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Send Orders for Reprints to [email protected] 16 Current Vascular Pharmacology, 2014, 12, 16-22 The Pathophysiological Basis of Carotid Baroreceptor Stimulation for the Treatment of Resistant Hypertension Dragan Lovic1*, Athanasios J. Manolis2, Branko Lovic1, Vesna Stojanov3, Milan Lovic4, Andreas Pittaras5 and Branko Jakovljevic3 1 Clinic for internal disease InterMedica, Nis, Serbia; 2Asklepeion General Hospital, Athens, Greece; 3 Medical School University Belgrade, Clinical Center Serbia, Belgrade, Serbia; 4Institute Niska Banja, Nis, Serbia; 5Mediton Medical Center Cardiology, Athens, Greece Abstract: The prevalence of resistant hypertension and existing limitations in antihypertensive drug therapy renders the interventional management of hypertension an attractive alternative. Carotid baroreceptors have been traditionally thought to be implicated only in short-term blood pressure regulation; however recent evidence suggests that the baroreceptors might play an important role even in the long-term blood pressure regulation. Electrical baroreflex stimulation appears safe and effective and might represent a useful adjunct to medical therapy in patients with resistant hypertension. This review endeavors to summarize the complex pathophysiology of blood pressure regulation, to describe the baroreflex circuit, its anatomy and physiology, to present previous data refuting a role for the baroreceptors in the long-term control of blood pressure and recent animal and human data suggesting an effective role of carotid baroreceptor activation in long-lasting blood pressure reduction. In this paper we attempt to critically evaluate existing information in this area and provide the scientific basis for carotid baroreceptor stimulation in the management of resistant hypertension. Keywords: Resistant hypertension, baroreceptors, carotid baroreceptor stimulation. INTRODUCTION Arterial hypertension is a multifactorial disease with several factors contributing to the pathogenesis of blood pressure elevation [1]. Hypertension is a major health problem worldwide, with a large prevalence in general population. According to World Health Organization data, about 30 50% of the adult population have hypertension. The prevalence of hypertension in 2025 is expected to increase by 60% (29.2% - 1.56 billion people) compared to 26.4% (972 million people) in year 2000 [2]. In the USA, the prevalence of hypertension (defined as BP 140/90 mmHg and/or the use of any antihypertensive drug) was estimated at 33.6%, or more than 73 million adults [3]. Hypertension is among the most important independent risk factors for cardiovascular (CHD) and chronic kidney diseases (CKD). The risk of endstage renal disease and myocardial infarction is four times higher in persons with systolic blood pressure above 160 mmHg in comparison to persons with normal blood pressure, and the risk of developing heart failure is two times higher in individuals over the age of forties [3,4]. blood pressure below target levels of <140/90 mmHg [5]. Recent European data reveal that 38.8% of treated hypertensive patients achieved the blood pressure target of <140/90 mmHg [6]. In some patients with uncontrolled hypertension, it is difficult to obtain blood pressure goals, despite the use of combinations of antihypertensive drugs. Resistant hypertension is defined as the inability to achieve blood pressure goals despite the use of at least three antihypertensive drugs (including a diuretic) in maximum tolerated doses [7,8]. Resistant hypertension also includes patients whose blood pressure is controlled by the use of four or more antihypertensive drugs [9]. Although major therapeutic strides in the hypertension province have been accomplished during the previous century, numerous frustrations still exist in antihypertensive drug therapy. Epidemiological studies worldwide indicate that, despite using powerful antihypertensive drugs, less than 30% of all patients with hypertension succeed to keep their While the exact prevalence of resistant hypertension is unknown, clinical studies suggest that it is not rare, probably diagnosed in 20-30% of all patients with hypertension. The incidence of resistant hypertension increases as the population becomes older and obese [10]. The estimated prevalence of resistant hypertension in the ALLHAT, VALUE, CONVINCE and ASCOTT studies ranged from 7% to 15% [11]. It has to be noted however that resistant hypertension and uncontrolled hypertension are two distinct entities, with resistant hypertension representing only a small fraction of uncontrolled hypertension. Uncontrolled hypertension includes patients with blood pressure levels above goal irrespective of the number and type of administered antihypertensive drugs. In contrast, resistant hypertension is restricted in patients taking 3 or more drugs, one of them being a diuretic. *Addresss correspondence to this author at the Clinic for internal disease InterMedica, Hypertension Centre, Jovana Ristica str. 20-2; 18000 Nis, Mediana, Serbia; E-mails: [email protected]; [email protected] Patients with resistant hypertension are at higher risk of cardiovascular morbidity and mortality compared with those whose hypertension is well controlled [9,10,12]. Increased cardiovascular risk among patients with resistant hyperten- 1875-6212/14 $58.00+.00 © 2014 Bentham Science Publishers The Pathophysiological Basis of Carotid Baroreceptor Stimulation sion depends on blood pressure [4] and the presence of associated co-morbidities, including diabetes mellitus, sleep apnea, obesity, left ventricular hypertrophy and renal disease [10,12,13]. Given the above, the treatment of patients with resistant hypertension in the last decade attracts growing attention. The need for alternative treatment approach has been widely recognized in recent years. That is why an interventional treatment of hypertension, which was abandoned after the mid of the twentieth century, was recently re-invented and gained intense scientific interest. In this respect, in the treatment of resistant hypertension, a special attention is paid to carotid baroreceptors stimulation and to sympathetic renal denervation, which show promising preliminary results [14,15]. An adequate control of blood pressure reduces cardiovascular risk independent of the class of drugs [16]. Any therapy that can reduce blood pressure in patients with resistant hypertension may be useful. HISTORY OF BARORECEPTOR INVESTIGATION Control of blood pressure by an arterial reflex has been probably known since ancient times. The observation in Ancient Rome that pressing on the arteries of the neck in animals produced sedation might have been the first notice of this homeostatic mechanism [17]. A Syrian doctor, Serapion, used carotid compression for curing headache during the ninth century [18]. Even in the beginning of the 20th century, it was well known that blood pressure increases in response to psychoemotional stimuli. Thus, it was widely held that the SNS contributed in initiating and maintaining hypertension. It has been suggested that the activation of the sympathetic splachnic nerves actually resulted in renal vasoconstriction and ischemia. Indeed, bilateral supradiaphragmatic splach- Fig. (1). Physiological view of the baroreceptors function. Current Vascular Pharmacology, 2014, Vol. 12, No. 1 17 nicectomy has been shown to improve hypertension and target organ damage in the long-term [19]. Since the arterial baroreflex represents a major inhibiting mechanism of the SNS, it seemed rational to assume that an alteration in baroreflex activity is implicated in hypertension’s pathogenesis [20]. Indeed, Folkow stated that: “The reflex control is primarily based on the general inhibition input from the various sets of stretch receptors” [21], and “Already early common variants of human primary hypertension, as well as spontaneously hypertensive rats, exhibit an evidently “primary” central hyper-reactivity to psychosocial stimuli” [22]. CARDIAC FACTOR BARORECEPTORS - NEUROGENIC The history of medicine is full of myths, misperceptions, and misconceptions. The role of arterial baroreflex in blood pressure control represents such an issue, although the reciprocal relationship between baroreceptor input and sympathetic output has been extensively studied over the years. The carotid baroreflexes are major sentinels in our homeostatic system of blood pressure control. The carotid sinuses monitor the blood pressure intra-arterially and then alter accordingly the sympathetic tone, through the vasomotor centers in the central nervous system. Specifically, when the blood pressure increases, the afferent impulse traffic is increased, and the vasomotor areas reduce the flow of the sympathetic signals to the periphery, with an end-result of blood pressure and heart rate reductions; the opposite effect is observed when blood pressure decreases. The importance of the carotid sinus in the modulation of autonomic tone and the regulation of blood pressure has been long recognized [23,24]. Baroreceptors in conjunction with 18 Current Vascular Pharmacology, 2014, Vol. 12, No. 1 the vasomotor center in the medulla oblongata and vagal nuclei, are involved in the regulation and maintenance of normal blood pressure (Fig. 1). Baroreceptors are located in the aortic arch and carotid sinus. The system of baroreceptors includes vasomotor center and vagal component, programmed to react to any change in blood pressure. Increase in blood pressure over baroreceptors afferent fibers leads to activation of inhibitory neurons, and thereby to inhibition of the vasomotor center and up-regulation of vagal center, which leads to reduction of blood pressure and decrease in total peripheral vascular resistance. It also leads to bradycardia due to increased vagal tone and to a decrease of minute volume and cardiac output. A decrease of blood pressure through the excitation of neurons leads to activation of the vasomotor center and vagal inhibition, which results in an increase in blood pressure due to peripheral vasoconstriction and in the increase in total peripheral vascular resistance and cardiac output [1]. Baroreceptors inhibit sympathetic output, reducing the release of renin and antidiuretic hormone, which reduce intravascular volume and tone [25]. The stimulation of carotid baroreceptors reduces renal sympathetic tone, which might contribute to blood pressure reduction [26]. Disruption of proper functioning of this system is thought to be among the important factors in the pathogenesis of essential hypertension. It is assumed that a reduced sensitivity of carotid baroreceptors to normal stimulation, or function at a higher sensitivity, might lead to the increase and maintenance of high blood pressure [1]. Experimental data support this hypothesis by showing that when continuously stimulated in arterial hypertension, baroreceptors may fail to lower blood pressure, which resets at a higher level [27]. THE ARTERIAL BARORECEPTOR AUTONOMIC REFLEX Autonomic function occurs mainly through autonomic reflexes, whereas a variety of factors might influence and modulate these reflexes. The baroreflex represents a typical paradigm of autonomic reflexes, involving sensory receptors, signal transmission and interpretation, motor neurons, and effector cells. The exact anatomy and function of the arterial baroreceptor autonomic reflex remain only partially known, despite extensive research in this field. The role of carotid baroreflex in blood pressure regulation is complex, multifactorial [28], and difficult to unveil, since experimental settings are very demanding and require microtechniques in tiny areas of the central nervous system. The carotid arterial baroreflex resembles a ‘bus-route’ with several stops and bus changes. Arterial baroreceptors consist of carotid and extra-carotid baroreceptors. Carotid baroreceptors are placed in the right and left carotid sinus, while extra-carotid baroreceptors are located in the aortic arch, the heart, and the pulmonary vessels [29]. Arterial baroreceptors represent the initial ‘busstop’ of the baroreflex arc, sensing the stretch induced by circulating blood on the arterial wall. Physiologic transduction of stretch is common to not only many species but to various organs and tissues as well; distension at visceral sites, light touch, and hearing represent such functions. Arterial baroreceptors are currently considered to belong in the Lovic et al. epithelial sodium channel (ENaC) family, a family of cation channels [30]. Although it seems strange to meet this cation family in the baroreflex circuit, we have to take in consideration that this family is involved in mechano-transduction in several species (light touch in the rat footpad, touch sensation in Caenorhabditis elegans) [31] and other stretch-related cells, like the osteoblasts [32]. The stretch on vessel wall sensed by arterial baroreceptor is transmitted to the central nervous system through the glossopharyngeal nerve (IX cranial nerve) from the carotid baroreceptors and the vagus nerve (X cranial nerve) from extra-carotid baroreceptors. Signals are transmitted to the brain medulla at the dorsal area and reach the nucleus tractus solitarii (NTS). At the same area arrive afferent fibers from the thoracic and abdominal region [33]; however, the exact nature as well as the physiological and pathophysiological significance of these afferent nerves remains to be clarified. A wealthy of experimental data indicates that NTS is the ‘final receiver’ of afferent baroreceptor signals [34-39]. NTS is not only an anatomical region but a functional center as well. Damage of the NTS area in the dorsal medulla is associated by attenuation of the arterial baroreflex, unveiling its key role in the baroreflex arc [40-42]. Both intra- and extracellular electrophysiological studies demonstrated that neurons in the NTS region receive synaptic inputs that are induced by baroreceptor activation [43-48]. Arriving afferent signals stimulate the NTS area resulting in release of neurotransmitters, primarily glutamate [49-53] but also a variety of other neurotransmitters including catecholamines, angiotensin II and nitric oxide [54-61]. Signal transmission seems to be regulated by another modulating mechanism, the type of afferent nerves fibers. Existing data suggests that A-type fibers have lower threshold levels, provide a dynamic reflex regulation, and modulate predominantly the heart rate, while C-type fibers have higher threshold levels, provide steadystate reflex responses, and are more involved in blood pressure regulation [62]. However, these data are not conclusive, and further research is needed in this area. Signal transmission leaves NTS and arrives at the caudal ventrolateral medulla (CVLM), a significant functional ‘stop’ for the baroreflex arc. Within this area the signal is converted and its so far excitatory nature becomes inhibitory [63-65]. So, the arterial baroreflex represents the essential ‘brake’ for the smooth function of the sympathetic system and the CVLM region seems to be the ‘converting’ point. The CVLM area consists of a rostral group of baroreceptorsensitive neurons and a caudal group of baroreceptorindependent neurons. In parallel, CVLM represents the interchange of excitatory signals that travel from the caudal pressor area (CPA) in the pyramidal decussation to the rostral ventrolateral medulla (RVLM); the physiological role of the CPA-induced sympatho-excitation and the potential interplay with the baroreflex remain to be elucidated. RVLM is the next ‘bus-stop’. Signals from CVLM, which are now of inhibitory nature, arrive to RVLM at the bulbospinal level. The bulbospinal area consists of presympathetic sympatho-excitatory neurons. Extensive research suggests that the baroreflex arc exerts its action by regulating the sympathetic activity at RVLM, in a manner that activation of baroreceptors inhibits the sympathetic nervous system The Pathophysiological Basis of Carotid Baroreceptor Stimulation Current Vascular Pharmacology, 2014, Vol. 12, No. 1 activity [66-73]. Glutamate seems to be the main mediator in this area as well, while other neurotransmitters have also been reported to be implicated in signal transmission [7479]. Another component of the baroreflex circuit in this region is thought to be the mu opioid receptors, which have been found in the RVLM area and originate from the midline raphe nuclei. Activation of the mu opioid receptors has been found to impair the sympathetic baroreflex, although the significance of this pathway remains to be determined. It has been reported that RVLM is receiving input from a variety of sources, and an interaction with the baroreflex input has to be considered. Apart from baroreceptors, the hypothalamus, cortex, amygdala, medullary raphe, chemoreceptors, somatosympathetic afferents, respiratory afferents, and PaO2 send signals to the RVLM region [64,65]. In summary, baroreceptors detect changes in stretch of the arterial wall, the signals are transmitted through sensory neurons to the central nervous system, signals are then integrated and converted from excitatory to inhibitory and efferent signals are finally transmitted to peripheral tissues to exert autonomic reflex actions. CAROTID BARORECEPTOR DENERVATION RESETTING AND An important role of the carotid baroreflex in the longterm blood pressure regulation has been significantly challenged for decades based on experiments showing baroreceptor resetting on one hand and absence of persistent hypertension following baroreceptor denervation on the other hand. Early studies of the baroreceptors role in blood pressure modulation date back in 1950’s. A study by McCubbin in 1956 investigating the baroreceptor of both normotensive and hypertensive dogs provided early evidence of the firing threshold and showed that a higher pressure was required to elicit baroreceptor function in the hypertensive dogs [80]. Baroreceptor resetting at a higher level in hypertension has been also shown in several experimental studies [81,82] confirming that resetting of carotid baroreceptor occurs within minutes and might be implicated in the pathogenesis of hypertension since the baroreceptors are no longer capable of lowering blood pressure in essential hypertesion. Denervation of either carotid or aortic baroreceptors was associated with a transient increase in blood pressure which was not sustained [83-85], suggesting that baroreceptors are implicated in the short-term but not in the long-term blood pressure regulation. However, recent experimental studies with more accurate methodological settings show persistent elevation of blood pressure during chronic unloading of carotid baroreceptors [86-89], pointing towards the implication of carotid baroreceptors in the long-term regulation of blood pressure levels. Human data with carotid baroreceptor denervation are limited and controversial [90-94]. Taken together, older carotid baroreceptor resetting and denervation studies suggest that the baroreflex is implicated in the short-term blood pressure regulation with small, if any, contribution in the long-term regulation of blood pressure levels. However, newer data challenge this long-standing point of view and point towards the involvement of the carotid baroreflex in long-lasting blood pressure elevation. 19 What is even more important however, is the effect of carotid baroreceptor stimulation on blood pressure levels. Warner et al. electrically stimulated the canine carotid sinus and found an arterial blood pressure reduction that was frequency-dependent and maintained even over a 90 min period of continuous stimulation [95]. Later studies in experimental animals have confirmed blood pressure reduction and found that it was maintained for the one-year study follow-up [96]. Based on these findings in animal studies, carotid nerve stimulation was studied in humans. Carlsten et al. in 1958 examined humans undergoing head and neck surgery and confirmed that carotid stimulation did reduce blood pressure in a frequency-dependent manner [97]. Several other studies have been performed in the 60’s and verified the role of carotid nerve stimulation in the treatment of refractory hypertension [98-101]. Peters et al. in 1980 reported on his experience with a device that matched stimulator frequency to patient heart rate [102], the idea being that heart rate elevations signaled increases in sympathetic tone that would need to be answered by greater activation of the baroreflex, in order to achieve blood pressure control [103]. Patients implanted with this device achieved blood pressure lowering both at rest and during exercise. Effective blood pressure lowering was subsequently reported 12 years after device implantation [102,104]. CURRENT DATA WITH CAROTID BARORECEPTOR STIMULATION In the past decade, more sophisticated research has developed with the understanding that nonpharmacologic means of controlling blood pressure may be a realistic and necessary alternative. The carotid sinus stimulator is a device called Rheos. It is manufactured by CVRx, Inc (MN, USA) and consists of an implanted pulse generator with leads that tunnel subcutaneously and bilaterally attach to the carotid sinuses. The device requires surgical implantation under general anesthesia and is fully programmable after implantation to allow adjustment stimulation parameters [105]. Lohmeier et al. in 2004 examined normotensive dogs that underwent sustained electrical stimulation of their carotid sinuses over a 7 days period. They found an immediate fall in the mean arterial pressure (MAP) of 25 mmHg, and over the full 7 days the dogs sustained a decrease in MAP [106]. Studies in humans have confirmed the efficacy of this interventional approach, witch was observed in animals. Schmidli et al. in 2005, reported on five patients who underwent chronic electrical activation of the baroreflex with a carotid stimulator [107]. The device produced a graded voltage dependent drop in blood pressure – a relationship that was sustained even with chronic activation of the baroreflex. Moreover, these patients were concurrently receiving maximal medical therapy including alpha and beta antagonist, suggesting that baroreflex activation provides incremental attenuation of sympathetic tone in the setting of oral antiadrenergic therapy. This theory is supported by experiments conducted by Irwin et al. on anesthezied dogs [108]. Schimidlli found that electrical carotid stimulation and esmolol infusion applied individually produced similar reduction in blood pressure and heart rate, but produced synergistic effect when applied simultaneously [109]. 20 Current Vascular Pharmacology, 2014, Vol. 12, No. 1 Acute blood pressure reduction was noted by using the Rheos device during elective carotid surgery [110]. Several case reports in patient with resistant hypertension have shown the clinical utility and long-lasting reductions in blood pressure with carotid baroreceptor stimulation, setting the basis for proof-of-concept, properly designed, clinical trials [111,112]. Studies performed up to now in patients with resistant hypertension revealed a significant reduction in both systolic and diastolic blood pressure, which was evident from the beginning of the study and was maintained thereafter [113-115]. However, more data is needed in order to verify the efficacy and safety of this interventional approach for the management of patients with resistant hypertension. Stimulation of carotid baroreceptors is associated with heart rate variability and heart rate turbulance changes that are consistent with a decrease of sympathetic activity and an increase of vagal tone. These changes are correlated with a significant decrease in blood pressure. Thus, the data suggest that the modulation of the autonomic nervous system contributes to a better blood pressure control through stimulation of carotid baroreceptors in severely hypertensive patients [116]. Lovic et al. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] CONCLUSION Resistant hypertension affects a significant number of patients and carries a high risk of cardiovascular events. As such, any novel therapy for blood pressure control deserves our attention. Therapeutic lifestyle modification and intensive drug therapy for these patients are frequently proven inadequate, leaving many patients at a dramatically elevated risk from the cardiovascular complications associated with uncontrolled hypertension. The carotid baroreflex represents an essential component of blood pressure regulation. The activation of the carotid baroreflex results in the attenuation of the sympathetic tone and subsequent blood pressure reduction. Carotid nerve activation has been used in the past for the treatment of severe hypertension, but it has been abandoned due to adverse events and several technical disadvantages. Recent technological advances have permitted the development of a new device that electrically stimulates carotid baroreceptors. As premature results are promising, further studies are needed to clarify the place of carotid baroreceptor stimulation in the management of patients with resistant hypertension. The exact clinical indications for this therapeutic modality have yet to be established, but its potential seems considerable. The role of electrical activation of the carotid nerves in the treatment of arterial hypertension is undefined, just as is the role of this therapeutic approach in other disease states. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. 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