Neuronal counting and parasympathetic dysfunction in the hearts of chronically Trypanosoma cruzi - infected rats

Ten male Wistar rats, chronically infected with Colombian, São Felipe (12SF) and Y strains of Trypanosoma cruzi and ten non-infected control animals were submitted to the bradycardia responsiveness test, an assessment of heart parasympathetic function, after phenylephrine injection. Six chagasic animals showed heart parasympathetic dysfuntion characterized by reduction in the index of bradycardia baroreflex responsiveness, as compared with the control group. Microscopic examination of the atrial heart ganglia of chagasic rats showed ganglionitis, but no statiscally significant reduction in the number of neurons.

Cardiorespiratory and Cardiac Autonomic Responses to 30-15 Intermittent Fitness Test in Team Sport Players

Buchheit, M, Al Haddad, H, Millet GP, Lepretre, PM, Newton, M, and Ahmaidi, S. Cardiorespiratory and cardiac autonomic responses to 30-15 Intermittent Fitness Test in team sport players. J Strength Cond Res 23(1): xxx-xxx, 2009-The 30-15 Intermittent Fitness Test (30-15IFT) is an attractive alternative to classic continuous incremental field tests for defining a reference velocity for interval training prescription in team sport athletes. The aim of the present study was to compare cardiorespiratory and autonomic responses to 30-15IFT with those observed during a standard continuous test (CT). In 20 team sport players (20.9 +/- 2.2 years), cardiopulmonary parameters were measured during exercise and for 10 minutes after both tests. Final running velocity, peak lactate ([La]peak), and rating of perceived exertion (RPE) were also measured. Parasympathetic function was assessed during the postexercise recovery phase via heart rate (HR) recovery time constant (HRRtau) and HR variability (HRV) vagal-related indices. At exhaustion, no difference was observed in peak oxygen uptake (&OV0312;o2peak), respiratory exchange ratio, HR, or RPE between 30-15IFT and CT. In contrast, 30-15IFT led to significantly higher minute ventilation, [La]peak, and final velocity than CT (p < 0.05 for all parameters). All maximal cardiorespiratory variables observed during both tests were moderately to well correlated (e.g., r = 0.76, p = 0.001 for &OV0312;o2peak). Regarding ventilatory thresholds (VThs), all cardiorespiratory measurements were similar and well correlated between the 2 tests. Parasympathetic function was lower after 30-15IFT than after CT, as indicated by significantly longer HHRtau (81.9 +/- 18.2 vs. 60.5 +/- 19.5 for 30-15IFT and CT, respectively, p < 0.001) and lower HRV vagal-related indices (i.e., the root mean square of successive R-R intervals differences [rMSSD]: 4.1 +/- 2.4 and 7.0 +/- 4.9 milliseconds, p < 0.05). In conclusion, the 30-15IFT is accurate for assessing VThs and &OV0312;o2peak, but it alters postexercise parasympathetic function more than a continuous incremental protocol.

Autonomic prediction of error-related ERP components in perceptual and conceptual tasks in older and younger adults

In studies of cognitive processing, the allocation of attention has been consistently linked to subtle, phasic adjustments in autonomic control. Both autonomic control of heart rate and control of the allocation of attention are known to decline with age. It is not known, however, whether characteristic individual differences in autonomic control and the ability to control attention are closely linked. To test this, a measure of parasympathetic function, vagal tone (VT) was computed from cardiac recordings from older and younger adults taken before and during performance of two attentiondemanding tasks - the Eriksen visual flanker task and the source memory task. Both tasks elicited event-related potentials (ERPs) that accompany errors, i.e., error-related negativities (ERNs) and error positivities (Pe's). The ERN is a negative deflection in the ERP signal, time-locked to responses made on incorrect trials, likely generated in the anterior cingulate. It is followed immediately by the Pe, a broad, positive deflection which may reflect conscious awareness of having committed an error. Age-attenuation ofERN amplitude has previously been found in paradigms with simple stimulus-response mappings, such as the flanker task, but has rarely been examined in more complex, conceptual tasks. Until now, there have been no reports of its being investigated in a source monitoring task. Age-attenuation of the ERN component was observed in both tasks. Results also indicated that the ERNs generated in these two tasks were generally comparable for young adults. For older adults, however, the ERN from the source monitoring task was not only shallower, but incorporated more frontal processing, apparently reflecting task demands. The error positivities elicited by 3 the two tasks were not comparable, however, and age-attenuation of the Pe was seen only in the more perceptual flanker task. For younger adults, it was Pe scalp topography that seemed to reflect task demands, being maximal over central parietal areas in the flanker task, but over very frontal areas in the source monitoring task. With respect to vagal tone, in the flanker task, neither the number of errors nor ERP amplitudes were predicted by baseline or on-task vagal tone measures. However, in the more difficult source memory task, lower VT was marginally associated with greater numbers of source memory errors in the older group. Thus, for older adults, relatively low levels of parasympathetic control over cardiac response coincided with poorer source memory discrimination. In both groups, lower levels of baseline VT were associated with larger amplitude ERNs, and smaller amplitude Pe's. Thus, low VT was associated in a conceptual task with a greater "emergency response" to errors, and at the same time, reduced awareness of having made them. The efficiency of an individual's complex cognitive processing was therefore associated with the flexibility of parasympathetic control of heart rate, in response to a cognitively challenging task.

NMDA receptors in the lateral hypothalamus have an inhibitory influence on the tachycardiac response to acute restraint stress in rats

The aim of the present study was to investigate the role of the lateral hypothalamus (LH) and its local glutamatergic neurotransmission in the cardiovascular adjustments observed when rats are submitted to acute restraint stress. Bilateral microinjection of the nonspecific synaptic inhibitor CoCl2 (0.1 nmol in 100 nL) into the LH enhanced the heart rate (HR) increase evoked by restraint stress without affecting the blood pressure increase. Local microinjection of the selective N-methyl-d-aspartate (NMDA) glutamate receptor antagonist LY235959 (2 nmol in 100 nL) into the LH caused effects that were similar to those of CoCl2. No changes were observed in the restraint-related cardiovascular response after a local microinjection of the selective non-NMDA glutamatergic receptor antagonist NBQX (2 nmol in 100 nL) into the LH. Intravenous administration of the muscarinic cholinergic receptor antagonist homatropine methyl bromide (0.2 mg/kg), a quaternary ammonium drug that does not cross the blood-brain barrier, abolished the changes in cardiovascular responses to restraint stress following LH treatment with LY235959. In summary, our findings show that the LH plays an inhibitory role on the HR increase evoked by restraint stress. Present results also indicate that local NMDA glutamate receptors, through facilitation of cardiac parasympathetic activity, mediate the LH inhibitory influence on the cardiac response to acute restraint stress. The bilateral microinjection of the CoCl2 or LY235959 into the LH enhanced the HR increase evoked by restraint stress without affecting the blood pressure increase. Intravenous administration of the homatropine methyl bromide abolished the changes in cardiovascular responses to restraint stress following LH treatment with LY235959. These results suggest that such LH influence is mediated by local NMDA glutamate receptors and involves parasympathetic nervous activation. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Role of Exercise Training on Autonomic Changes and Inflammatory Profile Induced by Myocardial Infarction

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Autonomic activity during human sleep as a function of time and sleep stage

While there is a developing understanding of the influence of sleep on cardiovascular autonomic activity in humans, there remain unresolved issues. In particular, the effect of time within the sleep period, independent of sleep stage, has not been investigated. Further, the influence of sleep on central sympathetic nervous system (SNS) activity is uncertain because results using the major method applicable to humans, the low frequency (LF) component of heart rate Variability (HRV), have been contradictory, and because the method itself is open to criticism. Sleep and cardiac activity were measured in 14 young healthy subjects on three nights. Data was analysed in 2-min epochs. All epochs meeting specified criteria were identified, beginning 2 h before, until 7 h after, sleep onset. Epoch values were allocated to 30-min bins and during sleep were also classified into stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. The measures of cardiac activity were heart irate (HR), blood pressure (BP), high frequency (HF) and LF components of HRV and pre-ejection period (PEP). During non-rapid eye movement (NREM) sleep autonomic balance shifted from sympathetic to parasympathetic dominance, although this appeared to be more because of a shift in parasympathetic nervous system (PNS) activity. Autonomic balance during REM was in general similar to wakefulness. For BP and the HF and LF components the change occurred abruptly at sleep onset and was then constant over time within each stage of sleep, indicating that any change in autonomic balance over the sleep period is a consequence of the changing distribution of sleep stages. Two variables, HR and PEP, did show time effects reflecting a circadian influence over HR and perhaps time asleep affecting PEP. While both the LF component and PEP showed changes consistent with reduced sympathetic tone during sleep, their pattern of change over time differed.

Influence of Parasympathetic Modulation in Doppler Mitral Inflow Velocity in Individuals without Heart Disease

Background: The relation between left ventricular filing velocities determined by Doppler echocardiography and autonomic nervous system function assessed by heart rate variability (HRV) is unclear. The aim of this study was to evaluate the influence of the autonomic nervous system assessed by the time and frequency domain indices of HRV in the Doppler indices of left ventricular diastolic filling velocities in patients without heart disease. Methods: We studied 451 healthy individuals (255 female [56.4%]) with normal blood pressure, electrocardiogram, chest x-ray, and treadmill electrocardiographic exercise stress test results, with a mean age of 43 +/- 12 (range 15-82) years, who underwent transthoracic Doppler echocardiography and 24-hour electrocardiographic ambulatory monitoring. We studied indices of HRV on time (standard deviation [SD] of all normal sinus RR intervals during 24 hours, SD of averaged normal sinus RR intervals for all 5-minute segments, mean of the SD of all normal sinus RR intervals for all 5-minute segments, root-mean-square of the successive normal sinus RR interval difference, and percentage of successive normal sinus RR intervals > 50 ms) and frequency (low frequency, high frequency, very low frequency, low frequency/high frequency ratio) domains relative to peak flow velocity during rapid passive filling phase (E), atrial contraction (A), E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Statistical analysis was performed with Pearson correlation and logistic regression. Results: Peak flow velocity during rapid passive filling phase (E) and atrial contraction (A), E/A ratio, and deceleration time of early mitral inflow did not demonstrate a significant correlation with indices of HRV in time and frequency domain. We found that the E/A ratio was < 1 in 45 individuals (10%). Individuals with an E/A ratio < 1 had lower indices of HRV in frequency domain (except low frequency/high frequency) and lower indices of the mean of the SD of all normal sinus RR intervals for all 5-minute segments, root-mean-square of the successive normal sinus RR interval difference, and percentage of successive normal sinus RR intervals > 50 ms in time domain. Logistic regression demonstrated that an E/A ratio < 1 was associated with lower HF. Conclusion: Individuals with no evidence of heart disease and an E/A ratio < 1 demonstrated a significant decrease in indexes of HRV associated with parasympathetic modulation. (J Am Soc Echocardiogr 2010;23: 762-5.)

Assessment of Autonomic Function by Phase Rectification of RRInterval Histogram Analysis in Chagas Disease

Background:In chronic Chagas disease (ChD), impairment of cardiac autonomic function bears prognostic implications. Phase‑rectification of RR-interval series isolates the sympathetic, acceleration phase (AC) and parasympathetic, deceleration phase (DC) influences on cardiac autonomic modulation.Objective:This study investigated heart rate variability (HRV) as a function of RR-interval to assess autonomic function in healthy and ChD subjects.Methods:Control (n = 20) and ChD (n = 20) groups were studied. All underwent 60-min head-up tilt table test under ECG recording. Histogram of RR-interval series was calculated, with 100 ms class, ranging from 600–1100 ms. In each class, mean RR-intervals (MNN) and root-mean-squared difference (RMSNN) of consecutive normal RR-intervals that suited a particular class were calculated. Average of all RMSNN values in each class was analyzed as function of MNN, in the whole series (RMSNNT), and in AC (RMSNNAC) and DC (RMSNNDC) phases. Slopes of linear regression lines were compared between groups using Student t-test. Correlation coefficients were tested before comparisons. RMSNN was log-transformed. (α < 0.05).Results:Correlation coefficient was significant in all regressions (p < 0.05). In the control group, RMSNNT, RMSNNAC, and RMSNNDCsignificantly increased linearly with MNN (p < 0.05). In ChD, only RMSNNAC showed significant increase as a function of MNN, whereas RMSNNT and RMSNNDC did not.Conclusion:HRV increases in proportion with the RR-interval in healthy subjects. This behavior is lost in ChD, particularly in the DC phase, indicating cardiac vagal incompetence.

Endogenous opioid peptides in parasympathetic, sympathetic and sensory nerves in the guinea-pig heart.

Research has suggested that exogenous opioid substances can have direct effects on cardiac muscle or influence neurotransmitter release via presynaptic modulation of neuronal inputs to the heart. In the present study, multiple-labelling immunohistochemistry was employed to determine the distribution of endogenous opioid peptides within the guinea-pig heart. Approximately 40% of cardiac ganglion cells contained immunoreactivity for dynorphin A (1-8), dynorphin A (1-17) and dynorphin B whilst 20% displayed leu-enkephalin immunoreactivity. Different populations of opioid-containing ganglion cells were identified according to the co-existence of opioid immunoreactivity with immunoreactivity for somatostatin and neuropeptide Y. Immunoreactivity for prodynorphin-derived peptides was observed in many sympathetic axons in the heart and was also observed, though to a lesser extent, in sensory axons. Leu-enkephalin immunoreactivity was observed in occasional sympathetic and sensory axons. No immunoreactivity was observed for met-enkephalin-arg-gly-leu or for beta-endorphin. These results demonstrate that prodynorphin-derived peptides are present in parasympathetic, sympathetic and sensory nerves within the heart, but suggest that only the prodynorphin gene is expressed in guinea-pig cardiac nerves. This study has shown that endogenous opioid peptides are well placed to regulate cardiac function via both autonomic and sensory pathways.

Neural regulation of pancreatic islet cell mass and function.

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and β-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β-cell mass expansion during the weaning period and β-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children

The 24-h heart rate variability and QT-interval adaptation was investigated in perinatally HIV-infected preschool children classified according to immunological status in order to assess autonomic function at early stages of infection. Thirty-five perinatally HIV-infected and clinically stable children (4.8 ± 0.3 years) were enrolled after approval of the study by the University Hospital Pedro Ernesto Ethics Committee and written informed parental consent was obtained. The children were classified according to peripheral CD4+ count (cells/µL) as follows: group 1, N = 11 (≥1000); group 2, N = 7 (≥500 and <1000); group 3, N = 17 (<500). Left ventricular ejection fraction (>55%), 24-h RR interval variability (RRV) indexes (NN, SDANN, SDNN index, r-MSSD) and 24-h QT and Bazett-corrected QT (QTc) were determined, and groups were matched for age, body surface area, and left ventricular ejection fraction, reducing biases in RRV. The peak differences (∆) between the highest and lowest RRV and QT indexes were extracted from nocturnal (1 am-6 am) and daytime (1 pm-6 pm) hourly assessed segments, respectively. Pearson’s correlation (r) and Kruskal-Wallis ANOVA were used to compare groups. CD4+ count correlated positively with ∆NN (r = 0.45; P = 0.003). There were no significant differences in daytime NN among groups. Nighttime SDNN index (P = 0.01), nighttime r-MSSD (P = 0.003), ∆NN (P = 0.01), ∆SDNN index (P = 0.03) and ∆r-MSSD (P = 0.004) were significantly lower in group 3 than in the other groups. Expected nighttime QTc-interval lengthening was not observed in all groups. In perinatally HIV-infected preschool children with preserved left ventricular systolic function, parasympathetic-mediated autonomic dysfunction parallels immune status, impairing both RRV and circadian QTc interval adaptation.

Effect of carotid and aortic baroreceptors on cardiopulmonary reflex: the role of autonomic function

We determined the sympathetic and parasympathetic control of heart rate (HR) and the sensitivity of the cardiopulmonary receptors after selective carotid and aortic denervation. We also investigated the participation of the autonomic nervous system in the Bezold-Jarish reflex after selective removal of aortic and carotid baroreceptors. Male Wistar rats (220-270 g) were divided into three groups: control (CG, N = 8), aortic denervation (AG, N = 5) and carotid denervation (CAG, N = 9). AG animals presented increased arterial pressure (12%) and HR (11%) compared with CG, while CAG animals presented a reduction in arterial pressure (16%) and unchanged HR compared with CG. The sequential blockade of autonomic effects by atropine and propranolol indicated a reduction in vagal function in CAG (a 50 and 62% reduction in vagal effect and tonus, respectively) while AG showed an increase of more than 100% in sympathetic control of HR. The Bezold-Jarish reflex was evaluated using serotonin, which induced increased bradycardia and hypotension in AG and CAG, suggesting that the sensitivity of the cardiopulmonary reflex is augmented after selective denervation. Atropine administration abolished the bradycardic responses induced by serotonin in all groups; however, the hypotensive response was still increased in AG. Although the responses after atropine were lower than the responses before the drug, indicating a reduction in vagal outflow after selective denervation, our data suggest that both denervation procedures are associated with an increase in sympathetic modulation of the vessels, indicating that the sensitivity of the cardiopulmonary receptors was modulated by baroreceptor fibers.

Increased Insulin Secretion by Muscarinic M1 and M3 Receptor Function from Rat Pancreatic Islets in vitro

Parasympathetic system plays an important role in insulin secretion from the pancreas. Cholinergic effect on pancreatic beta cells exerts primarily through muscarinic receptors. In the present study we investigated the specific role of muscarinic M1 and M3 receptors in glucose induced insulin secretion from rat pancreatic islets in vitro. The involvement of muscarinic receptors was studied using the antagonist atropine. The role of muscarinic MI and M3 receptor subtypes was studied using subtype specific antagonists. Acetylcholine agonist, carbachol, stimulated glucose induced insulin secretion at low concentrations (10-8-10-5 M) with a maximum stimulation at 10-7 M concentration. Carbachol-stimulated insulin secretion was inhibited by atropine confirming the role of muscarinic receptors in cholinergic induced insulin secretion. Both M1 and M3 receptor antagonists blocked insulin secretion induced by carbachol. The results show that M3 receptors are functionally more prominent at 20 mM glucose concentration when compared to MI receptors. Our studies suggest that muscarinic M1 and M3 receptors function differentially regulate glucose induced insulin secretion, which has clinical significance in glucose homeostasis.

Immediate and long-term effects of psychological stress during adolescence in cardiovascular function: comparison of homotypic vs heterotypic stress regimens

Adolescence has been proposed as an ontogenic period of vulnerability to stress. Nevertheless, the impact of stressful events during adolescence in cardiovascular activity is poorly understood. Therefore, the purpose of this study was to investigate the immediate and long-lasting effects of exposure to stressful events during adolescence in cardiovascular function of rats. To this end, we compared the impact of 10-days exposure to two chronic stress protocols: the repeated restraint stress (RRS, homotypic) and chronic variable stress (CVS, heterotypic). Independent groups of animals were tested 24 h (immediate) or three weeks (long-lasting) following completion of stress period. Exposure to CVS, but not RRS, during adolescence increased basal HR values without affecting arterial pressure, which was followed by augmented power of oscillatory component at low frequency (sympathetic-related) of the pulse interval (PI). RRS enhanced variance of the PI with an increase in the power of both low and high (parasympathetic-related) frequency components. RRS also increased the baroreflex gain. Neither RRS nor CVS affected systolic arterial pressure variability. The RRS-evoked changes in PI variability were long-lasting and persisted into adulthood while all alterations evoked by the CVS were reversed in adulthood. These findings indicate a stress type-specific influence in immediate and long-term effects of stress during adolescence in cardiovascular function. While immediate changes in cardiovascular function were mainly observed following CVS, long-lasting autonomic consequences in adulthood were observed only in animals exposed to RRS during adolescence.

Ciguatoxins: Cyclic polyether modulators of voltage-gated Iion channel function

Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na+-dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.