Heart rate dynamics in iNOS knockout mice

Nitric oxide has both an inhibitory and excitatory role in the regulation of pre-ganglionic sympathetic neurons, involving the iNOS and nNOS systems respectively. The aim of the present study was to examine cardiovascular autonomic activity in iNOS knockout mice using spectral analysis of heart rate variability (HRV), and to determine the role of iNOS in altered HRV in endotoxaemia. Electrocardiograms were recorded in anaesthetised mice, and the R-R intervals digitized for spectral analysis of HRV and cardiac rhythm regularity using sample entropy analysis. The basal heart rate was higher in iNOS knockout mice compared with controls (465+/-8 vs 415+/-13 beat/min P<0.05), with a significant increase in the low frequency power of HRV spectra in iNOS knockout mice compared with controls (49.4+/-4.3 vs 33.8+/-5.6 normalized units, P<0.05), consistent with increased cardiac sympathetic activity. Endotoxaemia is known to decrease HRV, but the role of iNOS is unknown. LPS (20 mg/kg i.p) increased basal heart rate in both wild type and iNOS knockout mice, but caused a depression of HRV and sample entropy in both groups. Studies in isolated beating atria showed that the changes of HRV under basal or post-LPS conditions disappeared in vitro, suggesting that the autonomic system is responsible for altered HRV. We conclude that disruption of iNOS gene leads to an increase in the low frequency power of HRV consistent with increased cardiac sympathetic activity. These data also demonstrate that LPS-induced decrease of HRV is independent of iNOS.     

Heart rate variability dynamics for the prognosis of cardiovascular risk

Statistical, spectral, multi-resolution and non-linear methods were applied to heart rate variability (HRV) series linked with classification schemes for the prognosis of cardiovascular risk. A total of 90 HRV records were analyzed: 45 from healthy subjects and 45 from cardiovascular risk patients. A total of 52 features from all the analysis methods were evaluated using standard two-sample Kolmogorov-Smirnov test (KS-test). The results of the statistical procedure provided input to multi-layer perceptron (MLP) neural networks, radial basis function (RBF) neural networks and support vector machines (SVM) for data classification. These schemes showed high performances with both training and test sets and many combinations of features (with a maximum accuracy of 96.67%). Additionally, there was a strong consideration for breathing frequency as a relevant feature in the HRV analysis.     

Caffeine and regional brain monoamine utilization in mice

Caffeine (100 and 200 mg/kg, 30 min., i.p.) selectively altered the regional utilization of monoamines in the brains of mice. This depended upon the specific neurotransmitter and metabolite studied. Caffeine increased serotonin (5HT) utilization a dramatic ten-fold in the OB but decreased 5HT utilization in the HT. No 5HT changes were seen in other brain regions. Caffeine markedly increased norepinephrine (NE) utilization in the olfactory bulbs (OB), olfactory tubercles (OT), prefrontal cortex (PC), amygdala (AMY), hypothalamus (HT) and hippocampus (HC). Caffeine increased dopamine (DA) utilization in the OB, OT, PC, septum (SP), HT and thalamus (TH) but by various metabolic routes. The selective regional alterations in monoamine utilization produced by caffeine may be relevant to caffeine's central stimulatory effects. Limbic structures are predominantly involved. These changes may have important clinical and research implications. For example, the profound effect of caffeine on OB monoamines indicates that it may serve as a meaningful tool in olfactory research, including the bulbectomy model. Caffeine may also be useful in other limbic system behavioral models.     

Heart rate variability in weightlifters

On the basis of the literature and original data, heart rate variability (HRV) in weightlifters has been studied. The results showed that the distribution mode (a parameter of mathematical analysis that is equal to the most frequent length of RR intervals) indicates the intensity of physical exercise. Specific changes in the autonomic balance in athletes as dependent on their degree of training and sports qualification are important characteristics of adaptations to physical loads. For example, the degree of training of weightlifters is reflected by the level of the respiratory component as an index of the activity of the parasympathetic nervous system. Adaptation to physical exercise leads to an increase in the power of the spectrum of neurohumoral modulation and to changes in the ratio between the levels of the total spectral power of HRV.     

Heart rate variability and sports

This article presents a review of the literature and some author’s data on the problem of using heart rate variability in sports and sports medicine practice.     

Heart rate variability analysis

The expansion of heart rate variability analysis has been facilitated by the remarkable development of computer sciences and digital signal processing during the last thirty years. The beat-to-beat fluctuation of the heart rate originates from the momentary summing of sympathetic and parasympathetic influences on the sinus node. According to the extensive associations of the autonomic nervous system, several factors affect heart rate and its variability such as posture, respiration frequency, age, gender, physical or mental load, pain, numerous disease conditions, and different drugs. Heart rate variability can be quantitatively measured by time domain and frequency domain methods that are detailed in the paper. Non-linear methods have not spread in the clinical practice yet. Various cardiovascular and other pathologies as well as different forms of mental and physical load are associated with altered heart rate variability offering the possibility of predicting disease outcome and assessing stress.     

Heart rate and blood pressure biofeedback

The experimental literature on the use of biofeedback with heart rate and blood pressure, published since 1972, was reviewed and summarized along several dimensions: magnitude of change, effects of extended training, type of feedback, temporal feedback factors, motivational factors, instructional effects, individual differences, and the mediation/specificity issue. The research on biofeedback and heart rate was found to be fairly well developed. Research on biofeedback and blood pressure, however, was found to be much less advanced. Moreover, most of the studies were done with hypertensive subjects.     

Heart rate and increased intravascular volume

The objective was to establish whether an intravascular volume increase leads to a heart rate (HR) increase without increased sympathetic tonus. HR changes at rest and at deep breathing (6/min - simulated increase of atrial filling pressure) were measured in patients after heart transplantation. Evaluation of dependency of HR changes on breathing depth was done through a new time series methodology. The data was evaluated through graphs displaying a significant increase in the graph area at deep breathing, when compared with breathing at rest (p<0.01). We presume that an increase in HR corresponds to increased intravascular volume and malfunctioning kidneys.     

Vesicular monoamine transporter 2 mediates fear behavior in mice

A subset of people exposed to a traumatic event develops post‐traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2‐LO mice) or 200% (VMAT2‐HI mice) of wild‐type levels of VMAT2 protein. We report that VMAT2‐LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2‐LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared with wild‐type mice and an anxiogenic‐like phenotype, but displayed no deficits in social function. By contrast, VMAT2‐HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity and greater dopamine release upon stimulation compared with wild‐type controls. Behaviorally, VMAT2‐HI mice were similar to wild‐type mice in most assays, with some evidence of a reduced anxiety‐like responses. Together, these data show that presynaptic monoamine function mediates PTSD‐like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD.     

Heart rate variability in normal and complicated pregnancies

The sympathetic division (SD) of the autonomic nervous system (ANS) was assessed by 23 tachometric parameters in 176 pregnant women using a Valenta medical diagnostic system. The activity of the ANS SD was shown to increase in the first trimester of pregnancy, progressively rise during the second and third trimesters, and decrease immediately before delivery. This is considered as a mechanism of adaptation to pregnancy. The activity of the ANS SD in pregnant women remained unchanged in mild gestosis; increased in moderate gestosis; and decreased in chronic hypertension, hypertensive circulatory disorders, and threatened preterm delivery. The role of the activity of the ANS SD in normal pregnancy and in obstetric complications is discussed.     

Increased baroreceptor response in mice deficient in monoamine oxidase A and B

The recent development of mice doubly deficient for monoamine oxidase A and B (MAO-A/B, respectively) has raised questions about the impact of these mutations on cardiovascular function, in so far as these animals demonstrate increased tissue levels of the vasoactive amines serotonin, norepinephrine, dopamine, and phenylethylamine. We recorded femoral arterial pressures and electrocardiograms in adult MAO-A/B-deficient mice during halothane-nitrous oxide anesthesia as well as 30 min postoperatively. During both anesthesia and recovery, systolic, diastolic, and mean arterial pressures were 10-15 mmHg lower in MAO-A/B-deficient mice compared with normal controls (P < 0.01). Mutants also showed a greater baroreceptor-mediated reduction in heart rate in response to hypertension after intravenous pulses of phenylephrine or angiotensin II. Tachycardia elicited in response to hypotension after nitroprusside was greater in mutants than in controls. Heart rate responsiveness to changes in arterial pressure was abolished after administration of glycopyrrolate, with no differences in this phenomenon noted between genotypes. These data suggest that prevention of hypertension may occur in chronic states of catecholaminergic/indoleaminergic excess by increased gain of the baroreflex.     

Insulin-like growth factor 1-induced alterations in lumbospinal monoamine dynamics.

A wealth of evidence indicates that insulin-like growth factor (IGF-1) is involved in neurotransmitter release, synaptic plasticity, morphogenesis and regulation of gene expression. RT-PCR and immunocytochemical-based techniques revealed that IGF-1 and its receptor are highly expressed by different neuronal elements of the spinal cord lumbar enlargement. Accordingly, the present study intended to examine lumbospinal monoamine dynamics in the context of the neurotrophic factor IGF-1. Spinal release of norepinephrine (NE) represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was enhanced by IGF-1. This action of IGF-1 was associated with a similar increase in both tyrosine hydroxylase (TH) immunoreactivity and the level of its mRNA. In contrast, neuronal contents of serotonin and its metabolite 5-hydroxyindoleacetic acid in IGF-1-treated animals remained at control level. Genistein, a tyrosine kinase inhibitor, which by itself had no effect on NE metabolism, abolished the induction effect of IGF-1 on TH and MHPG/NE ratio. Our results suggest that IGF-1 augments the lumbospinal noradrenergic system by an intracellular mechanism involving a receptor-linked tyrosine kinase. The physiological consequences of the IGF-1 actions are discussed in terms of neuroprotection and nociception.