Wioletta Pijacka

The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension

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.

Purinergic receptors in the carotid body as a new drug target for controlling hypertension

In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

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.

P2X3 receptors and sensitization of autonomic reflexes.

A great deal of basic and applied physiology and pharmacology in sensory and autonomic neuroscience has teased apart mechanisms that drive normal perception of mechanical, thermal and chemical signals and convey them to CNS, the distinction of fiber types and receptors and channels that mediate them, and how they may become dysfunctional or maladaptive in disease. Likewise, regulation of efferent autonomic traffic to control organ reflexes has been well studied. In both afferent and efferent limbs, a wide array of potential therapeutic mechanisms has surfaced, some of which have progressed into clinic, if not full regrastration. One conversation that has been less well progressed relates to how the afferent limb and its sensitization shapes the efferent outputs, and where modulation may offer new therapeutic avenues, especially for poorly addressed and common signs and symptoms of disease. Therapeutics for CV disease (HF, hypertension), respiratory disease (asthma, COPD), urological disease (OAB), GI disease (IBS), and inter alia, have largely focused on the efferent control of effector cells to modulate movement, contraction and secretion; medicinal needs remain with limits to efficacy, AEs and treatment resistance being common. We now must turn, in the quest for improved therapeutics, to understand how sensation from these organs becomes maladapted and sensitized in disease, and what opportunities may arise for improved therapeutics given the abundance of targets, many pharmacologically untapped, on the afferent side. One might look at the treatment resistant hypertension and the emerging benefit of renal denervation; or urinary bladder overactivity / neurogenic bladder and the emergence of neuromodulation, capsaicin instillation or botox injections to attenuate sensitized reflexes, as examples of merely the start of such progress. This review examines this topic more deeply, as applies to four major organ systems all sharing a great need from unsatisfied patients.

CrossTalk opposing view: Which technique for controlling resistant hypertension? Carotid chemoreceptor denervation/modulation.

L. E. K. Ratcliffe, W. Pijacka, F. D. McBryde, A. P. Abdala, D. J. Moraes, P. A. Sobotka, E. C. Hart, K. Narkiewicz, A. K. Nightingale and J. F. R. Paton CardioNomics Research Group, Clinical Research and Imaging Centre and School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK Department of Physiology, University of Auckland, Auckland, New Zealand Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049-900, SP, Brazil The Ohio State University, 2015 Marywood Lane West, St Paul, MN 55118, USA Department of Hypertension and Diabetology, Medical University of Gdansk, Debinki 7c, 80-952 Gdansk, Poland

Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension

Neurohormonal overactivation plays an important role in pulmonary hypertension (PH). In this context, renal denervation, which aims to inhibit the neurohormonal systems, may be a promising adjunct therapy in PH. In this proof-of-concept study, we have demonstrated in 2 experimental models of PH that renal denervation delayed disease progression, reduced pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular diastolic stiffness, most likely by suppression of the renin-angiotensin-aldosterone system.

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

Carotid bodies play a critical role in maintaining arterial pressure during hypoxia and this has important implications when considering resection therapy of the carotid body in disease states such as hypertension. Curbing hypertension in patients whether resting or under stress remains a major global health challenge. We demonstrated previously the benefits of removing carotid body afferent input into the brain for both alleviating sympathetic overdrive and reducing blood pressure in neurogenic hypertension. We describe a new approach in rats for selective ablation of the carotid bodies that spares the functional integrity of the carotid sinus baroreceptors, and demonstrate the importance of the carotid bodies in the haemodynamic response to forced exercise, hypoxia and hypercapnia in conditions of hypertension. Selective ablation reduced blood pressure in hypertensive rats and re‐set baroreceptor reflex function accordingly; the increases in blood pressure seen during exercise, hypoxia and hypercapnia were unaffected, abolished and augmented, respectively, after selective carotid body removal. The data suggest that carotid body ablation may trigger potential cardiovascular risks particularly during hypoxia and hypercapnia and that suppression rather than obliteration of their activity may be a more effective and safer route to pursue.

Cooperative Oxygen Sensing by the Kidney and Carotid Body in Blood Pressure Control

Oxygen sensing mechanisms are vital for homeostasis and survival. When oxygen levels are too low (hypoxia), blood flow has to be increased, metabolism reduced, or a combination of both, to counteract tissue damage. These adjustments are regulated by local, humoral, or neural reflex mechanisms. The kidney and the carotid body are both directly sensitive to falls in the partial pressure of oxygen and trigger reflex adjustments and thus act as oxygen sensors. We hypothesize a cooperative oxygen sensing function by both the kidney and carotid body to ensure maintenance of whole body blood flow and tissue oxygen homeostasis. Under pathological conditions of severe or prolonged tissue hypoxia, these sensors may become continuously excessively activated and increase perfusion pressure chronically. Consequently, persistence of their activity could become a driver for the development of hypertension and cardiovascular disease. Hypoxia-mediated renal and carotid body afferent signaling triggers unrestrained activation of the renin angiotensin-aldosterone system (RAAS). Renal and carotid body mediated responses in arterial pressure appear to be synergistic as interruption of either afferent source has a summative effect of reducing blood pressure in renovascular hypertension. We discuss that this cooperative oxygen sensing system can activate/sensitize their own afferent transduction mechanisms via interactions between the RAAS, hypoxia inducible factor and erythropoiesis pathways. This joint mechanism supports our view point that the development of cardiovascular disease involves afferent nerve activation.

Rebuttal from L. E. K. Ratcliffe, W. Pijacka, F. D. McBryde, A. P. Abdala, D. J. Moraes, P. A. Sobotka, E. C. Hart, K. Narkiewicz, A. K. Nightingale and J. F. R. Paton

Renal denervation (RDN) and carotid sinus stimulation (CSS) reduce blood pressure in some patients with resistant hypertension (rHTN). Both Schlaich et al. (2014) and Jordan (2014) provide convincing arguments for their use. The key question is how do we clinically phenotype patients in order to offer the most effective anti-hypertensive treatment with minimal adverse effects? Schlaich et al. outline the importance of identifying patients characterised by sympathetic overactivity. However, recording muscle sympathetic nerve activity (MSNA) requires specialised equipment and highly skilled staff, limiting its use as a screening technique. In addition, response to RDN does not always correlate with baseline MSNA or change in MSNA (Brinkmann et al. 2012; Hart et al. 2013). An alternative may be to look at response to drugs targeting the autonomic nervous system or baroreflex sensitivity (Zuern et al. 2013). These may be particularly relevant in screening prior to CSS, perhaps targeting those with disrupted baroreflex response or the subset of rHTN patients with labile blood pressure. Given the need for clinical phenotyping prior to entry into well-conducted studies, it would seem appropriate to restrict these techniques to experienced and specialised hypertension research centres. There is no way to identify the location of the renal nerves prior to ablation, and no intra-procedural feedback to indicate successful RDN. Renal nerves rarely track the aorta to follow the origin of the renal artery coursing its entire length; they can join the artery close to the renal pelvis. Symplicity-HTN 3 (Bhatt et al. 2014) highlights the importance of operators with significant procedural experience, delivering a circumferential ablation pattern. A recent report presented histological assessment of nerve ablation post RDN. Despite a total of 11 ablations, histological sectioning suggested that RDN would not have resulted in complete denervation (Vink et al. 2014). The push for greater ablation numbers, with the aim of complete denervation, needs to be weighed up against the risk of complications such as renal artery stenosis (Chandra et al. 2014; Jaen Aguila et al. 2014). Jordan emphasised the relative invasive nature, high cost and adverse effect profile of CSS, with 7/42 experiencing a procedure-related significant adverse event (Scheffers et al. 2010). CSS has the advantage of being reversible allowing procedural success to be demonstrated. CSS would benefit from integration of blood pressure feedback and ECG entrainment to refine its action, making it more representative of the normal physiological system and preventing inappropriate blood pressure lowering which could cause cerebral hypoperfusion. With relatively short follow-up to date, the longer term effects of both RDN and/or CSS may not yet be apparent. This emphasises the importance of long-term (e.g. >10 years) patient follow-up, at least at a registry level. Carotid body (CB) modulation may offer patient phenotyping through relatively simple tests of CB activation and inactivation while measuring blood pressure and respiration. CB resection should provide clues as to the potential efficacy of this treatment in rHTN patients but the scientific challenge is to understanding the basis of the aberrant discharge and how to temper this without removing peripheral chemosensitivity. Interventional procedures are not a hypertension panacea and the rHTN population is a heterogeneous group requiring further clinical phenotyping. Interest in the sympathetic system as a target for HTN treatment seems renewed, and will perhaps stimulate further research into interventional and reversible pharmacological treatments targeting this system.