Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex

Abstract

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

INTRODUCTION

Hypertension is one of the major risk factors for the development of cardiovascular disease contributing to morbidity and mortality rates worldwide (89, 128, 141, 182). In the United States, the estimated prevalence of drug-resistant hypertension is 9%, and it has been shown that these patients have a higher risk for adverse cardiovascular events, hence the need for greater efforts in improving the effectiveness of the treatments for hypertension (1, 15, 129a, 186). Targeting sympathetic nervous system (SNS) activation has been a therapeutic goal, given its major contribution to elevated blood pressure secondary to high sodium chloride intake (18, 21, 30), chronic kidney disease (83, 88, 153), obesity (2, 67–69, 102), and essential hypertension (63, 64, 189).

Excitatory sympathetic reflexes that participate in the tonic control of efferent sympathetic outflow and therefore peripheral vascular resistance of the cardiovascular system have been extensively reviewed (40, 65, 93, 151). In fact, numerous clinical studies have shown that renal nerve ablation could be an effective treatment for drug-resistant, essential hypertension (22, 74, 136, 165). However, it is still controversial whether the reduction in blood pressure is due to denervation of the sympathetic efferent nerves, the sensory afferent nerves, or both. Yet the current understanding of how the manipulation of sensory signals could be used as an approach for clinical intervention is limited. Although β-adrenergic blockers are a standard treatment for hypertension associated with obesity, there are associated adverse effects such as metabolic dysregulation and body weight gain, most likely due to the reduced capacity to dissipate calories (84, 106, 183). Notably, a rising number of preclinical studies suggest that adipose afferent signals may play a key role in modulating sympathetic outflow to key organs involved in blood pressure control (184), uncovering new potential treatments for hypertension secondary to obesity and metabolic syndrome.

The focus of this review is to highlight the contribution of afferent, sensory signals from adipose tissue in the control of cardiovascular function in health and disease. A better understanding of the underlying pathophysiological mechanisms contributing to blood pressure regulation is a critical step to improve the treatment of obesity-associated hypertension.

AFFERENT REFLEXES ARC OVERVIEW

Reflex arcs sense peripheral stimuli from sensory receptors and integrate the information in the brain, tonically modulating the sympathetic efferent outflow to organs and tissues (154). Afferent fibers with sensory receptor endings have been described in heart (117, 120, 138, 177), aorta (27, 116, 137), carotid body (37, 79, 85), pulmonary veins (118, 175), blood vessels (109, 159), adrenal glands (56, 152, 173), visceral organs (14, 70, 93, 139), kidney (54, 95, 122, 187), skeletal muscle (87, 110), and adipose tissue (7, 9, 162, 185). In physiological conditions, afferent nerve activity is critical for maintaining vascular tone, coronary vascular blood flow, water and electrolyte balance, renal microcirculation, lipolysis, and lipid redistribution.

Sensory receptors in the body are activated by temperature, mechanical deformation, and/or chemical stimuli such as changes in pH, CO_2, or O₂. The activation of these receptors causes an influx of ions that depolarize adjacent and nearby afferent sensory neurons transducing sensory signals into action potentials (107, 130). Certain afferent neurons have somas in the dorsal ganglion root that transmit the electrical signals to the spinal cord and subsequently to the central nervous system (CNS) modulating sympathetic outflow in physiological conditions. In the CNS, the paraventricular nucleus of the hypothalamus (PVN) is one of the major integrative centers that receives sensory signals from the periphery and participates in the control of SNS outflow and cardiovascular function via the activation of preautonomic neurons (for reviews, see 52, 68, 142). These neurons in the PVN project to the rostral ventrolateral medulla (RVLM), a key brain area that regulates basal and reflex control of sympathetic outflow, blood pressure, baroreflex, and chemo- and cardiopulmonary reflexes (66, 101, 105, 170). The PVN also projects to the nucleus tractus solitary (NTS) and spinal cord, regulating sympathetic tone and blood pressure from the hindbrain (142, 144).

Another major site for afferent signal integration is the NTS that receives sensory information from stretch-sensitive mechanoreceptors in the carotid sinus and aortic arch (aortocarotid baroreflexes), the cardiac atria and ventricles (cardiopulmonary baroreflexes), and chemo/mechanoreceptors from the viscera (3, 32, 55, 86). The NTS also receives sensory inputs from the area postrema that lacks a complete blood brain barrier and senses changes in ionic and hormonal composition of blood and cerebrospinal fluid (12, 71, 179). In turn, the NTS sends excitatory (glutamatergic) projections to the caudal and rostral ventrolateral medulla, mediating autonomic and cardiovascular regulation (32, 112, 172).

Therefore, the precise balance between sensory afferent and sympathetic efferent signals to and from the central nervous system is critical for the maintenance of physiological functions, including blood pressure regulation.

ADIPOSE AFFERENT REFLEX: AN OVERLOOKED PLAYER IN BLOOD PRESSURE REGULATION

The adipose afferent reflex (AAR) is the sympathoexcitatory reflex that initiates in adipose tissue and is activated by sensory stimulation (e.g., nociceptive, mechanoceptive, and chemoreceptive). In physiological conditions, activation of the AAR prevents fat deposition by inducing lipolysis and lipid mobilization in white adipose tissue (WAT) and promoting leptin release to reduce body weight and increase energy expenditure (13, 46, 131, 149). In response to AAR activation, WAT also secretes adiponectin that acts in the central nervous system to control appetite and energy expenditure (51, 129). Moreover, electrical or chemical stimulation of subcutaneous and visceral WAT promotes lipid mobilization as well as free fatty acid production (29, 46, 60, 147). Therefore, the AAR is a neural mechanism that, in normal conditions, contributes to body weight and fat deposition regulation by modulating sympathetic outflow to adipose tissue. Whereas the AAR in WAT is involved in lipolysis and lipid redistribution, the reflex arc in brown adipose tissue (BAT) is critical for the regulation of thermogenesis (11, 19, 103). Although the adipose afferent reflex was elegantly reviewed by Xiong et al. (185) in 2014, recent studies have shown further evidence of AAR dysfunction in the context of metabolic disease (20, 31, 44–46).

Dr. Niijima (132, 133) first described the adipose reflex arc in 1998 while studying leptin “sensors” in WAT and their role in regulating WAT metabolic functions. Leptin injections (10 ng/mL and 100 ng/mL, 0.2 mL) into epididymal WAT evoked reflex activation of sympathetic nerve activity in WAT, BAT, and other organs such as the liver and pancreas and a decrease in vagal nerve activity, suggesting reflex activation associated with metabolic functions. The sensory afferent projections from WAT contain markers for sensory innervation, such as calcitonin gene-related peptide (CGRP) and substance P (SP; 13, 160, 161). Both surgical and chemical denervation using high doses of capsaicin or resiniferatoxin (a potent capsaicin analog) selectively decreased CGRP and SP immunostaining, but not the efferent marker tyrosine hydroxylase, in both inguinal and epididymal WAT (160–162). Although it has been previously shown that CGRP is a potent vasodilator that decreases blood pressure when released from the nerve endings of sensory neurons in the proximity of blood vessels (38, 90, 148), its role in lowering blood pressure when released from adipose tissue is not well understood.

In addition to leptin, several experimental studies have demonstrated that AAR can be activated by adenosine, bradykinin, protons, or low doses of capsaicin in WAT (162). Specifically, bilateral capsaicin injections in inguinal WAT and retroperitoneal WAT significantly increase renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) within 20 min in rats. Conversely, inguinal WAT surgical denervation prevented both MAP and RSNA from capsaicin-induced activation (162, 184). Capsaicin acts via the vanilloid receptor TRPV1, a ligand-gated, nonselective cation channel receptive to the activation of nociceptive afferent neurons: unmyelinated (C fibers) and thinly myelinated axons (Aδ fibers) (113, 174). TRPV1 can be also activated by noxious heat, bradykinin, and adenosine (49, 50). In adipose tissue, small diameter, unmyelinated (C fibers) sensory nerves express TRVP1 that mediate sensory-driven negative feedback control of adiposity (9). Furthermore, TRPV1 are involved in the “sensory-effector” mechanism by releasing CGRP and SP (176). Motter and Ahern (125) demonstrated that TRPV1-null mice fed an 11% fat diet gained significantly less mass and adiposity and displayed increased thermogenic capacity when compared with wild-type animals. Thus, TRPV1 participates in promoting fat accumulation and weight gain, possibly via direct adipose afferent nerve stimulation (125).

Sensory afferent neurons from WAT project to the dorsal root ganglia (DRG) (53) and from the DRG to the hypothalamus and brainstem (for reviews, see 7, 8, 10, 185). Postganglionic sensory afferents from the fat have been extensively studied using anterograde and retrograde neuronal tracers in Siberian hamsters (150, 166). Injections of the transneuronal viral tracer H129 strain of the herpes simplex virus-1 in combination with the transneuronal retrograde tracer pseudorabies virus (PRV) in inguinal and perigonadal WAT in male hamsters showed that afferent sensory neurons project to the PVN and RVLM (9, 150, 166). These projections have a key role in autonomic and cardiovascular regulation by modulating sympathetic outflow to organs critical to metabolism and blood pressure regulation (36, 48, 142, 158).

To further investigate the AAR in normotensive rats, Shi et al. (162) lesioned the PVN with kainic acid. These lesions abolished MAP or RSNA increases in response to capsaicin injections in inguinal WAT, confirming a predominant role of the PVN as an integration center of the sensory afferent projections from WAT and thus controlling sympathetic outflow in the AAR response. Similarly, leptin injections in WAT increase the number of c-Fos-positive cells, a marker of neuronal activation, in the PVN (127). Shi et al. (163) measured activity of PVN neurons in response to capsaicin infusion in inguinal WAT and retroperitoneal WAT and were able to evoke excitatory discharges in 30% of the spontaneously active neurons in the PVN. Insulin injections into the PVN induced a greater increase in baseline sympathetic nerve activity and a further increase of RSNA and MAP after AAR stimulation in insulin-resistant rats but not in normal rats (45). Although these studies established a pivotal role for PVN regulating sympathetic outflow and blood pressure, the highly heterogeneous composition of this nucleus demands a careful study of the specific subset and localization of neurons involved in the AAR.

To determine the mechanisms that modulate the AAR in the PVN, Li et al. (104) evaluated the contribution of melanocortin receptors (MC3/4Rs) in RSNA and MAP changes after AAR stimulation with capsaicin. Microinjections of an MC3/4R agonist [melanotan II (MTII)] into the PVN enhanced RSNA and MAP, and similarly, an MC3/4R antagonist (SHU9119) or MC4R antagonist (HS024) attenuated these responses. Moreover, SHU9119 was able to abolish the increase in cAMP in the PVN in response to capsaicin infusion in inguinal WAT and in response to MTII microinjections. They also showed that AAR stimulation increases superoxide anion production and NADPH oxidase activity in the PVN (47). In these experiments, microinjections of superoxide dismutase-polyethylene glycol (PEG-SOD), tempol, and apocynin, an NADPH oxidase inhibitor, in the PVN were able to decrease RSNA and MAP in response to AAR stimulation with capsaicin in inguinal adipose tissue. These results suggest that AAR activation generates superoxide anions in the PVN that could be responsible for increased sympathetic activation and, consequently, blood pressure. Furthermore, they demonstrate that the activation of γ-aminobutyric acid (GABA) receptors GABA_A and GABA_B in the PVN inhibits the AAR, whereas the selective blockade of these receptors exacerbates this reflex (43). It is important to note that all of these experiments were conducted under anesthesia and the AAR was chemically stimulated. It will be extremely useful to test these mechanisms in animal models of genetic obesity where the baseline AAR could be exacerbated.

The excess adiposity is one of the major causes of sympathetic activation and increased blood pressure (48, 100, 145, 168). In the last decade, only a few studies have investigated the importance of AAR dysregulation during obesity-induced hypertension (184, 185). Xiong et al. (184) reported that a high-fat diet for 12 wk increased the AAR in response to capsaicin. Bilateral injections of capsaicin into inguinal WAT further enhanced MAP and RSNA response in obese hypertensive rats compared with normotensive rats. Plasma renin, angiotensin II, and norepinephrine levels were elevated in obese hypertensive rats after capsaicin stimulation, suggesting that the AAR activation could also increase the renin angiotensin aldosterone system (RAAS), thereby contributing to the elevated blood pressure in obese animals. Additionally, the neuronal activation of the PVN increased in all groups after capsaicin injection, with a greater increase in PVN activity in obese hypertensive animals. However, these studies do not clarify whether this increased neuronal activation is due to exacerbated afferent nerve activity or to an increased number of sensory afferent neurons projecting to the PVN. Finally, chemical inguinal WAT and retroperitoneal WAT denervation with resiniferatoxin, an ultrapotent capsaicin analog that induces selective ablation of sensory neurons (171), as well as lidocaine injections in the PVN reduced sympathetic nerve activity and blood pressure in obese rats. This decrease was greater in obese hypertensive animals compared with obese normotensive rats. Ionotropic glutamate receptors in the PVN of rats are likely responsible for sympathetic outflow in response to capsaicin-induced AAR activation (31). Therefore, microinjections of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists in the PVN before AAR stimulation with capsaicin attenuated increased renal sympathetic nerve activity and blood pressure in response to the AAR stimulation (31).

In a follow-up study (44), the same group showed that acute injections of tumor necrosis factor α(TNFα) in the PVN increased NADPH oxidase activity and reactive oxygen species (ROS) levels, exacerbating the capsaicin-induced AAR in obese hypertensive rats. PEG-SOD and apocynin were able to decrease ROS production, NADPH oxidase activity, RSNA, and MAP after TNFα-induced enhancement of AAR. Moreover, chronic treatment with pentoxifylline, a cytokine blocker, decreased NADPH oxidase and ROS in the PVN and the elevated RSNA and blood pressure in obese hypertensive rats. These results highlight the role of inflammatory cytokines in the exacerbated AAR during obesity-induced hypertension.

In a recent report, Cao et al. (20) showed that high-fat and high-salt diet (HFHS) impairs glucose uptake in adipose tissue and skeletal muscle and leads to insulin resistance. HFHS increased angiotensinogen expression and angiotensin II levels in adipose tissue, skeletal muscle, and the subfornical organ and PVN. Additionally, HFHS elevated efferent sympathetic nerve activity to adipose tissue and muscle. Total denervation of epididymal adipose tissue or afferent denervation with resiniferatoxin were able to downregulate RAAS components in the brain, decrease adipose inflammation and efferent sympathetic nerve activity, and improve glucose uptake in adipose tissue. Similar results were observed after tempol treatment showing that HFHS elevated efferent nerve activity increased the local production of ROS. The authors concluded that HFHS enhanced afferent signals from adipose tissue, promoting RAS and ROS activation, increased efferent nerve activity, and impaired glucose uptake leading to insulin resistance.

To date, all the AAR studies have been conducted in rats and Siberian hamsters. To further elucidate the mechanistic role of this reflex in different models of hypertension, we measured blood pressure changes in response to the AAR stimulation in male mice. In these experiments, we tested the MAP response to the stimulation of several tissues with capsaicin solution (5 ng capsaicin, 20 μL ethanol, 10 μL Tween 80/mL saline) or vehicle (20 μL ethanol, 10 μL Tween 80/mL saline). The AAR was induced by the injection of 1.5 pmol capsaicin (8 μL of capsaicin solution over a period of 2 min in 4 different sites, bilaterally). Capsaicin did not change MAP from baseline when infused in the blood stream via the jugular vein (Fig. 1A), intramuscular infusion into the adjacent skeletal muscle (Fig. 1B), or subcutaneous WAT (Fig. 1C). However, capsaicin induced a significant MAP increase from baseline in epidydimal WAT stimulation (Fig. 1D). Subcutaneous or epidydimal WAT stimulation with vehicle did not influence baseline MAP in either fat depot. Figure 1E shows the MAP 5-min average in response to vehicle or capsaicin solution. Thus, these data are the first to show that adipose tissue-blood pressure axis response is present in mice, which allows for the design of studies to test the contribution of the AAR in different genetic and/or experimental models of obesity-induced hypertension.

Fig. 1.

Mean arterial pressure (MAP) in response to vehicle or capsaicin (Cap) infusion in male mice in intravascular space (I.V., n = 5) (A), skeletal muscle (SM; n = 5) (B), subcutaneous white adipose tissue (scWAT; n = 5) (C), epidydimal white adipose tissue (eWAT; n = 7) (D), and scatter plot of MAP 5-min average after vehicle of Cap infusion (E). MAP was measured under anesthesia in 5- to 6-mo-old C57BL/6J male mice. The adipose afferent reflex (AAR) was induced as described previously by Shi et al. (162). The AAR was induced by the injections of Cap (8 μL of Cap 0.5 μg% over a period of 2 min in 4 different sites, bilaterally). Data are represented as mean ± SE and analyzed using SigmaPlot v.11 (Systat Software, CA). One-way analysis of variance (ANOVA) with repeated measures, followed by Tukey’s post hoc test, was used to analyze the effects of vehicle or Cap infusion. *P < 0.05 vs. baseline and vehicle infusion.

Taken together, there is compelling evidence indicating that AAR is exacerbated during obesity-induced hypertension, contributing to increased sympathetic outflow to organs involved in blood pressure control, such as the kidneys (Fig. 2). More studies are needed to determine the exact extent of the AAR contribution to hypertension, its connection with vasoactive peptides production during obesity, and its interplay with other afferent reflexes during obesity-induced hypertension. Moreover, it is imperative to investigate whether adipose afferent denervation could be a therapeutic approach to treat obese hypertensive patients. Notably, all these studies were conducted only in male rodents; therefore, it will be extremely valuable to study potential sex differences in the AAR activation and response and whether gonadal steroids are able to modulate this reflex. Finally, understanding how different subsets of PVN neurones are sensing the increased AAR, as well as the role of other brain areas such as the RVLM and NTS, will be critical for the development of therapeutic approaches within the brain.

Fig. 2.

Integrated schematic diagram showing the white adipose tissue, kidney, heart, and vasculature afferent reflexes. In physiological conditions (left), these afferent reflexes work to maintain the normal physiological functions. In pathophysiological conditions (right), the overactivation of sensory signals promotes obesity, hypertension, heart failure, and vascular constriction via increase of the sympathetic outflow. In the context of metabolic disease, adipose afferent reflex (AAR) overstimulation reduces lipolysis and increases the efferent outflow to other organs involved in blood pressure control. This dysfunctional activation of AAR favors the development of obesity and hypertension. RAAS, renin-angiotensin-aldosterone system.

OTHER AFFERENT REFLEXES INFLUENCING BLOOD PRESSURE REGULATION

As mentioned above, in addition to AAR, several afferent reflexes involved in blood pressure regulation have been extensively studied. We briefly review some of these afferent reflexes, including the renorenal reflex, the cardiac afferent reflex, and the arterial baroreflex.

In the kidney, electrophysiological studies have shown the existence of afferent sensory nerve activity generated from chemoreceptor and mechanoreceptor stimulation in the renal pelvis. Renal chemoreceptors are activated by changes in the intrarenal chemical (ion) composition, i.e., during renal ischemia and backflow of urine into the renal pelvis (99, 122, 146). Other agents such as potassium chloride, bradykinin, and capsaicin infusions have been reported to activate sensory neurons (122, 187). On the other hand, renal mechanoreceptors are stimulated by increases in renal arterial and venous pressure, stretching of the renal pelvis, and changes in pressure in the renal pelvis and ureters (121, 123, 124, 167). These sensory signals are discussed in relation to other visceral afferent nerves and their role in renal nociception elsewhere (122, 124). The stimulation of renal afferent sensory neurons is implicated in renorenal reflexes that “enable total renal function to be self-regulated and balanced between the two kidneys” or a “self-regulated renorenal reflex loop” (41, 42, 82, 95). Numerous studies in rats have demonstrated that during hypertension (96), congestive heart failure (97), and diabetes (25, 98), impaired responsiveness of the afferent renal mechanosensory nerves inhibits renorenal reflexes. Similarly, studies by Chen et al. (24–26) have shown that inhibition of the renorenal reflex significantly blunts natriuresis following acute saline volume expansion. Renal chemo- and mechanoreceptor afferent stimulation projects to neuronal populations within the PVN, NTS, and RVLM that regulate efferent sympathetic outflow to the kidneys (28, 153, 188). Additionally, the circumventricular organs that respond to changes in plasma osmolality and circulating angiotensin II also project to the PVN, contributing to water and electrolyte balance and blood pressure regulation (77, 91, 92, 119). Although the afferent nerves in the kidney may participate in the pathogenesis of hypertension, its contribution depends on the experimental model of hypertension. In DOCA-salt-induced hypertension (56, 80) and spontaneously hypertensive rats (81), total renal denervation delays and attenuates the development of hypertension, whereas selective ablation of the renal afferent nerves does not have a significant effect on blood pressure. Furthermore, Banek et al. (4–6) have shown that elevated afferent renal nerve activity mediates the increase in blood pressure in response to DOCA salt, suggesting an afferent neural component in the development and maintenance of hypertension. Renal afferent nerves are also critical in the development of one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertension in rats; in dogs with chronic aortic coarctation hypertension (135); and in models of hypertension associated with chronic renal failure (16, 17). Both renal artery stenosis (49) and acute reductions in renal blood flow (126) activate afferent renal nerve activity, which results in systemic neurogenic hypertension. It has also been proposed that the renal afferent reflex may play a critical role in chronic renal hypertension when the baroreflex is impaired and activation of the RAAS is reduced (49).

The cardiac afferent reflex (CSAR) is a chemosensitive, sympathoexcitatory, cardiac vagal reflex that is also implicated in blood pressure regulation. In physiological conditions, CSAR works in conjunction with the baroreflex to regulate cardiac sympathetic tone (111, 115, 140, 191). Induction of the CSAR occurs via stimulation of chemoreceptors by endogenous humoral factors, including bradykinin and adenosine, or exogenous factors such as capsaicin that increase sympathetic outflow and blood pressure (58, 114, 180, 181). Afferent fibers from the subepicardium and myocardium project to the NTS in the brainstem; from there, they project to the PVN and RVLM (34, 143, 177). In normal rats, cardiac sympathetic afferents reduced arterial baroreflex sensitivity mediated by AT1 receptors (23, 59). In contrast, the enhanced effect of the CSAR initiated by the chemoreflex occurs via left ventricular electrical and capsaicin-induced stimulation of cardiac afferent reflexes. This response is abolished after bilateral microinjection of losartan into the NTS, confirming that the NTS is a key intermediary between these two reflexes (57). Spontaneously hypertensive rats displaying elevated CSAR and microRNA interference of angiotensin AT1a receptors in the PVN attenuated the hypertension in this strain (50). Similarly, the exacerbated CSAR during chronic heart failure is normalized after AT1 receptor blockade (190, 192) or resiniferatoxin afferent denervation (24, 78, 177, 178). Taken together, these studies demonstrate that angiotensin II plays a key role in the regulation of the CSAR.

Finally, the arterial baroreflex of the carotid sinus participates in acute blood pressure regulation by controlling heart rate, contractility, and systemic vascular resistance (39, 73, 75, 108). The baroreflex is a rapid sympathoinhibitory feedback loop that decreases heart rate and, consequently, blood pressure. Baroreceptors in the carotid sinus and aortic arch sense changes in blood pressure and transmit this information to the NTS to regulate sympathetic tone and blood pressure. During increases in blood pressure, the NTS activates, via glutamatergic projections, the caudal ventrolateral medulla that in turn inhibits, via GABAergic projections, the RVLM and decreases sympathetic tone and blood pressure (35, 155–157, 169). Several studies have shown a baroreflex dysfunction in clinical and experimental hypertension. In this regard, Dahl salt-sensitive and spontaneously hypertensive rats display impaired baroreflex sensitivity, similar to what has been reported in hypertensive humans (35, 61, 72, 164). In recent years, carotid baroreflex activation has been proposed as a novel therapy for resistant hypertension; however, the results are not consistent due to the lack of adequate randomized control trials and the presence of other negative conditions, such as obesity and chronic kidney disease (62, 76, 134).

CONCLUSIONS

Overall, the exacerbated activation of the afferent reflexes during experimental obesity impair blood pressure control. Given that obesity increases the risk of drug-resistant hypertension, advances in our understanding of how the AAR contributes to enhance sympathetic activation may help to develop therapeutic approaches for successfully managing blood pressure in obese patients. A comprehensive understanding of how multiple afferent reflexes contribute to uncontrolled blood pressure may provide significant insights into improving antihypertensive therapeutic approaches.

GRANTS

This study was supported by funds from the National Institutes of Health National Heart, Lung, and Blood Institute, Grant Nos. R01 HL135158 (to A. S. Loria) and R01 HL135158S1 (to J. R. Leachman).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.D. and A.S.L. conceived and designed research; C.D. and A.S.L. performed experiments; C.D., J.R.L., and A.S.L. analyzed data; C.D., J.L.O., and A.S.L. interpreted results of experiments; C.D. and A.S.L. prepared figures; C.D., J.R.L., J.L.O., and A.S.L. drafted manuscript; C.D., J.R.L., J.L.O., and A.S.L. edited and revised manuscript; C.D., J.R.L., J.L.O., and A.S.L. approved final version of manuscript.