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Changes in vascular structure contribute to vascular events and loss of brain health. We examined the inherent structural plasticity of cerebral arterioles during and after a period of hypertension. Arteriolar wall thickness, diameter, wall-to-lumen ratio, and biological stiffness changed rapidly during hypertension and recovered with blood pressure. In contrast, inward remodeling developed slowly and did not recover. This lack of recovery of arteriolar diameter has implications for the long-term impact of hypertension on vascular determinants of brain health.

The Bezold–Jarisch reflex is a powerful inhibitory reflex initiated by activation of cardiopulmonary vagal nerves during myocardial ischemia, hemorrhage, and orthostatic stress leading to bradycardia, vasodilation, hypotension, and vasovagal syncope. This clinically relevant reflex has been studied by measuring heart rate (HR) and mean arterial pressure (MAP) responses to injections of a variety of chemical compounds. We hypothesized that reflex responses to different compounds vary due to differential activation of vagal afferent subtypes and/or variable coactivation of excitatory afferents. HR and MAP responses to intravenous injections of the transient receptor potential vanilloid-1 (TRPV1) agonist capsaicin and the serotonin 5-HT3 receptor agonist phenylbiguanide (PBG) were measured in anesthetized C57BL/6 mice before and after bilateral cervical vagotomy. Capsaicin and PBG evoked rapid dose-dependent decreases in HR and MAP followed by increases in HR and MAP above baseline. Bezold–Jarisch reflex responses were abolished after vagotomy, whereas the delayed tachycardic and pressor responses to capsaicin and PBG were differentially enhanced. The relative magnitude of bradycardic versus depressor responses (↓HR/↓MAP) in vagus-intact mice was greater with capsaicin. In contrast, after vagotomy, the magnitude of excitatory tachycardic versus pressor responses (↑HR/↑MAP) was greater with PBG. Although capsaicin-induced increases in MAP and HR postvagotomy were strongly attenuated or abolished after administration of the ganglionic blocker hexamethonium, PBG-induced increases in MAP and HR were mildly attenuated and unchanged, respectively. We conclude that responses to capsaicin and PBG differ in mice, with implications for delineating the role of endogenous agonists of TRPV1 and 5-HT3 receptors in evoking cardiopulmonary reflexes in pathophysiological states.

The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2and CO2and pH, eliciting reflex ventilatory, cardiovascular, and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiological responses, and its role in maintaining health and potentiating disease. Emphasis is placed on 1) transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ion channels; 2) synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; 3) integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological, or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and 4) the contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension, and metabolic diseases and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways.NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.

Heart rate and blood pressure control PIEZO1 and PIEZO2 are two mechanically activated ion channels that are highly expressed in lungs, bladder, and skin. Zeng et al. found that both ion channels are expressed in sensory neurons of a ganglion complex that contribute to the baroreflex, a homeostatic mechanism that helps to keep blood pressure stable (see the Perspective by Ehmke). Conditional double knockout of PIEZO1 and PIEZO2 in these neurons abolished the baroreflex and disrupted blood pressure regulation and heart rates in mice. These changes were very similar to those seen in patients with baroreflex failure. In mice, selective activation of PIEZO2-expressing ganglion neurons triggered immediate increases in heart rate and blood pressure. Science , this issue p. 464 ; see also p. 398

Vascular remodeling is a feature of small vessel disease (SVD), predictive of vascular events, brain injury, and cognitive decline. Hypertension alters vascular structure including diameter and cross-sectional area (CSA) of the vessel wall. While effects of hypertension on large arteries have been studied relatively widely, detailed quantification, including recovery from hypertension in microvessels, is rare. Previously, angiotensin II (Ang II)-dependent hypertension produced increased CSA but reduced internal diameter (ID) of cerebral arterioles (inward remodeling) in brain. Because cerebral arterioles are targets of SVD, we examined the hypothesis that brain microvessels can recover from hypertension after return of mean arterial pressure (MAP) to normal levels. MAP was measured using radiotelemetry in adult male C57BL6J mice at baseline, during infusion of vehicle or Ang II (1.4 mg/kg per day using osmotic mini-pumps) for 28 days, and during a 28 day recovery period (n=5 in each group). Prior to treatment, MAP was similar in both groups, with MAP remaining stable in vehicle treated mice. With Ang II treatment, MAP began to rise on day 3, steadily increasing until day 28. On day 30, MAP began to decrease, reaching levels seen with vehicle on days 46-47. In anesthetized mice, we measured pressure, diameter, and CSA of the vessel wall in maximally dilated arterioles (baseline diameter of 62±3 microns) at 1, 3, 7, 14, 28, and 56 days after pump implantation (n=7-9 in each group). At day 1, ID and CSA were similar in both groups. With vehicle, there was no significant change in CSA or ID at any time point. With Ang II, CSA increased at day 7 and was maintained at days 14 and 28 (P=0.023). ID did not change at day 3 or 7, but was reduced (by ~15%, P=0.011) at 14 and 28 days. During recovery (day 56), CSA returned 63% of the way to normal (compared to vehicle), while ID remained at day 14 and 28 values. In conclusion, CSA changed rapidly during hypertension onset and largely recovered with a reduction in MAP. Inward remodeling developed slowly and did not recover after return of MAP to control levels. The lack of recovery after hypertension has implications for the impact of SVD including hypoperfusion, impaired vasodilation, and augmented injury during ischemia.

Calcitonin gene-related peptide (CGRP) can cause migraines, yet it is also a potent vasodilator that protects against hypertension. Given the emerging role of CGRP-targeted antibodies for migraine prevention, an important question is whether the protective actions of CGRP are mediated by vascular or neural CGRP receptors. To address this, we have characterized the cardiovascular phenotype of transgenic nestin/hRAMP1 mice that have selective elevation of a CGRP receptor subunit in the nervous system, human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice had relatively little hRAMP1 RNA in blood vessels and intravenous injection of CGRP caused a similar blood pressure decrease in transgenic and control mice. At baseline, nestin/hRAMP1 mice exhibited similar mean arterial pressure, heart rate, baroreflex sensitivity, and sympathetic vasomotor tone as control mice. We previously reported that expression of hRAMP1 in all tissues favorably improved autonomic regulation and attenuated hypertension induced by angiotensin II (Ang II). Similarly, in nestin/hRAMP1 mice, hypertension caused by Ang II or phenylephrine was greatly attenuated, and associated autonomic dysregulation and increased sympathetic vasomotor tone were diminished or abolished. We conclude that increased expression of neuronal CGRP receptors is sufficient to induce a protective change in cardiovascular autonomic regulation with implications for migraine therapy.

Rationale: Renal inflammation contributes to the pathophysiology of hypertension. CD161a + immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation. Objective: We aimed to phenotype CD161a + immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension. Methods and Results: Studies used young SHR and WKY (Wistar–Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a + /CD68 + macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats. Conclusions: A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a + /CD68 + macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.

Hypertension alters vascular structure including diameter, cross-sectional area (CSA), and stiffness of the vessel wall. Inward remodeling is a feature of small vessel disease (SVD), predictive of vascular events and cognitive decline. While effects of prevention of hypertension on large arteries have been studied widely, quantification of temporal changes and recovery from hypertension in microvessels is rare. Previously, angiotensin II (Ang II)-dependent hypertension produced increased CSA but reduced internal diameter (ID) of maximally dilated arterioles (inward remodeling) in brain. Because cerebral arterioles are targets of SVD, we examined time course and whether microvessels recover from hypertension. Mean arterial pressure (MAP) was measured using radiotelemetry in adult male C57BL6J mice prior to, during infusion of vehicle or Ang II (1.4 mg/kg per day using osmotic mini-pumps) for 28 days, and a 28 day recovery period. Prior to treatment, MAP was similar in both groups. Throughout recording, MAP was stable in vehicle treated mice. With Ang II, MAP began to rise on day 3, steadily increasing until day 28. On day 30, MAP began to decrease, reaching levels seen with vehicle on days 46-47. In anesthetized mice, we measured pressure, diameter, and CSA of the vessel wall (histologically) in maximally dilated arterioles (baseline diameter of 63±1 microns) at 1, 3, 7, 14, 28, and 56 days after pump implantation (n=7-9 in each group). At day 1, ID and CSA were similar in both groups. With vehicle, there was no significant change in CSA or ID at any time point. With Ang II, CSA increased at day 7 and was maintained at days 14 and 28 (P=0.023). ID did not change at day 3 or 7, but was reduced (by ~15%, P=0.011) at 14 and 28 days. During recovery (day 56). CSA returned 63% of the way to normal (compared to vehicle), while ID remained at day 14 and 28 values. In conclusion, CSA changed rapidly during hypertension onset and largely recovered with a reduction in MAP. Inward remodeling developed slowly and did not return to vehicle levels with MAP. The lack of recovery of ID after a period of hypertension has implications for the impact of SVD including hypoperfusion, impaired vasodilation, and augmented injury during ischemia.

Background Vasovagal reflex is the most common form of syncope, but the pathophysiological mechanisms that initiate the reflex are not well understood. We aimed to study supine and early orthostatic levels of the neurohormones involved in control of circulatory homeostasis in relation to the onset of tilt‐induced vasovagal syncope (VVS). Methods and Results A total of 827 patients who were investigated for unexplained syncope with head‐up tilt test (HUT) and optional nitroglycerin provocation (Italian protocol) had blood samples collected while supine and after 3‐minutes of HUT. Of these, 173 (20.9%) patients developed VVS during drug‐free HUT, 161 of whom (males 44.7%; age 45±21 years) had complete data. We analyzed levels of epinephrine, norepinephrine, C‐terminal pro–arginine vasopressin, C‐terminal endothelin‐1, and midregional fragments of pro–atrial natriuretic peptide and pro‐adrenomedullin in relation to time from tilt‐up to onset of VVS. We applied a linear regression model adjusted for age and sex. The mean time to syncope was 11±7 minutes. Older age (β=0.13; SE=0.03, P, See Editorial Williford et al

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca(2+)-activated chloride (Cl(–)) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca(2+)-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.

Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition ( Nω-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (−2.3 ± 1.2 μm, P < 0.05) in sham, but was maintained (−0.7 ± 0.8 μm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (−9.7 ± 2.2%, P < 0.05) and distensibility (−2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (−3.8 ± 3.8%, −0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 ( r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 ( r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chronic-vagal-nerve-stimulation-in-stroke-prone-shr/ .

Introduction Human papillomavirus (HPV) vaccination has been anecdotally connected to development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. Objectives To critically evaluate a potential connection between HPV vaccination and above noted conditions. Methods We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. Results At this time the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, POTS or other forms of dysautonomia. Conclusions Certain conditions are prevalent in the same patient populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is insufficient proof of causality.

High fat diet (HFD) leads to obesity and the metabolic syndrome. However, the effect are less pronounced in females than in males. We suggest that a gender difference is in their response to the satiety peptide Cholecystokinin (CCK). We previously reported that the Ca 2+ -activated Cl - channel (CaCC) subunit Ano2 /TMEM16B is essential for the CCK-induced current in intestinal nodose neurons in male mice, and is down regulated in obese mice fed on HFD. We hypothesize that the CCK-induced current in female mice is mediated predominantly by Ano1 /TMEM16A, the alternative subunit of TMEM16B. We studied the CCK-induced current in nodose neurons from female C57BL/6 mice using whole cell patch-clamp. We found that 10nM of CCK induces an inward current in these neurons with a current density averaging 13.4±2.5 pA/pF (n=7), and this current is inhibited to 3.1±1.2 pA/pF (n=7, pinhi-A01 . We further tested whether HFD which effectively suppressed the expression of TMEM16B in male mice, would also decrease TMEM16A in female mice. Our results show that the CCK-induced TMEM16A current in nodose neurons is not decreased in female, but tend to increase from 12.5±1.6 (n=10) in control to 17.4±4.1 pA/pF (n=11, p=0.298) in female mice fed on HFD. Concurrently the mRNA level of Ano1 in mice fed on HFD also show a trend to increase by 1.33±0.41 fold (n=2 pairs of mice, p=0.37) compared to mice on regular chow. Our findings indicate that activation of CCK-sensitive Ano1 /TMEM16A may partially protect female mice from HFD induced obesity and metabolic syndrome.

Sarcomere gene mutations cause hypertrophic cardiomyopathy (HCM). Hallmark features include cardiac hypertrophy, fibrosis, excessive cardiac sympathetic tone, and increased risk of arrhythmias and sudden death. The mechanism(s) of increased sympathetic tone is poorly understood. We hypothesized that cardiac spinal (sympathetic) afferents are sensitized by metabolites (e.g., H+) produced during myocyte energy depletion in HCM, resulting in an enhanced cardiac sympathetic afferent reflex (CSAR). We studied mice with cardiac-specific expression of mutated alpha-tropomyosin (Glu180Gly), an established model of HCM. The CSAR was assessed by measuring mean arterial pressure (MAP) and heart rate (HR) responses to epicardial application of the TRPV1 agonist capsaicin (2.5mM, 2μL) to the left ventricle in anesthetized, ventilated HCM (n=5) and wild-type (WT) littermate control (n=5) mice. Pressor and tachycardic responses to capsaicin were markedly enhanced in HCM mice (Table). Blocking the tonic influence of cardiac afferent activity by epicardial application of the local anesthetic lidocaine (2%) caused small, significant decreases in MAP in both groups of mice; but decreased HR markedly in HCM mice only (n=5) (Table). mRNA expression (qPCR) of acid-sensing ion channel 3 was increased by 2-fold in dorsal root ganglia (T1-T9) of HCM vs. WT mice (n=6 each, P

New Findings What is the central question of this study? Is autonomic dysregulation in a mouse model of muscular dystrophy dependent on left ventricular systolic dysfunction and/or activation of the renin–angiotensin system (RAS) and does it predict development of dilated cardiomyopathy (DCM)? What is the main finding and its importance? The results demonstrate that autonomic dysregulation precedes and predicts left ventricular dysfunction and DCM in sarcoglycan-δ-deficient (Sgcd−/−) mice. The autonomic dysregulation is prevented by treatment of young Sgcd−/− mice with the angiotensin II type 1 receptor blocker losartan. Measurements of RAS activation and autonomic dysregulation may predict risk of DCM, and therapies targeting the RAS and autonomic dysregulation at a young age may slow disease progression in patients. Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin–angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan-δ-deficient (Sgcd−/−) mice and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10–12 weeks of age, when left ventricular function assessed by echocardiography remained normal, Sgcd−/− mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity and cardiovagal tone and increased sympathetic tone compared with age-matched C57BL/6 control mice (P

Cholecystokinin (CCK) is a well-known satiety peptide that inhibits food intake. The CCK induced satiety signal in intestinal vagal afferents is attenuated in mice on a High Fat Diet (HFD). We have shown that down regulation of a Ca 2+ -activated Cl - channel (CaCC) downstream of CCK receptors is responsible for the neuronal insensitivity to CCK. We also found that the CaCC subunit Ano2/TMEM16B is essential for the CCK-induced current in nodose neurons. In this study we tested the hypothesis that reduction of this subunit in vivo contributes to weight gain. One allele of the Ano2/TMEM16B was knocked out in sensory neurons by crossing the ano2 fl/ fl mice with Nav1.8Cre mice to generate the Nav1.8Cre;ano2 fl /wt mice. The Cre negative littermates were used as control. We found that CCK-induced suppression of food intake is eliminated in male Nav1.8Cre;ano2 fl /wt mice. Food intake measured over 4 hours was 1.21±0.11g (n=5) in male wild type (wt) mice injected with saline and was reduced to 0.77±0.18 g (n=7, p0.05) in CCK injected male Nav1.8Cre;ano2 fl /wt mice. However, the CCK injection did not affect food intake in either female wt or Nav1.8Cre;ano2 fl /wt mice. The male Nav1.8/ano2 fl/wt mice were on the average 5.5g heavier than wt mice at 40 weeks of age (39.8±1.4 g, n=13 vs 34.3±1.4 g, n=14, pfl /wt mice (30.4±1.0 g, n=14 vs 28.5±1.0 g, n=11, p=0.20 respectively). Single cell mRNA level of Ano2 and CCK-induced TMEM16 currents in nodose neurons were reduced significantly in male Nav1.8Cre;ano2 fl/wt mice compared to Cre negative controls, but such changes were not seen in female mice. We conclude that heterozygote knockout of Ano2/TMEM16B specifically in sensory neurons causes neuronal insensitivity to CCK and excessive weight gain in male but not female mice. Reduction of this subunit may contribute to the HFD induced obesity. The reason for the phenotype and allele expression variability between sexes is unclear.

In vivo cholinergic activation with nicotine induces renal infiltration of M1 inflammatory CD161a+/CD68+ macrophages and the development of hypertension. Renal denervation has been proposed as a treatment for essential hypertension. Based on this we hypothesized that the renal sympathetic nerves play a role in these processes. Bilateral renal denervation was performed surgically in 3-4 week old Spontaneously Hypertensive Rats (SHR), a genetic model of essential hypertension. Following one week recovery, animals received subcutaneous infusion of nicotine (15mg/kg/day) via osmotic pumps for 2 weeks. Blood pressure was measured by tail-cuff and kidneys harvested on completion of infusion. Prior to nicotine infusion, at baseline, there was no difference between the systolic blood pressures of the sham treated (n=7) and renal denervation (n=10) groups, 132 ± 4 vs 128 ± 3 mmHg, respectively (p>0.05). In contrast, nicotine infusion significantly raised the systolic blood pressure in the sham treated group (159 ± 3mmHg), but not in the renal denervation group (135 ± 5 mmHg) (p

The innate immune system plays a key role in onset and maintenance of hypertension. We showed that the toll-like receptor (TLR) adaptor protein TRIF (toll interleukin receptor domain-containing adaptor-inducing interferon-b), but not MyD88 (myeloid differentiation 88), is required for angiotensin II (Ang II) induced hypertension in mice. TRIF transduces signals from TLR3 and TLR4, to induce inflammatory gene expression. In this study, we sought to determine which TLR is responsible for TRIF-mediated hypertensive effects of Ang II. We used a TLR4 deficient mice (TLR4-del) that have TLR4 gene deleted and the wild type (WT) control strain (C57BL/10). We also used a TLR3-knockout mice (TLR3ko) that have the exon 1 of the Tlr3 gene deleted. Saline or Ang II (1000 ng/kg/min) was infused subcutaneously for 3 weeks using mini-osmotic pumps and systolic blood pressure (SBP) was measured by tail cuff. Ang II increased peak SBP in WT (from 108 ± 1.3 mmHg to 136.0 ± 12.7 mmHg, n= 3) and TLR4-del (from 115.6 ± 2.7 mmHg to 154.4 ± 3.3 mmHg, n=3) mice. In contrast, peak SBP was not increased significantly with Ang II infusion in TLR3ko mice (from 111.3 ± 4.5 to 122.2 ± 18.6 mmHg, n=6) nor was it increased in WT mice after selective inhibition of TLR3 signaling with CU CPT 4a. Thus, the TLR3/TRIF, but not TLR4, pathway is essential for Ang II hypertension. In parallel with the pressure responses to Ang II, renal expression of Nox4 was significantly decreased in TLR3ko mice but was unchanged in TLR4-del and WT mice. In contrast to Ang II-induced hypertension, AngII-induced cardiac hypertrophy, measured as heart weight to body weight ratio, after 3 weeks of Ang II infusion was reduced in both TLR4-del (5.38 ± 0.19 mg/g) and TLR3ko (4.99 ± 0.15 mg/g) compared to WT (7.14 ± 0.49 mg/g). Thus, cardiac hypertrophy is abrogated in TLR4-del despite a robust pressor response to Ang II. The cardiac pro-inflammatory gene expression of tumor necrosis factor alpha ( Tnfa ), NADPH oxidase 4 ( Nox4 ), and matrix metalloproteinase 9 ( Mmp9 ) was increased in WT heart but attenuated in both TLR4-del and TLR3ko hearts. The results indicate a selective dependence of Ang II hypertension on TLR3/TRIF pathway whereas Ang II-induced cardiac hypertrophy depends on both TLR3 and TLR4, likely through the common TRIF adaptor protein.

The leucine rich repeat containing protein 8A (LRRC8A), or SWELL1, is an essential component of the volume-regulated anion channel (VRAC) that is activated by cell swelling and ionic strength. We report here for the first time to our knowledge its expression in a primary cell culture of nodose ganglia neurons and its localization in the soma, neurites, and neuronal membrane. We show that this neuronal VRAC/SWELL1 senses low external pH (pHo) in addition to hypoosmolarity. A robust sustained chloride current is seen in 77% of isolated nodose neurons following brief exposures to extracellular acid pH. Its activation involves proton efflux, intracellular alkalinity, and an increase in NOX-derived H2O2. The molecular identity of both the hypoosmolarity-induced and acid pHo-conditioned VRAC as LRRC8A (SWELL1) was confirmed by Cre-flox-mediated KO, shRNA-mediated knockdown, and CRISPR/Cas9-mediated LRRC8A deletion in HEK cells and in primary nodose neuronal cultures. Activation of VRAC by low pHo reduces neuronal injury during simulated ischemia and N-methyl-D-aspartate-induced (NMDA-induced) apoptosis. These results identify the VRAC (LRRC8A) as a dual sensor of hypoosmolarity and low pHo in vagal afferent neurons and define the mechanisms of its activation and its neuroprotective potential.

Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-δ), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F). Previously, we have reported that Sgcd-deficient (Sgcd−/−) mice exhibit AngII (angiotensin II)-induced autonomic and skeletal muscle dysfunction at a young age, which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory RAS (renin–angiotensin system) pathways have been identified: deleterious actions of AngII acting on the AT1R (AngII type 1 receptor) compared with the protective actions of Ang-(1–7) [angiotensin-(1–7)] acting on the receptor Mas. We propose that the balance between the AngII/AT1R and Ang-(1–7)/Mas axes is disturbed in Sgcd−/− mice. Control C57BL/6J and Sgcd−/− mice were treated with Ang-(1–7) included in hydroxypropyl β-cyclodextrin (in drinking water) for 8–9 weeks beginning at 3 weeks of age. Ang-(1–7) treatment restored the AngII/AT1R compared with Ang-(1–7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd−/− mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang-(1–7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy.

While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.

Carotid body glomus cells are the primary sites of chemotransduction of hypoxaemia and acidosis in peripheral arterial chemoreceptors. They exhibit pronounced morphological heterogeneity. A quantitative assessment of their functional capacity to differentiate between these two major chemical signals has remained undefined. We tested the hypothesis that there is a differential sensory transduction of hypoxia and acidosis at the level of glomus cells. We measured cytoplasmic Ca2+ concentration in individual glomus cells, isolated in clusters from rat carotid bodies, in response to hypoxia ( mmHg) and to acidosis at pH 6.8. More than two-thirds (68%) were sensitive to both hypoxia and acidosis, 19% were exclusively sensitive to hypoxia and 13% exclusively sensitive to acidosis. Those sensitive to both revealed significant preferential sensitivity to either hypoxia or to acidosis. This uncoupling and reciprocity was recapitulated in a mouse model by altering the expression of the acid-sensing ion channel 3 (ASIC3) which we had identified earlier in glomus cells. Increased expression of ASIC3 in transgenic mice increased pH sensitivity while reducing cyanide sensitivity. Conversely, deletion of ASIC3 in the knockout mouse reduced pH sensitivity while the relative sensitivity to cyanide or to hypoxia was increased. In this work, we quantify functional differences among glomus cells and show reciprocal sensitivity to acidosis and hypoxia in most glomus cells. We speculate that this selective chemotransduction of glomus cells by either stimulus may result in the activation of different afferents that are preferentially more sensitive to either hypoxia or acidosis, and thus may evoke different and more specific autonomic adjustments to either stimulus.

Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated.We tested the hypothesis that enhanced TWe measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs.SHRs exhibited an abnormally large population of CD161SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

The autonomic and the immune systems play major roles in the pathogenesis of cardiovascular disease and hypertension. To date, those 2 systems have been studied extensively but independently by cardiovascular biologists and by immunologists. The notion that the autonomic system can modulate the immune system and thereby influence the pathogenesis of cardiovascular disease and hypertension and their clinical outcome is novel and critical. In this brief review we focus on that interaction and an integrated understanding of the neuro-immune axis. We also highlight recent progress and future research directions. The main theme is that dysregulation of the autonomic system enhances the inflammatory response of the innate and adaptive immune systems leading to the initiation or acceleration of pathological processes and worsening of cardiovascular risks. The therapeutic potential of restoring an optimal autonomic control of the immune system is very promising. Both components of the neuro-immune axis may be involved in its disruption. One is the autonomic nervous system, which may be dysregulated or imbalanced with increased sympathetic and decreased parasympathetic activation. The other is the immune system itself, which may be abnormally sensitive to the modulatory influence of the autonomic system. These 2 components are briefly described below. #### Autonomic Dysregulation in Chronic Hypertension The complexity of cardiovascular mechanisms that contribute to hypertension has been challenging. The roles of vascular and renal abnormalities are undeniable. Changes in vasomotor tone, sodium retention, and renal renin release are all well established. For decades the contribution of the sympathetic nervous system to chronic hypertension was not fully appreciated. Its importance is now well recognized.1–5 In a 1982 review, we described the neural sites and mechanisms involved in exaggerated sympathetic nerve activity (SNA) in several animal models, as well as in human hypertension.1 Moreover, there has been a surge of data highlighting the damaging cardiovascular effects …

Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for G(q/11)α and G(i/o)α subunits. RGS2 deficiency is linked to hypertension in mice and humans, although causative mechanisms are not understood. Because endothelial dysfunction and increased peripheral resistance are hallmarks of hypertension, determining whether RGS2 regulates microvascular reactivity may reveal mechanisms relevant to cardiovascular disease. Here we have determined the effects of systemic versus endothelium- or vascular smooth muscle-specific deletion of RGS2 on microvascular contraction and relaxation. Contraction and relaxation of mesenteric resistance arteries were analyzed in response to phenylephrine, sodium nitroprusside, or acetylcholine with or without inhibitors of nitric oxide (NO) synthase or K(+) channels that mediate endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation. The results showed that deleting RGS2 in vascular smooth muscle had minor effects. Systemic or endothelium-specific deletion of RGS2 strikingly inhibited acetylcholine-evoked relaxation. Endothelium-specific deletion of RGS2 had little effect on NO-dependent relaxation but markedly impaired EDHF-dependent relaxation. Acute, inducible deletion of RGS2 in endothelium did not affect blood pressure significantly. Impaired EDHF-mediated vasodilatation was rescued by blocking G(i/o)α activation with pertussis toxin. These findings indicated that systemic or endothelium-specific RGS2 deficiency causes endothelial dysfunction resulting in impaired EDHF-dependent vasodilatation. RGS2 deficiency enables endothelial G(i/o) activity to inhibit EDHF-dependent relaxation, whereas RGS2 sufficiency facilitates EDHF-evoked relaxation by squelching endothelial G(i/o) activity. Mutation or down-regulation of RGS2 in hypertension patients therefore may contribute to endothelial dysfunction and defective EDHF-dependent relaxation. Blunting G(i/o) signaling might improve endothelial function in such patients.

We have reported that angiotensin II (Ang II) induces toll-like receptors (TLRs) in the innate immune system. Here we tested which of the two major adaptor proteins of TLRs, the myeloid differentiation protein 88 (MyD88) or the TIR-domain containing adaptor inducing interferon β (TRIF) mediates the Ang II-induced responses. Infusion of Ang II (3000 ng/kg/min) subcutaneously for 3 weeks in WT mice (C57BL/6J) increased systolic blood pressure to a peak value of 147 ± 4 mm Hg and resulted in a 40% increase in heart weight to body weight ratio (HW/BW). Surprisingly, in MyD88-/- mice the pressor response was enhanced significantly to 163 ± 6 mm Hg (P

Objective— Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice. Approach and Results— Control, hypertensive, hypercholesterolemic ( Apoe −/− ), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice. Conclusions— Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.

The methods used to assess cardiac parasympathetic (cardiovagal) activity and its effects on the heart in both humans and animal models are reviewed. Heart rate (HR)-based methods include measurements of the HR response to blockade of muscarinic cholinergic receptors (parasympathetic tone), beat-to-beat HR variability (HRV) (parasympathetic modulation), rate of post-exercise HR recovery (parasympathetic reactivation), and reflex-mediated changes in HR evoked by activation or inhibition of sensory (afferent) nerves. Sources of excitatory afferent input that increase cardiovagal activity and decrease HR include baroreceptors, chemoreceptors, trigeminal receptors, and subsets of cardiopulmonary receptors with vagal afferents. Sources of inhibitory afferent input include pulmonary stretch receptors with vagal afferents and subsets of visceral and somatic receptors with spinal afferents. The different methods used to assess cardiovagal control of the heart engage different mechanisms, and therefore provide unique and complementary insights into underlying physiology and pathophysiology. In addition, techniques for direct recording of cardiovagal nerve activity in animals; the use of decerebrate and in vitro preparations that avoid confounding effects of anesthesia; cardiovagal control of cardiac conduction, contractility, and refractoriness; and noncholinergic mechanisms are described. Advantages and limitations of the various methods are addressed, and future directions are proposed.

SummaryArterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of circulation. Our goal was to test the hypothesis that a member of the acid-sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggest that mechanosensitivity is diminished in ASIC2 null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and defines a molecular defect that may be relevant to its development.

The baroreflex control of heart rate (HR) is reduced following chronic intermittent hypoxia (CIH). Since the nucleus ambiguus (NA) plays a key role in baroreflex control of HR, we examined whether CIH remodels vagal efferent projections to cardiac ganglia. C57BL/6J mice (3-4 months of age) were exposed to either room air (RA) or CIH for 3 months. Confocal microscopy was used to examine NA axons and terminals in cardiac ganglia following Fluoro-Gold (FG) injections to label cardiac ganglia, and microinjections of tracer DiI into the left NA to anterogradely label vagal efferents. We found that: 1) Cardiac ganglia were widely distributed on the dorsal surface of the atria. Although the total number of cardiac ganglia did not differ between RA and CIH mice, the size of ganglia and the somatic area of cardiac principal neurons (PNs) were significantly decreased (P0.01), and the size of the PN nuclei was increased following CIH (P0.01). 2) NA axons entered cardiac ganglia and innervated PNs with dense basket endings in both RA and CIH mice, and the percentage of innervated PNs was similar (RA: 50 +/- 1.0%; CIH: 49 +/- 1.0%; P0.10). In CIH mice, however, swollen cardiac axons and terminals without close contacts to PNs were found. Furthermore, varicose endings around PNs appeared swollen and the axonal varicose area around PNs was almost doubled in size (CIH: 163.1 +/- 6.4 microm(2); RA: 88 +/- 3.9 microm(2), P0.01). Thus, CIH significantly altered the structure of cardiac ganglia and resulted in reorganized vagal efferent projections to cardiac ganglia. Such remodeling of cardiac ganglia and vagal efferent projections provides new insight into the effects of CIH on the brain-heart circuitry of C57BL/6J mice.

Baroreflex control of heart rate (HR) is impaired after chronic intermittent hypoxia (CIH). However, the location and nature of this response remain unclear. We examined baroreceptor afferent, vagal efferent, and central components of the baroreflex circuitry. Fischer 344 (F344) rats were exposed to room air (RA) or CIH for 35–50 days and were then anesthetized with isoflurane, ventilated, and catheterized for measurement of mean arterial blood pressure (MAP) and HR. Baroreceptor function was characterized by measuring percent changes of integrated aortic depressor nerve (ADN) activity (Int ADNA) relative to the baseline value in response to sodium nitroprusside- and phenylephrine-induced changes in MAP. Data were fitted to a sigmoid logistic function curve. HR responses to electrical stimulation of the left ADN and the right vagus nerve were assessed under ketamine-acepromazine anesthesia. Compared with RA controls, CIH significantly increased maximum baroreceptor gain or maximum slope, maximum Int ADNA, and Int ADNA range (maximum − minimum Int ADNA), whereas other parameters of the logistic function were unchanged. In addition, CIH increased the maximum amplitude of bradycardic response to vagal efferent stimulation and decreased the time from stimulus onset to peak response. In contrast, CIH significantly reduced the maximum amplitude of bradycardic response to left ADN stimulation and increased the time from stimulus onset to peak response. Therefore, CIH decreased central mediation of the baroreflex but augmented baroreceptor afferent function and vagal efferent control of HR.

Chronic intermittent hypoxia (CIH) leads to increased sympathetic nerve activity and arterial hypertension. In this study, we tested the hypothesis that CIH impairs baroreflex (BR) control of heart rate (HR) in mice, and that decreased cardiac chronotropic responsiveness to vagal efferent activity contributes to such impairment. C57BL/6J mice were exposed to either room air (RA) or CIH (6-min alternations of 21% O2and 5.7% O2, 12 h/day) for 90 days. After the treatment period, mice were anesthetized (Avertin) and arterial blood pressure (ABP) was measured from the femoral artery. Mean ABP (MABP) was significantly increased in mice exposed to CIH (98.7 ± 2.5 vs. RA: 78.9 ± 1.4 mmHg, P < 0.001). CIH increased HR significantly (584.7 ± 8.9 beats/min; RA: 518.2 ± 17.9 beats/min, P < 0.05). Sustained infusion of phenylephrine (PE) at different doses (0.1–0.4 μg/min) significantly increased MABP in both CIH and RA mice, but the ABP-mediated decreases in HR were significantly attenuated in mice exposed to CIH ( P < 0.001). In contrast, decreases in HR in response to electrical stimulation of the left vagus nerve (30 μA, 2-ms pulses) were significantly enhanced in mice exposed to CIH compared with RA mice at low frequencies. We conclude that CIH elicits a sustained impairment of baroreflex control of HR in mice. The blunted BR-mediated bradycardia occurs despite enhanced cardiac chronotropic responsiveness to vagal efferent stimulation. This suggests that an afferent and/or a central defect is responsible for the baroreflex impairment following CIH.