Revelations About Carotid Body Function Through it

Authors: Julian F R Paton Laura Ratcliffe Dagmara Hering Jacek Wolf Paul A Sobotka Krzysztof Narkiewicz

Publish Date: 2013/07/05

Volume: 15, Issue: 4, Pages: 273-280

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Abstract

Much recent attention has been given to the carotid body because of its potential role in cardiovascular disease states One disease neurogenic hypertension characterised by excessive sympathetic activity appears dependent on carotid body activity that may or may not be accompanied by sleepdisordered breathing Herein we review recent literature suggesting that the carotid body acquires tonicity in hypertension We predict that carotid glomectomy will be a powerful way to temper excessive sympathetic discharge in diseases such as hypertension We propose a model to explain that signalling from the ‘hypertensive’ carotid body is tonic and hypothesise that there will be a subpopulation of glomus cells that channel separately into reflex pathways controlling sympathetic motor outflowsThe aetiology of many modernday diseases such as the metabolic syndrome is often associated with alterations in the autonomic nervous system The relatively sudden acceptance that autonomic imbalance is both causative and essential for the maintenance of disease states in animal models and humans has led to an eruption of interventional approaches to manage these diseases Modulation of the autonomic nervous system whether via stimulation 1 2 or ablation of organspecific afferents and denervation of sympathetic postganglionic fibres targeting selected vascular beds 3• is a strong current trend producing spectacular results Here we consider an intervention that is based on preclinical proof of principle data and previously published clinical results supporting carotid body modulation as a treatment for neurogenic hypertensionCarey has recently proposed that 14  of the world’s treated hypertensive patients are resistant to contemporary pharmacological therapy 4 Even if this number is an overestimate we are still left with a substantial clinical problem given that there are presently almost 1 billion hypertensives worldwide 5 Most hypertensive patients are well managed with antihypertensive drugs yet there appears to be an increasing trend to greater resistance 4 As Carey reports resistant hypertensives have increased from 55  in 1988–1994 to 85  in 1999–2004 and 118  in 2005–2008 4 A resistant hypertensive is a patient with office blood pressure 140/90 mmHg despite taking ≥3 antihypertensive medications ideally including a diuretic 6 However we believe the clinical problem of blood pressure management extends beyond drug resistance and includes hypertensive patients that are drug intolerant due to adverse effects impacting on quality of life often a consequence of high drug dosing and multipill therapy If accepted that the sympathetic nervous system is in part responsible in the etiology and maintenance of hypertension 7 8 9 10• 11 12 then we need to find innovative ways to control it Although highly effective the early attempts at gross surgical 13 14 and then pharmacological sympathectomy 15 are unsurprisingly poorly tolerated Given that sympathetic nervous system function is controlled differentially the idea of targeted sympathectomy such as to the kidney 3• 17• or splanchnic vascular bed 16 has had considerable success in lowering blood pressure clinically and in animal models However the majority of patients receiving renal denervation have remained on antihypertensive medication and hypertensive 3• 17• Given the hypothetical aim of curing hypertension and reducing/removing antihypertensive medication especially those with severe life quality impeding side effects further exploration into novel interventional therapies is warranted We will discuss the idea of removing a distinct sympathoexcitatory afferent drive as a novel treatment for neurogenic hypertensionThe peripheral or arterial chemoreceptors located in the carotid body send signals via a branch of the carotid sinus nerve to the nucleus of the solitary tract located in the dorsomedial medulla 18 The carotid body consists of supporting cells or type II cells analogous to astrocytes and glomus cells type I cells that embryologically originate from neural crest cells Glomus cells are morphologically distinct as large and spherical in shape and are highly sensitive to oxygen delivery arterial oxygen and carbon dioxide levels blood pH reduced blood flow eg hemorrhage inorganic phosphate and sodium cyanide 19 the latter being used as a convenient experimental tool to produce tissue hypoxia and profound stimulation 20 The carotid body is profusely perfused with blood 21 and the arterioles are innervated by the sympathetic nervous system This is an important point as excessive sympathetic activity could potentially trigger activation of the chemoreceptor via hypoperfusion Persistent sympathetic activity might also remodel carotid body arterioles causing alterations in perfusion that could directly affect sensitivity of the chemoreceptor The carotid body cells produce a vast array of chemical transmitters including dopamine noradrenaline substance P that are released to trigger a receptor potential on nearby afferent endings resulting in their depolarisation and action potential generation 22 In some species such as rabbit cat and human there are additional glomus tissue accumulations on the aorta and subclavian arteries 23 Aortic chemoreceptors have a distinct reflex response 23 compared to those evoked from carotid chemoreceptors see below and for this reason our focus will be on the carotid bodyStimulation of the carotid body chemoreceptors triggers hyperventilation an important protective reflex mechanism ensuring blood gas homeostasis The peripheral chemoreceptors may also contribute to dyspnoea 24 and arousal 25 which is likely due to their suprabulbar projections 26The reflex cardiovascular response evoked from the carotid body is interesting as it comprises a primary and secondary response 27 28 The pattern of response evoked is dependent on the degree to which respiration increases Hyperventilation recruits into play an afferent signal originating from mechanoreceptors surrounding bronchioles that on inflation trigger the pulmonary stretch receptor HeringBreuer reflex giving the secondary response This secondary response consists of tachycardia and vasodilatation the former is mediated by cardiac vagal withdrawal and increased cardiac sympathetic tone and the latter via inhibition of sympathetic vasomotor tone This competes with the primary response of profound bradycardia vagally mediated and sympathetically mediated vasoconstriction The resultant response depends on the relative strength of the two afferent reflexes and the magnitude of the respiratory response which is dependent on animal species The primary response prevails in the following examples a diving mammal human face immersion into cold water sleep apnea sudden infant death syndrome and in anesthetised and mechanically ventilated animals The bradycardia is potent abolished with atropine and most likely protective in function to reduce cardiac metabolism and preserve oxygen Intriguingly despite the potent bradycardia the sympathetic nervous system targeting the heart is coactivated 29 along with the cardiac vagal system and may increase cardiac force of contractionThe type of stimulus used to activate the peripheral chemoreceptors will also dictate the response pattern Using systemic hypoxia for example will produce a direct hyperpolarising effect on the vascular smooth muscle causing blood pressure to fall This will unload baroreceptors that may trigger a compensatory response although it is acknowledged that their interaction with peripheral chemoreceptors is antagonistic 20 30 31 Finally the strength of the stimulus may also produce a graded response perhaps overturning coincident reflexes originating from pulmonary receptors in spontaneously breathing animals When the stimulus is intense peripheral chemoreceptors can trigger an alerting response including the classical behavioural and visceral adjustments associated with fight or flight 19 25 In the context of carotid chemoreceptors and hypertension this is most relevant as it has been hinted that continuous activation of the fight or flight response so called defence response could lead to systemic hypertension 32The peripheral chemoreceptor reflex sensitivity has been shown to be significantly enhanced in both patients with primary hypertension 33 34 35 36 37 38• 39 and spontaneously hypertensive SH rat 40•• this has included the ventilatory and sympathetic nerve activity response components Incidentally an increased hypoxic ventilatory response is characteristic of heart failure patients This increased peripheral chemoreceptor sensitivity is a prognostic indicator for mortality in these patients 41

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