogenic hypertension. On the basis of these data, and that CB resection has

been performed and well tolerated for the treatment of dyspnoea in ~5,600 patients with asthma and chronic obstructive pulmonary disease (reviewed in ref. 14), we recently proposed that CB

ablation may be an effective interventional strategy to control blood pressure in drug-resistant hypertensive patients11,14.

To assess the mechanisms underlying the hypotensive effect of CSD, we have made direct long-term simultaneous recordings of blood pressure and renal sympathetic nerve activity (RSA) before

and after CSD in conscious SH and Wistar rats. Given the current clinical interest and application of renal denervation (RD) in the treatment of drug-resistant hypertension25,26,27,28,29, we

have characterized the interaction between CSD and RD in combination to establish the type of interaction: summative, occlusive or facilitatory. Given that T lymphocytes have been shown to

contribute to both angiotensin II and neurally mediated chronic hypertension30,31, we have assessed immune function following CSD. Unlike Wistar rats, we find that the CB of the SH rat has

resting tone driving hypertension, which is not dependent on renal nerves, depresses both the cardiac and sympathetic vasomotor baroreflex and attenuates the adaptive immune response. We

hypothesize that these findings may translate to patients with neurogenic hypertension.

All numerical data are reported as mean±s.e.m., with statistical significance (P