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The role of brain natriuretic peptide in maintaining myometrial quiescence during pregnancy

01 March 2014

Myometrial quiescence is a physiological stage of the myometrium during pregnancy. It is a period of active relaxation of the myometrial smooth muscle cells; myometrial quiescence is responsible for maintaining pregnancy. The precise mechanisms underlying myometrial quiescence have not been completely elucidated, although many mediators and cellular pathways have been described as playing a role. Fetal membranes (chorion and amnion) produce and release one or more substances that inhibit myometrial contractions, playing a central role in the maintenance of myometrial quiescence. Brain natriuretic peptide (BNP) is more potent than any other natriuretic peptide in inhibiting myometrial contractions in vitro. Brain natriuretic peptide is produced by the chorion and amnion, mainly during myometrial quiescence, and decreasing towards the end of pregnancy. Production of BNP is reduced in fetal membranes obtained from women in preterm labour. It is postulated that BNP, acting in a paracrine fashion, plays a key role in the maintaining myometrial quiescence and, therefore, controlling the duration of pregnancy. Furthermore, it is postulated that a premature decrease of BNP production by the fetal membranes may cause preterm labour and preterm birth.

Myometrial physiology - time to translate?

01 March 2014

In this short review, we discuss how recent insights into myometrial physiology may be taken forward and translated into much-needed novel therapies for problems associated with labour. We consider excitation–contraction coupling in the myometrium and how this relates to our understanding of the changes that occur to produce myometrial contractions and successful labour. We then discuss how this information has already been used in the development of drugs to either stimulate or relax the myometrium, to address the needs of women with either slow (dystocic) labours or threatened preterm labours, respectively. We next present the data showing how basic physiological findings pertaining to hypoxia and lactate production have been taken and translated into a tool for predicting and thus better managing difficult labours. We then highlight examples of where physiological research has started to provide mechanistic insight into clinical problems associated with labour and parturition (obesity, diabetes, advanced maternal age, postdate and twin pregnancies) and suggest how these findings could be translated into new therapies for difficult labours.

Kv7 and Kv11 channels in myometrial regulation

01 March 2014

Ion channels play a key role in defining myometrial contractility. Modulation of ion channel populations is proposed to underpin gestational changes in uterine contractility associated with the transition from uterine quiescence to active labour. Of the myriad ion channels present in the uterus, this article will focus upon potassium channels encoded by the KCNQ genes and ether-à-go-go-related (ERG) genes. Voltage-gated potassium channels encoded by KCNQ and ERG (termed Kv7 and Kv11, respectively) are accepted as major determinants of neuronal excitability and the duration of the cardiac action potential. However, there is now growing appreciation that these ion channels have a major functional impact in vascular and non-vascular smooth muscle. Moreover, Kv7 channels may be potential therapeutic targets for the treatment of preterm labour.

Assessment of myometrial transcriptome changes associated with spontaneous human labour by high-throughput RNA-seq

01 March 2014

The transition of the human uterus from a quiescent to a contractile state takes place over a number of weeks. On such biological time scales, cellular phenotype is modified by changes in the transcriptome, which in turn is under the control of the underlying endocrine, paracrine, and biophysical processes resulting from the ongoing pregnancy. In this study, we characterize the transition of the human myometrial transcriptome at term from not in labour (NIL) to in labour (LAB) using high throughput RNA sequencing (RNA-seq). RNA was isolated from the myometrium of uterine biopsies from patients at term who were not in labour (n = 5) and at term in spontaneous labour (n = 5) without augmentation. A total of 143.6 million separate reads were sequenced, achieving, on average, ~13 times coverage of the expressed human transcriptome per sample. Principal component analysis indicated that the NIL and LAB transcriptomes could be distinguished as two distinct clusters. A comparison of the NIL and LAB groups, using three different statistical approaches (baySeq, edgeR, and DESeq), demonstrated an overlap of 764 differentially expressed genes. A comparison with currently available microarray data revealed only a partial overlap in differentially expressed genes. We conclude that the described RNA-seq data sets represent the first fully annotated catalogue of expressed mRNAs in human myometrium. When considered together, the full expression repertoire and the differentially expressed gene sets should provide an excellent resource for formulating new hypotheses of physiological function, as well as the discovery of novel therapeutic targets.

The importance of the smooth muscle cytoskeleton to preterm labour

01 March 2014

Multiple mechanisms have been shown to regulate the onset of labour in a co-operative and complex manner. One factor, myometrial stretch and associated increases in wall tension, has been implicated clinically in the initiation of labour and especially the aetiology of preterm labour. Recent work on the mechanisms involved has led to the finding that the intracellular Ca2+ requirement for activation of the myometrial contractile filaments increases during gestation. The decreased Ca2+ sensitivity correlates with an increase in the expression of caldesmon, an actin-binding protein and inhibitor of myosin activation, during pregnancy. In late pregnancy, an increase in extracellular signal-regulated kinase-mediated caldesmon phosphorylation occurs, which appears to reverse the inhibitory action of caldesmon during labour. Force generated by the myometrial contractile filaments is communicated across the plasmalemma to the uterine wall through focal adhesions. Phospho-tyrosine screening and mass spectrometry of stretched myometrial samples identified several stretch-activated focal adhesion proteins. This Src-mediated focal adhesion signalling appears to provide a tunable, i.e. regulated, tension sensor and force transmitter in the myometrial cell. In other parallel studies, biophysical measurements of smooth muscle compliance at both the cellular and tissue levels suggest that decreases in cellular compliance due to changing interactions of the actin cytoskeleton with the focal adhesions may also promote increases in uterine wall tension. These results, taken together, suggest that focal adhesion proteins and their interaction with the cytoskeleton may present a new mode of regulation of uterine contractility.

Finding new agents in medicinal plants to act on the myometrium

01 March 2014

This report summarizes work investigating the effects of some medicinal plants on uterine contraction. As there is a clinical need to find better drugs to help control uterine activity, and novel compounds are sought, the mechanisms whereby the medicinal plants exert their effects, as well as their major compounds, are discussed. By identifying the plants, major constituents and mechanisms, this review also illustrates the potential for development of new drugs, so that better ways to treat uterine disorders will be available to women worldwide.

Elevated levels of branched-chain amino acids have little effect on pancreatic islet cells, but L-arginine impairs function through activation of the endoplasmic reticulum stress response

01 March 2014

Recent metabolic profiling studies have identified a correlation between branched-chain amino acid levels, insulin resistance associated with prediabetes and susceptibility to type 2 diabetes. Glucose and lipids in chronic excess have been reported to induce toxic effects in pancreatic β-cells, but the effect of elevated amino acid concentrations on primary islet cell function has not been investigated to date. The aim of this study was to investigate the effect of chronic exposure to various amino acids on islet cell function in vitro. Isolated rat islets were incubated over periods of 48 h with a range of concentrations of individual amino acids (0.1 μm to 10 mm). After 48 h, islets were assessed for glucose-dependent insulin secretion capacity, proliferation or islet cell apoptosis. We report that elevated levels of branched-chain amino acids have little effect on pancreatic islet cell function or viability; however, increased levels of the amino acid l-arginine were found to be β-cell toxic, causing a dose-dependent decrease in insulin secretion accompanied by a decrease in islet cell proliferation and an increase in islet cell apoptosis. These effects were not due to l-arginine-dependent increases in production of nitric oxide but arose through elicitation of the islet cell endoplasmic reticulum stress response. This novel finding indicates, for the first time, that the l-arginine concentration in vitro may impact negatively on islet cell function, thus indicating further complexity in relationship to in vivo susceptibility of β-cells to nutrient-induced dysfunction.

Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure

01 March 2014

While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1 month after CBR [median (interquartile range): age, 58.5 (56–61) years old; and ejection fraction, 32 (25–34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (91%, P < 0.05), SBP (71%, P < 0.05) and DBP slopes (59%, P = 0.07). In contrast, the HR slope remained unchanged. The dissociation between the blood pressure and HR responses after CBR shows involvement of a different chemoreceptive site(s) maintaining the response to acute hypoxia. We conclude that carotid bodies are responsible for ventilatory and blood pressure responses, while the HR response might be mediated by the aortic bodies. The significant reduction of the blood pressure response to hypoxia after CBR suggests a decrease in sympathetic tone, which is of particular clinical relevance in congestive heart failure.

The effect of increased physical activity on pulmonary diffusing capacity in unfit women

01 March 2014

The purpose of the study was to determine whether short-term high-intensity aerobic interval training improves resting pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO). Twenty-eight sedentary women [mean (SD) age 32 (11) years, body mass index 24.3 (5.7) kg m–2] were randomly assigned to either a self-directed moderate-intensity physical activity (n = 14) group or a supervised high-intensity aerobic interval training group (n = 14). The moderate physical activity group and the aerobic interval training group increased weekly physical activity energy expenditure by 800 and 1600 kcal week–1, respectively. After 6 weeks, aerobic capacity increased to a similar exent in both groups (mean improvement 8%, effect size 0.39). The DLNO, but not DLCO, increased to a similar extent in both groups, by 4% or 3.0 (5.7) [95% confidence interval 0.8, 5.2] ml min–1 mmHg–1 m–2 from pre- to post-training (effect size 0.27). There was no correlation between the change in aerobic capacity and the change in DLNO (P > 0.05) or between the change in aerobic capacity and the change in total weekly physical activity energy expenditure (P > 0.05). Interval training does not provide additional improvements in DLNO or aerobic capacity compared with self-directed moderate-intensity physical activity (4–6 metabolic equivalent tasks, 800 kcal week–1, for 6 weeks) in unfit women. Despite the slight improvement in both DLNO and aerobic capacity, true meaningful physiological changes in these parameters remain questionable.

Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats

01 March 2014

Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/H+. A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b+TH–) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP–SAP) into the RTN destroyed Phox2b+TH– neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP–SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO2) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b+TH– neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b+TH– neurons is a plausible cause of the respiratory deficits observed after injection of SSP–SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.

Assessment of dynamic cerebral autoregulation and cerebrovascular CO2 reactivity in ageing by measurements of cerebral blood flow and cortical oxygenation

01 March 2014

With ageing, cerebral blood flow velocity (CBFV) decreases; however, to what extent dynamic cerebral autoregulation and cerebrovascular CO2 reactivity are influenced by ageing is unknown. The aim was to examine the dynamic responses of CBFV and cortical oxygenation to changes in blood pressure (BP) and arterial CO2 across different ages. Fifty-eight participants in three age groups were included, as follows: young (n = 20, 24 ± 2 years old), elderly (n = 20, 66 ± 1 years old), and older elderly (n = 18, 78 ± 3 years old). The CBFV was measured using transcranial Doppler ultrasound, simultaneously with oxyhaemoglobin (O2Hb) using near-infrared spectroscopy and beat-to-beat BP measurements using Finapres. Postural manoeuvres were performed to induce haemodynamic fluctuations. Cerebrovascular CO2 reactivity was tested with hyperventilation and CO2 inhalation. With age, CBFV decreased (young 59 ± 12 cm s–1, elderly 48 ± 7 cm s–1 and older elderly 42 ± 9 cm s–1, P < 0.05) and cerebrovascular resistance increased (1.46 ± 0.58, 1.81 ± 0.36 and 1.98 ± 0.52 mmHg cm–1 s–1, respectively, P < 0.05). Normalized gain (autoregulatory damping) increased with age for BP–CBFV (0.88 ± 0.18, 1.31 ± 0.30 and 1.06 ± 0.34, respectively, P < 0.05) and CBFV–O2Hb (0.10 ± 0.09, 0.12 ± 0.04 and 0.17 ± 0.08, respectively, P < 0.05) during the repeated sit–stand manoeuvre at 0.05 Hz. Even though the absolute changes in CBFV and cerebrovascular resistance index during the cerebrovascular CO2 reactivity were higher in the young group, the percentage changes in CBFV, cerebrovascular resistance index and O2Hb were similar in all age groups. In conclusion, there was no decline in dynamic cerebral autoregulation and cerebrovascular CO2 reactivity with increasing age up to 86 years. Despite the decrease in cerebral blood flow velocity and increase in cerebrovascular resistance with advancing age, CBFV and cortical oxygenation were not compromised in these elderly humans during manoeuvres that mimic daily life activities.

Editorial Board

01 February 2014

The neural regulation of the kidney in hypertension and renal failure

01 February 2014
New Findings

  • What is the topic of this review?

    Reports that bilateral renal denervation in resistant hypertensive patients results in a long-lasting reduction in blood pressure raise the question of the underlying mechanisms involved and how they may be deranged in pathophysiological states of hypertension and renal failure.

  • What advances does it highlight?

    The renal sensory afferent nerves and efferent sympathetic nerves work together to exert an important control over extracellular fluid volume, hence the level at which blood pressure is set. This article emphasizes that both the afferent and the efferent renal innervation may contribute to the neural dysregulation of the kidney that occurs in chronic renal disease and resistant hypertension.

  • Autonomic control is central to cardiovascular homeostasis, and this is exerted not only at the level of the heart and blood vessels but also at the kidney. At the kidney, the sympathetic neural regulation of renin release and fluid reabsorption may influence fluid balance and, in the longer term, the level at which blood pressure is set. The role of the renal innervation in the regulation of blood pressure has received renewed attention over the past few years, following the reports that bilateral renal denervation of resistant hypertensive patients resulted in a marked reduction in blood pressure, which has been maintained for several years. Such has been the interest that this approach of renal denervation is being applied in other patient groups with diabetes, obesity and renal failure, with the hope that there may be a sustained reduction in blood pressure as well as the amelioration of some aspects of the metabolic syndrome. However, the factors that come into play to cause the rise in blood pressure in these patient groups, particularly the resistant hypertensive patients, are far from clear. Moreover, the mechanisms leading to the fall in blood pressure following renal denervation of resistant hypertensive patients currently elude our understanding and is therefore an area that requires much more investigation to enhance our insight.

    Vagal modulation of cardiac ventricular arrhythmia

    01 February 2014
    New findings

  • What is the topic of this review?

    This article addresses the relationship between vagus nerve activity and malignant ventricular arrhythmias. It focuses on the clinical association of an impaired vagal tone in cardiac disease states with high mortality from sudden cardiac death and the potential underlying mechanisms.

  • What advances does it highlight?

    The article summarizes the mounting evidence that vagal innervation in the cardiac ventricle plays a key direct role in the prevention of the initiation of ventricular fibrillation. Data are presented on the role that nitric oxide plays in mediating the effects of vagal protection against ventricular fibrillation, supporting the notion that a separate non-muscarinic, nitrergic population of vagal neurons is responsible for this protection.

  • Sudden cardiac death remains a significant unresolved clinical problem, with many of the deaths being due to malignant ventricular arrhythmias. Markers of abnormal autonomic function have been shown to be strong prognostic predictors, highlighting the important relationship between reduced vagal tone and malignant ventricular arrhythmias, such as ventricular fibrillation, in cardiac patients. Exploring the mechanisms underlying the autonomic modulation of ventricular fibrillation, my group has shown that vagus nerve stimulation protects against ventricular fibrillation in the innervated isolated heart preparation. We have provided direct evidence that nitric oxide is released in the ventricle with cervical vagus nerve stimulation and NO mediates the antifibrillatory actions of vagus nerve stimulation in the ventricle. Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors and, dogmatically, that there is little vagal effect in the ventricle, as innervation was believed to be sparse. Mounting evidence from many species now supports the presence of a rich vagal innervation in the ventricle. Data from my group showing that the protective actions of vagus nerve stimulation against ventricular fibrillation and NO release are preserved in the presence of muscarinic block support the notion that a population of nitrergic neurons could be responsible. This potentially exploitable downstream pathway together with the availability of vagus nerve stimulators make it an exciting time to investigate the development of an effective strategy of vagal protection against ventricular fibrillation in the clinical setting.

    Autonomic control of the heart during exercise in humans: role of skeletal muscle afferents

    01 February 2014
    New findings

  • What is the topic of this review?

    The autonomic nervous system plays a key role in bringing about the cardiovascular responses to exercise necessitated by the increased metabolic requirements of the active skeletal muscle. The complex interaction of central and peripheral neural control mechanisms evokes a decrease in parasympathetic activity and an increase sympathetic activity to the heart during exercise.

  • What advances does it highlight?

    This review presents some of the recent insights provided by human studies into the role of mechanically and metabolically sensitive skeletal muscle afferents in the regulation of cardiac autonomic control during exercise.

  • The autonomic responses to exercise are orchestrated by the interactions of several central and peripheral neural mechanisms. This report focuses on the role of peripheral feedback from skeletal muscle afferents in the autonomic control of the heart during exercise in humans. Heart rate responses to passive calf stretch are abolished with cardiac parasympathetic blockade, indicating that the activation of mechanically sensitive skeletal muscle afferents (muscle mechanoreceptors) can inhibit cardiac parasympathetic activity and is likely to contribute to the increase in heart rate at the onset of exercise. Recent experiments show that the partial restriction of blood flow to the exercising skeletal muscles, to augment the activation of metabolically sensitive skeletal muscle afferents (muscle metaboreceptors) in humans, evokes an increase in heart rate that is attenuated with β1-adrenergic blockade, thus suggesting that this response is principally mediated via an increase in cardiac sympathetic activity. Heart rate remains at resting levels during isolated activation of muscle metaboreceptors with postexercise ischaemia following hand grip, unless cardiac parasympathetic activity is inhibited, whereupon a sympathetically mediated increase in heart rate is unmasked. During postexercise ischaemia following leg cycling exercise, heart rate appears to remain elevated due to withdrawal of parasympathetic tone and/or the activation of sympathetic activity to the heart. Although the importance of skeletal muscle afferent feedback to the autonomic control of the heart during exercise is incontrovertible, the complexity of cardiac sympathetic–parasympathetic interactions and the absence of direct intraneural recordings in humans mean that it remains incompletely understood.

    Muscle afferents and cardiorespiratory control: the Birmingham connection

    01 February 2014
    New findings

  • What is the topic of this review?

    This brief review describes the work of Professor John Coote and colleagues at the University of Birmingham, which has contributed to understanding of the role of muscle afferent involvement in cardiorespiratory control in exercise.

  • What advances does it highlight?

    The seminal findings of John Coote's early work are highlighted, as well as more recent developments in the field, especially the role of muscle afferents in the control of human ventilation during exercise.

  • Through the work of John Coote, research into the role of muscle afferent involvement in cardiorespiratory control has had strong links with Birmingham since the late 1960s. This brief review gives an historical background to John's early work and how his research and mentorship of colleagues continues to have a profound influence on the field today.

    Cardiovascular control from cardiac and pulmonary vascular receptors

    01 February 2014
    New Findings

  • What is the topic of this review?

    The purpose of this review is to summarize present knowledge of the function of the afferent nerves arising from the heart and the coronary and pulmonary arteries. Although there is abundant evidence that atrial receptor stimulation influences heart rate and urine flow, with little or no effect elsewhere, and that ventricular receptors are strongly excited only by chemical stimuli, there is still the erroneous belief that they act as a homogeneous group causing cardiovascular depression.

  • What advances does it highlight?

    Coronary receptors deserve to be recognized as a potentially important additional group of baroreceptors. Stimulation of pulmonary arterial baroreceptors at physiological pressures causes reflex vasoconstriction and could have a hitherto unacknowledged important role in cardiovascular control, for example in exercise.

  • Although there has been a tendency to regard cardiac and pulmonary receptors as a single population of ‘cardiopulmonary receptors’, this cannot be justified as the various receptor types all induce their own particular pattern of responses. Stimulation of atrial receptors increases activity in sympathetic nerves to the sino-atrial node, causing tachycardia, but there is no effect on activity to the myocardium or to most blood vessels. Renal nerve activity, however, is decreased, and secretion of antidiuretic hormone is inhibited, causing diuresis. Ventricular receptors induce a powerful depressor response, but only in response to abnormal chemical stimulation and possibly to myocardial injury. Coronary arterial receptors function as baroreceptors, but have a lower threshold and a more prolonged effect than other baroreceptors. Pulmonary arterial baroreceptors induce vasoconstriction and respiratory stimulation at physiological pressures and may be of importance in mediating some of the responses to exercise, as well as in hypoxic conditions.

    Deep brain stimulation and autonomic control

    01 February 2014
    New Findings

  • What is the topic of this review?

    This article reviews data from studies on human participants and animal models showing how electrical stimulation in deep brain structures (deep brain stimulation) can influence autonomic function.

  • What advances does it highlight?

    Focusing on the control of the cardiovascular system and bladder function, it highlights the potential for development of deep brain stimulation as a new treatment option for patients with autonomic dysfunction.

  • Deep brain stimulation (DBS) in humans has come of age as a tool to treat movement disorders including Parkinson's disease tremor and dystonia as well as a panoply of other disease states including headache, epilepsy, obesity, eating disorders, depression, obsessive compulsive disorder, Tourette's syndrome, addiction and chronic pain. Increasingly, practitioners of DBS are reporting autonomic side effects, which intriguingly, sometimes result in improved autonomic function. Focussing on the effects of stimulation at periaqueductal and periventricular sites on cardiovascular function and control of micturition, this review shows that data obtained from studies in animals is now being confirmed in humans. Lowering of blood pressure and improved baroreflex function can be evoked in humans by DBS at these midbrain sites as well as increased bladder capacity. The findings highlight the tantalizing possibility that DBS could be developed for treatment of dysfunctional autonomic states in humans.