Carotid baroreceptor stimulation prevents oxidative stress by inhibiting MAO-A and prevents cardiac remodeling in obese rats.

OBJECTIVE: Sympathetic nervous system overactivation and abnormal lipid metabolism are featured in obesity and may lead to cardiac remodeling. The effects of carotid baroreceptor stimulation (CBS) on cardiac remodeling in obese rats and the underlying mechanisms were explored. METHODS: An obesity model was induced by 16-week high-fat diet feeding. A CBS device was implanted at the 8th week. Body weight and blood pressure measurements, electrocardiography, echocardiography, and glucose and insulin tolerance tests were conducted before sampling. Plasma analysis and histological and biological analyses of left ventricle were also performed. Neonatal rat cardiomyocytes cocultured with 3T3-L1 in transwell chambers were used to investigate the mechanisms. RESULTS: CBS alleviated several manifestations of obesity, including increased body weight, high blood pressure, hyperlipidemia, and enhanced sympathetic activity. In obese hearts, norepinephrine levels decreased, and the monoamine oxidase A (MAO-A) and reactive oxygen species level increased; these changes, as well as cardiac fibrosis, lipid metabolic disorders, and heart dysfunction, were inhibited by CBS. Neonatal rat cardiomyocytes incubated with norepinephrine showed MAO-A upregulation, increased reactive oxygen species levels, lipid metabolic disorders, and inflammatory response, which were inhibited by clorgyline, a selective MAO-A inhibitor. CONCLUSIONS: CBS effectively suppresses sympathetic nervous system activity and oxidative stress mediated by MAO-A and prevents cardiac remodeling in obese rats.

Changes in fetal baroreceptor sensitivity during intrauterine inflammation in preterm fetal sheep.

OBJECTIVE: Baroreflex is a regulatory mechanism that slows the fetal heart rate. This study aimed to investigate the effects of lipopolysaccharide (LPS)-induced endotoxemia on fetal baroreceptor sensitivity in preterm fetal sheep. METHODS: The changes in fetal baroreceptor sensitivity were measured in seven chronically instrumented preterm fetal sheep. Fetal baroreceptor sensitivity was measured in three phases: (A) control phase, defined as the 24 h before the first injection of LPS; (B) acute phase, defined as the 24 h between the first and second injections of LPS; and (C) fetal acidosis phase, defined as the time from the second LPS injection until intrauterine fetal death. Histological examinations of the fetal membrane and umbilical cord were also conducted. RESULTS: Each fetus developed metabolic acidosis after the second injection of LPS. The fetuses died 24.7 (SD = 6.1) hours after the second injection of LPS. Both the umbilical cord and fetal membranes showed histological evidence of severe inflammation. In total, 163 fetal baroreceptor measurements were performed in this experiment (A, n = 77 times; B, n = 60 times; C, n = 26 times). Fetal baroreceptor sensitivity showed significant differences in all three phases (A: 2.7 [SD = 0.2]; B: 2.5 [SD = 0.2]; and C: 1.5 [SD = 0.2]). Post hoc tests showed that baroreceptor sensitivity in the acidosis phase had decreased significantly compared to that in the control and acute phases (p<.001 and p=.002, respectively). CONCLUSIONS: Fetal baroreceptor sensitivity decreased during fetal acidosis induced by LPSs.

Afferent Baroreflex Dysfunction: Decreased or Excessive Signaling Results in Distinct Phenotypes.

Head and neck tumors can affect afferent baroreceptor neurons and either interrupt or intermittently increase their signaling, causing blood pressure to become erratic. When the afferent fibers of the baroreflex are injured by surgery or radiotherapy or fail to develop as in familial dysautonomia, their sensory information is no longer present to regulate arterial blood pressure, resulting in afferent baroreflex failure. When the baroreflex afferents are abnormally activated, such as by paragangliomas in the neck, presumably by direct compression, they trigger acute hypotension and bradycardia and frequently syncope, by a mechanism similar to the carotid sinus syndrome. We describe our observations in a large series of 23 patients with afferent baroreflex dysfunction and the cardiovascular autonomic features that arise when the sensory baroreceptor neurons are injured or compressed. The management of afferent baroreceptor dysfunction is limited, but pharmacological strategies can mitigate blood pressure swings, improve symptoms, and may reduce hypertensive organ damage. Although rare, the prevalence of afferent baroreflex dysfunction appears to be increasing in middle-aged men due to human papillomavirus related oropharyngeal cancer.

Predominant role of neural arc in sympathetic baroreflex resetting of spontaneously hypertensive rats.

BACKGROUND: There is ongoing controversy over whether neural or peripheral factors are the predominant cause of hypertension. The closed-loop negative feedback operation of the arterial baroreflex hampers understanding of how arterial pressure (AP) is determined through the interaction between neural and peripheral factors. METHODS AND RESULTS: A novel analysis of an isolated open-loop baroreceptor preparation to examine sympathetic nervous activity (SNA) and AP responses to changes in carotid sinus pressure (CSP) in adult spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) was conducted. In the neural arc (CSP-SNA relationship), the midpoint pressure (128.9±3.8 vs. 157.9±8.1 mmHg, P<0.001) and the response range of SNA to CSP (90.5±3.7 vs. 115.4±7.6%/mmHg, P=0.011) were higher in SHR. In the peripheral arc (SNA-AP relationship), slope and intercept did not differ. A baroreflex equilibrium diagram was obtained by depicting neural and peripheral arcs in a pressure-SNA plane with rescaled SNA (% in WKY). The operating-point AP (111.3±4.4 vs. 145.9±5.2 mmHg, P<0.001) and SNA (90.8±3.2 vs. 125.1±6.9% in WKY, P<0.001) were shifted towards a higher level in SHR. CONCLUSIONS: The shift of the neural arc towards a higher SNA range indicated a predominant contribution to baroreflex resetting in SHR. Notwithstanding the resetting, the carotid sinus baroreflex in SHR preserved an ability to reduce AP if activated with a high enough pressure.

[Permanent cardiac pacing in vasovagal syncope and carotid sinus syndrome].

Vasovagal syncope and carotid sinus syndrome are common conditions in young and elderly people, respectively, mostly with benign prognosis. Nevertheless, severe or "malignant" syncopal attacks in some patients may be associated with life-threatening injury. Unfortunately, up to now almost all drug trials have failed to demonstrate any benefit in preventing syncope and interventional approach (pacemaker) may be appropriate. This article contains literature review and discussion of indications for pacing in vasovagal syncope and carotid sinus syndrome.

Coupling between respiratory and sympathetic activities as a novel mechanism underpinning neurogenic hypertension.

Enhanced sympathetic outflow to the heart and resistance vessels greatly contributes to the onset and maintenance of neurogenic hypertension. There is a consensus that the development of hypertension (clinical and experimental) is associated with an impairment of sympathetic reflex control by arterial baroreceptors. More recently, chronic peripheral chemoreflex activation, as observed in obstructive sleep apnea, has been proposed as another important risk factor for hypertension. In this review, we present and discuss recent experimental evidence showing that changes in the respiratory pattern, elicited by chronic intermittent hypoxia, play a key role in increasing sympathetic activity and arterial pressure in rats. This concept parallels results observed in other models of neurogenic hypertension, such as spontaneously hypertensive rats and rats with angiotensin II-salt-induced hypertension, pointing out alterations in the central coupling of respiratory and sympathetic activities as a novel mechanism underlying the development of neurogenic hypertension.

Methods for exploring the morpho-functional relations of the aortic depressor nerve in experimental diabetes.

The present study investigated morpho-functional relations of the aortic depressor nerve (ADN) 5, 15 and 120 days after the onset of streptozotocin-induced diabetes in rats. Time control animals received vehicle. Under pentobarbital anesthesia, ADN activity was recorded simultaneously with arterial pressure. After the recordings, nerves were prepared for light microscopy study and morphometry. ADN function was accessed by means of pressure-nerve activity curve (fitted by sigmoidal regression) and cross-spectral analysis between mean arterial pressure (MAP) and ADN activity. The relation between morphological (myelinated fibers number and density, total myelin area, total fiber area and percentage of occupancy) and functional (gain, signal/noise relation, frequency) parameters were accessed by linear regression analysis and correlation coefficient calculations. Functional parameters obtained by means of the sigmoidal regression curve as well as by cross-spectral analysis were similar in diabetic and control rats. Morphometric parameters of the ADN were similar between groups 5 days after the onset of diabetes. Average myelin area and myelinated fiber area were significantly smaller on diabetic rats 15 and 120 days after the onset of diabetes, being the myelinated fiber and respective axons area and diameter also smaller on 120 days group. Nevertheless, G ratio (ratio between axon and fiber diameter) was nearly 0.6 and not different between groups or experimental times. No significant relationship between morphological and functional parameters was detected in all experimental groups. The present study suggests that ADN diabetic neuropathy was time-dependent, with damage to myelinated fibers to be the primary event, not evidenced by physiological methods.

Protective effect of the daming capsule on impaired baroreflexes in STZ-induced diabetic rats with hyperlipoidemia.

BACKGROUND: The Daming capsule (DMC) is a traditional Chinese medicine used to treat hyperlipoidemia. Both clinic trials and studies on animal models have demonstrated that DMC is beneficial against diabetic symptoms. Impairment of the baroreflex can cause life-threatening arrhythmias and sudden cardiac death in patients with diabetes mellitus (DM). This study was designed to elucidate the effects of DMC on baroreflexes in streptozocin (STZ)-induced diabetic rats with hyperlipoidemia. METHODS: Wistar rats were randomly divided into three groups: untreated controls, rats pretreated STZ and high lipids (a diabetes model or DM rats), and DM rats treated with DMC. The baroreflex sensitivity was examined during intravenous injection of phenylephrine (PE) or sodium nitroprusside (SNP) and quantified by the change in heart rate over the change in mean arterial blood pressure (ΔHR/ΔMABP). Morphological remodeling of baroreceptors was analyzed by transmission electron microscopy (TEM). The mRNA levels and expression of GluR2 and a GABAA receptor subunit were measured by quantitative RT-PCR and Western blotting. RESULTS: Compared to untreated DM rats, DMC significantly elevated the ratio of ΔHR/ΔMABP by enhancing the compensatory reduction in HR (-ΔHR) in response to PE-induced hypertension (+ΔMABP) (P < 0.05). In the presence of SNP, DMC increased the ΔMABP (P < 0.05). In addition, DMC markedly shortened the duration of blood pressure changes elicited by PE or SNP in DM rats compared to the untreated DM group (P < 0.05). Electron microscopy revealed disrupted myelin sheaths, swollen ER, and lysed mitochondria in the nucleus ambiguous (NAm) DM rats. These signs of neuropathology were largely prevented by treatment with DMC for 30 days. Treatment with DMC elevated both mRNA and protein level of GluR2 in the NAm of DM rats, but had no effect on GABAA receptor expression. CONCLUSION: The Daming capsule partially reversed the parasympathetic baroreflex impairment observed in STZ-induced diabetic rats with hyperlipoidemia. Treatment with DMC also prevented the degeneration of neurons and myelinated axons in the brain stem NAm and reversed the down-regulation of GluR2 mRNA. Rescue of NAm function may contribute to the medicinal properties of DMC in diabetic rats.

[Receptor system of brain vessels in arterial hypertension].

We conducted a post-mortem study of the receptor system of brain vessels in patients with arterial hypertension (AG), stages I-III, and healthy people using impregnation and a method of measuring NADPH-diaphorase. The receptor system of arterial wall is represented by treelike and glomerular structures with moderate enzyme activity. Reactive and destructive disturbances of the receptor system that were distinctly seen on histochemical preparations were found in brain arteries of AG patients. The intensity of changes in the nervous apparatus of brain vessels was closely related to the artery caliber, their localization, disease duration and severity, with the most early and deep changes in the afferent fibers and receptors of the pia mater arteries. In intracerebral arteries, reactive changes in receptor structures were found in long-term hypertension and destructive changes were found in AG, stages II-III.

Baroreceptor sensitivity and baroreceptor effectiveness index in cirrhosis: the relevance of hepatic venous pressure gradient.

BACKGROUND: Autonomic dysfunction has been reported as one of the complications of cirrhosis. AIMS: The aim of this study was to test autonomic dysfunction in cirrhotic patients by analysing the baroreflex sensitivity and the baroreceptor effectiveness index (BEI), in order to determine its correlation with the severity and the aetiology of liver disease. Moreover, we explored the relationship between baroreceptor function and mortality in our cohort of patients. METHODS: Clinical and laboratory evaluation, hepatic venous pressure gradient (HVPG) and haemodynamic setting and baroreceptor function were assessed in 45 cirrhotic patients (median age 55, range 38-72 years) divided in groups according to the severity of their disease (26 patients Child A, 13 patients Child B and six patients Child C). RESULTS: Baroreceptor sensitivity and BEI were impaired in more advanced cirrhotic patients compared with subjects with milder disease (P<0.001). HVPG was significantly, independently and inversely correlated with baroreceptor sensitivity (P=0.003). More severe impairment of baroreceptor function was associated with a higher mortality (P=0.04) and subjects with alcohol-related cirrhosis presented worse baroreceptor function (P=0.032) and poorer survival (P=0.003) compared with subjects with post-viral liver disease. CONCLUSIONS: These data support the hypothesis that liver disease severity and particularly portal hypertension have an important role in the derangement of baroreceptor function. The aetiology of cirrhosis seems to be related to baroreceptor impairment as well. Mortality rate is higher in subjects with a more damaged autonomic system, strengthening the idea of a worse prognosis in cirrhotic patients with autonomic neuropathy.

Carotid barochemoreceptor pathological findings regarding carotid plaque status and aging.

BACKGROUND: Carotid barochemoreceptor pathological lesions have been studied in animals, but few human necropsies have been performed. Therefore, data rely on case patients following surgery, radiotherapy and carotid endarterectomy. Almost no data are available regarding whether the effect of aging prevails over pathological conditions, despite the classic description that glomic fibrosis increases with age. OBJECTIVE: To morphometrically characterize the alterations of the carotid barochemoreceptors and their supplying arteries. METHODS: Patients (n=23) who had suffered and died from stroke, with and without complicated internal carotid atheromatosis, were divided by age (group 1: older than 80 years; group 2: 65 to 80 years; and group 3: younger than 65 years). Carotid segments were obtained at autopsy. The specimens were stained for light microscopy and immunohistochemistry. RESULTS: Carotid glomus presented from moderate-to-severe atrophy and fibrosis. A focal decrease in vascularization (CD34-positive) of the glomus (greater than 50%) was observed in areas of atrophy and fibrosis. Damaged nerve endings (S100 protein-positive) were observed at the media of the carotid sinus. Morphometric data showed no differences between groups for glomus area, number of type 1 and 2 cells, and the wall to lumen arteriole ratio. No statistical differences were demonstrated in the pathological findings of the carotid glomus when comparing complicated with noncomplicated plaques or age groups. CONCLUSION: Severe carotid chemoreceptor damage exists in patients who have died from stroke and suffered from carotid atheromatosis. These findings were independent from aging and plaque type. However, damage was correlated with a marked narrowing of the supplying arterioles as a consequence of hemodynamic and/or metabolic alterations (dyslipidemia, diabetes).

The role of neuron numbers of the petrosal ganglion in the determination of blood pressure: an experimental study.

BACKGROUND: Baroreceptor reflexes are regulated by nerve terminals of the glossopharyngeal and vagal nerves. The body of pressure-sensitive neurons of these nerves is located in the petrosal ganglion of both nerves. We examined whether there is a relationship between the neuron numbers of the inferior ganglion of the glossopharyngeal nerve and blood pressure values. METHODS: Petrosal ganglions were examined in 18 male hybrid rabbits divided into three equal groups: Group A normotensive (TA=90-100 mmHg), Group B hypertensive (TA>100 mmHg); and Group C hypotensive (TA<90 mmHg). After examination of blood pressure for one week, all animals were sacrificed, and the petrosal ganglions extracted bilaterally and examined histopathologically using the physical dissector method. RESULTS: The mean (+/-SD) neuronal density was: Group A 8700+/-200, Group B 7800+/-250 and Group C 9800+/-300, respectively. The difference between the groups B and C as compared to A was significant (p<0.01) while the difference between Groups B and C was highly significant (p<0.001). CONCLUSIONS: An inverse relationship was noticed between the neuronal density in the petrosal ganglion and blood pressure values with potential implications in the study of the etiology of hypertension.

Reduced baroreceptor sensitivity and elasticity of the carotid artery in a preeclamptic patient.

Baroreflex sensitivity, distensibility coefficient, and intima-media thickness (IMT) of the common carotid artery were determined in a preeclamptic patient during 1st and 3rd trimesters as well as after childbirth. From the beginning of her pregnancy, baroreflex sensitivity and distensibility coefficient of the carotid artery exhibited a parallel decline, whereas the IMT increased as compared with normotensive pregnancies. The values of all parameters examined returned to their initial levels after 14 weeks of delivery. These results suggest that augmented IMT and carotid stiffness coupled to baroreceptor dysfunction may have contributed to the perturbation of blood pressure control in our preeclamptic patient.

The role of the sympathetic nervous system in congestive heart failure.

Congestive heart failure is usually accompanied by cardiovascular signs of an increased sympathetic and a decreased parasympathetic efferent activity. A current hypothesis for these autonomic changes holds the baroreceptor mechanisms mainly responsible for this complex neural reflex pattern together with a decreased responsiveness of cardiac vagal afferent ffibers. An alternative hypothesis is proposed here. Afferent sympathetic fibers with sensory endings in the atria and in the pulmonary veins are progressively excited by volume load. In cats with a chronic spinal section at C8, breathing spontaneously, an infusion of saline induces a reflex tachycardia through a sympatho-sympathetic neural circuit. In chronic dogs with intact cardiovascular innervation, the stimulation of aortic or cardiac sympathetic afferent fibers elicits an excitatory sympathetic reflex leading to hypertension and tachycardia; in addition, the sensitivity of baroreflexes is markedly reduced. Therefore, in congestive heart failure, especially in the absence of hypotension, the reflex excitation of the sympathetic outflow and the inhibition of the vagal efferent activity directed to the heart could be due to reflex mechanisms mediated by sympathetic cardiovascular afferents.

Chronic localized hypotension and resetting of carotid sinus baroreceptors. Electrophysiological and histological studies in the dog.

Resetting of carotid sinus (CS) baroreceptors to chronically elevated systemic pressure in hypertension has been demonstrated. The effects of chronic system hypotension on CS baroreceptor afferents has not been elucidated, however. The purpose of the present study was to determine the electrophysiological and histological characteristics of CS baroreceptors exposed to chronic hypotension. Chronic unilateral hypotension was produced by anastomosis of the common carotid artery to the external jugular vein. CS nerve activity and histology of the normotensive sinus (mean CS pressure +/- SD = 96 +/- 10.9 torr) were compared to those of the hypotensive sinus (mean CF pressure 50 +/- 14.2 torr) 44-49 days after anastomosis in nine mongrel dogs. An isolated CS pouch preparation was used to produce standard pressure changes. Threshold pressure for hypotensive sinuses (15.5 +/- 5.19 torr) was significantly less (P less than 0.05) than for normotensive sinuses (40.6 +/- 9.73 torr). Saturation pressure was also significantly less in the hypotensive sinus (P less than 0.05). There were no significant differences between slopes of the stimulus-response curve or in architecture of intima or media of the two sides. Thus, the stimulus-response curve was shifted to the left in chronic CS hypotension, and this effect could not be related to a change in CS light microscopic histology.