Human sympathetic nerve biology : parallel influences of stress and epigenetics in essential hypertension and panic disorder

Patients with panic disorder provide a clinical model of stress. On a "good day," free from a panic attack, they show persistent stress-related changes in sympathetic nerve biology, including abnormal sympathetic nerve single-fiber firing ("salvos" of multiple firing within a cardiac cycle) and release of epinephrine as a cotransmitter. The coreleased epinephrine perhaps originates from in situ synthesis by phenylethanolamine N-methyltransferase (PNMT). In searching for biological evidence that essential hypertension is caused by mental stress—a disputed proposition—we note parallels with panic disorder, which provides an explicit clinical model of stress: (1) There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. (2) For both, epinephrine cotransmission is present in sympathetic nerves. (3) In panic disorder and essential hypertension, but not in health, single-fiber sympathetic nerve firing salvos occur. (4) Tissue nerve growth factor is increased in both conditions (nerve growth factor is a stress reactant). (5) There is induction of PNMT in sympathetic nerves. Essential hypertension exhibits a further manifestation of mental stress: there is activation of noradrenergic brain stem neurons projecting to the hypothalamus and amygdala. These pathophysiological findings strongly support the view that chronic mental stress is important in the pathogenesis of essential hypertension. A hypothesis now under test is whether in both disorders, under prevailing conditions of ongoing stress, PNMT induced in sympathetic nerves acts as a DNA methylase, causing the norepinephrine transporter (NET) gene silencing that is present in both conditions. PNMT can have an intranuclear distribution, binding to DNA. We have demonstrated that the reduced neuronal noradrenaline reuptake present in both disorders does have an epigenetic mechanism, with demonstrable reduction in the abundance of the transporter protein, the NET gene silencing being associated with DNA binding by the methylation-related inhibitory transcription factor MeCP2.

Chronic mental stress is a cause of essential hypertension : presence of biological markers of stress

1. In searching for biological evidence that essential hypertension is caused by chronic mental stress, a disputed proposition, parallels are noted with panic disorder, which provides an explicit clinical model of recurring stress responses.
2. There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. Plasma cortisol is elevated in both.
3. In panic disorder and essential hypertension, but not in health, single sympathetic nerve fibres commonly fire repeatedly within an individual cardiac cycle; this appears to be a signature of stress exposure. For both conditions, adrenaline cotransmission is present in sympathetic nerves.
4. Tissue nerve growth factor is increased in both (nerve growth factor is a stress reactant). There is induction of the adrenaline synthesizing enzyme, phenylethanolamine-N-methyltransferase, in sympathetic nerves, an explicit indicator of mental stress exposure.
5. The question of whether chronic mental stress causes high blood pressure, still hotly debated, has been reviewed by an Australian Government body, the Specialist Medical Review Council. Despite the challenging medicolegal implications, the Council determined that stress is one proven cause of hypertension, this ruling being published in the 27 March 2002 Australian Government Gazette. This judgement was reached after consideration of the epidemiological evidence, but in particular after review of the specific elements of the neural pathophysiology of essential hypertension, described above.

Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1 : contribution to hypertension and endothelial dysfunction

Background— Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension. We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism.

Methods and Results— We have identified a novel C/T polymorphism in the 3′UTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 gene (SLC7A1). The minor T allele significantly attenuates reporter gene expression (P<0.01) and is impaired in its capacity to form DNA-protein complexes (P<0.05). In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects (P<0.001). Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives (P<0.001). To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing l-arginine transporter SLC7A1. The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (−log EC50 for wild-type versus Slc7A1 transgenic: 6.87±0.10 versus 7.56±0.13; P<0.001). This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells.

Conclusions— The present study identifies a key, functionally active polymorphism in the 3′UTR of SLC7A1. As such, this polymorphism may account for the apparent link between altered endothelial function, l-arginine, and nitric oxide metabolism and predisposition to essential hypertension.

Developmental origins of obesity-related hypertension

1. In the past 30 years the prevalence of obesity and overweight have doubled. It is now estimated that globally over 500 million adults are obese and a further billion adults are overweight. Obesity is a cardiovascular risk factor and some studies suggest that up to 70% of cases of essential hypertension may be attributable, in part, to obesity. Increasingly, evidence supports a view that obesity-related hypertension may be driven by altered hypothalamic signalling, which results in inappropriately high appetite and sympathetic nerve activity to the kidney.

2. In addition to the adult risk factors for obesity and hypertension, the environment encountered in early life may ‘programme’ the development of obesity, hypertension and cardiovascular disease. In particular, maternal obesity or high dietary fat intake in pregnancy may induce changes in fetal growth trajectories and predispose individuals to develop obesity and related sequelae.

3. The mechanisms underlying the programming of obesity-related hypertension are becoming better understood. However, several issues require clarification, particularly with regard to the role of the placenta in transferring fatty acid to the fetal compartment, the impact of placental inflammation and cytokine production in obesity.

4. By understanding which factors are most associated with the development of obesity and hypertension in the offspring, we can focus therapeutic and behavioural interventions to most efficiently reduce the intergenerational propagation of the obesity cycle.

The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses.

The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients.

Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic ‘co-morbidity’ perhaps underlies the clinical concordance.

Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

Diet and hypertension in the Asia-pacific region : a brief review

In this paper, the possible reasons for the prevalence of hypertension in the Asia–Pacific region are examined, along with its likely dietary, nutritional and sociocultural causes. This brief survey indicates the need for more comprehensive blood pressure monitoring and surveillance throughout the region. Findings from research conducted in the region and elsewhere suggest that a variety of aetiological factors predict the occurrence of hypertension, most of which are similar to those observed in western populations. However, several lines of research suggest that obesity, abdominal obesity and a number of dietary constituents, in addition to salt, may play relatively greater roles than in western populations. It is argued that hypertension may be prevented via a combination of individual, community and governmental approaches which promote social capital, environmentally sustainable food production and the public health.

Adaptive behaviour in Australia : what items are essential for assessing independent living?

Adaptive behaviour is important in the assessment of eligibility for intellectual disability services. However, there is some question about which behaviours should be assessed. The purpose of the present study was to clarify which everyday behaviours are considered essential for independent functioning by young adults in the Australian community. Parents, disability workers, and young adults judged the importance of 130 everyday behaviours. Items that assessed safety, health, self-care, functional literacy and numeracy, respecting others' rights, and day-to-day decisionmaking were most frequently rated as essential for independent functioning. Our findings raise important questions about the assessment of adaptive behaviour in Australia, and point to the need for a more valid approach to the measurement of adaptive behaviour for the purpose of eligibility assessment. The research provides a first step towards providing such a scale for use in the Australian context.

Understanding the role of mediating risk factors and proxy effects in the association between socio-economic status and untreated hypertension

The association between socio-economic status (SES) and untreated hypertension varies according to a country's level of development and racial/ethnic group. We sought to confirm this variation in women from China and the United States (US) as well as to investigate the impact of SES on several mediating risk factors. We also investigate the extent to which SES explains racial/ethnic differences in untreated hypertension in the US. We used cross-sectional data from 1814 non-pregnant women in China (China Health and Nutrition Survey (CHNS), 1997) and 3266 non-pregnant women in the United States (National Health and Nutrition Examination Survey (NHANES III), 1988–1994) respectively. A variety of statistical modelling techniques was used to predict untreated hypertension as a function of several mediating factors and to simulate the impact of changes in SES. The age-adjusted prevalence of untreated hypertension was significantly higher (p<0.01) for low-income White and Black women compared to Mexican American or Chinese women. Untreated hypertension was not significantly associated with income or education in Mexican Americans or women in China. Obesity and light physical activity had the largest mediating effect on the association between SES and untreated hypertension for all racial/ethnic groups. However, this effect was not as strong as the proxy effect of income and education. SES did not completely explain racial/ethnic differences in hypertension in the US. While SES was more strongly associated with hypertension in Blacks than Whites, Blacks were still 1.97 (95% CI 1.47–2.64) times more likely to have untreated hypertension than Whites after adjusting for SES differences. The association between SES and untreated hypertension varied by country and racial/ethnic group. An important explanation for this variation was the differential effect of SES on mediating risk factors. SES disparities between Whites and Blacks in the US partly explain differences in the prevalence of untreated hypertension between these racial/ethnic groups.

Applying a quality use of medicines framework to using essential oils in nursing practice

Nurses are increasingly incorporating complementary therapies into their practices. Aromatherapy is one of the most popular therapies. The basis of aromatherapy is essential oils, which are chemically active substances with a long history of safe traditional use and a growing evidence base to support their use in nursing care. In Australia, essential oils are classified and regulated under the same policies as conventional medicines such as the National Medicines Policy and the Quality Use of Medicines (QUM) framework applies. QUM is a framework for selecting and using medicines safely and effectively if medicines are indicated. The key elements of QUM are a systems-based approach to using medicines based on relevant evidence, partnerships, and informed client consent. Clients are placed at the centre of a QUM medication management process, which is consistent with holistic care. Applying a QUM approach to essential oil use, Quality Use of Essential Oils (QUEO), involves developing effective systems for managing essential oils from an holistic perspective that includes structured assessment and diagnostic processes to enable effective essential oil prescribing and outcome monitoring. In a QUEO approach, essential oils are integrated into the client's overall medication regimen and care plan rather than being used as ‘add-ons’. Adopting QUEO is consistent with the current national focus on the quality use of therapeutic substances, increases the profile of aromatherapy in nursing care and provides important information to guide future aromatherapy practices.

Retention of essential amino acids during extrusion of protein and reducing sugars

This research investigates the retention of essential amino acid profiles of products during the extrusion of proteins and reducing sugars. Animal proteins (egg and milk protein at 10 and 30% levels) and reducing sugars (fructose and galactose at 0, 2, and 8% levels), with pregelatinized wheat flour, were extruded at 110 and 125 °C product temperatures and feed moistures of 19 and 23.5% for egg protein and 13.75 and 16% for milk protein. The nutritional property analyzed was essential amino acid retention, and sugar retention was also considered to understand the relationship of sugars with retention of amino acids. Lysine showed the lowest retention (up to 40%) of all the essential amino acids. Retention of other essential amino acids varied from 80 to 100% in most situations. Apart from lysine,  tryptophan, threonine, and methionine were found to be significantly changed (P < 0.05) with processing conditions. Increased protein and sugar levels resulted in a significant degradation of lysine. Greater lysine retention was found at a lower temperature and higher feed moisture. Results of sugar retention also showed similar patterns. The products made from fructose had greater lysine retention than products made from galactose with any type of protein. The outcomes of this research suggested that the combination of milk protein and fructose at a lower temperature and higher feed moisture is most favorable for developing high-protein extruded products.

The Omp85 family of proteins is essential for outer membrane biogenesis in mitochondria and bacteria

Integral proteins in the outer membrane of mitochondria control all aspects of organelle biogenesis, being required for protein import, mitochondrial fission, and, in metazoans, mitochondrial aspects of programmed cell death. How these integral proteins are assembled in the outer membrane had been unclear. In bacteria, Omp85 is an essential component of the protein insertion machinery, and we show that members of the Omp85 protein family are also found in eukaryotes ranging from plants to humans. In eukaryotes, Omp85 is present in the mitochondrial outer membrane. The gene encoding Omp85 is essential for cell viability in yeast, and conditional omp85 mutants have defects that arise from compromised insertion of integral proteins like voltage-dependent anion channel (VDAC) and components of the translocase in the outer membrane of mitochondria (TOM) complex into the mitochondrial outer membrane.