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Autonomic and neuroendocrine dysfunction in chronic disease

The following papers were presented at a symposium entitled: ‘Autonomic and neuroendocrine dysfunction in chronic disease’ that took place at the University of São Paulo, Ribeirão Preto, Brazil, 7–9 August 2014. The symposium was organised by Professors Jose Antunes Rodrigues (University of São Paulo) and David Murphy (University of Bristol) with the aim to focus on the integrated autonomic, neuroendocrine and behavioural mechanisms that function to control cardiovascular homeostasis in health and disease. These five presentations illustrate the state-of-the-art in the field of autonomic control of homeostasis from gene to behaviour. A brief synopsis of each presentation follows. The ability of circulating factors such as salt, plasma osmolality and hormones to influence the activity of brain nuclei have been known for a long while. One route of communication is via circumventricular organs (CVOs) characterised by neurones embedded in a dense network of highly fenestrated capillaries; these allow circulating factors to modulate the activity of CVO neurones that are important, for example in hydromineral homeostasis. Hindmarch & Ferguson (2016) have performed, for the first time, a transcriptomic analysis of one CVO, the subfornical organ (SFO). In addition to confirming receptors predicted to be present based on previous experimental evidence, they reveal receptors for a number of factors controlling metabolism such as leptin and adiponectin. They show how food withdrawal for 48 h, or dehydration, affects the expression of these receptors demonstrating substantial plasticity based on physiological state. Thus, the SFO forms an integrative interface between blood-borne agents and homeostatic pathways within the central nervous system that is remarkably plastic. An interesting new route through which blood-borne agents may affect the central nervous system in pathophysiological conditions was described by Biancardi & Stern (2016). Remarkably, they show that the blood–brain barrier (BBB) becomes permeable in conditions of hypertension. An agent that triggers BBB permeabilisation was shown to be circulating angiotensin II. These authors propose that this breakdown of barrier function allows angiotensin II to cross the BBB to activate microglia and set off a cascade of pro-inflammatory reactions in the brain that contribute to the further excitation of sympathoexcitatory networks and advancement of the hypertensive condition. Given that angiotensin II plays a pivotal role in the pathogenesis of cardiovascular diseases, an understanding of how the angiotensin type 1a receptor (AT1a) triggers a plethora of different intracellular signalling pathways and how these might be differentially antagonised is unknown but clinically most relevant. Adenine, uracil and guanine (AUG) is the most common start codon that codes for methionine. Yosten et al. (2016) report that AUGs and short open reading frames exist in the 5′-leader sequence of the gene encoding the AT1a receptor. They propose that the multiple start codons in the 5′-leader sequence may regulate translation. They show that the presence of upstream AUG sequences can inhibit both downstream receptor translation and receptor signal transduction. They demonstrate that a seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor inhibits non-G protein-coupled signalling of angiotensin II but is without effect on the classical G protein-coupled pathway. Such an exciting finding may now allow new antagonists to be developed that block selected signalling pathways stimulated by angiotensin II. This clearly has potential for numerous cardiovascular diseases in which angiotensin II activity is predominant. Little is known about the control of hydromineral homeostasis during sickness. De Luca et al. (2016) used non-septic doses of lipopolysaccharide (LPS) in rodents to induce sickness and found a reduction in thirst and sodium appetite even in sodium-depleted animals. These responses were abolished by blocking α2-adenoceptors using either systemic or intra-cerebroventricular administration of antagonists. The authors describe how non-septic doses of LPS trigger characteristic behavioural responses associated with sickness and via a cascade system involving central noradrenergic neuronal networks trigger a release of cytokines that act on the neurohypophysial system causing a reduction of water and salt ingestion. Given their essential role in body function, these studies may have important clinical implications in correcting hydromineral imbalance in patients. This may be particularly relevant to those on drugs that act centrally to modulate α2-adrenoceptors such as clonidine used for the treatment of high blood pressure. Another homeostatic process is in the control of food intake. Leptin released by adipocytes is known to have direct effects on the brain to control food appetite. This system appears disrupted in conditions of obesity. Obesity is often associated with breathing problems where physical obstruction of the upper airway plays a role. However, changes within the central nervous system can also contribute to breathing irregularities, apnoeas and loss of airway tone especially during sleep. Bassi et al. (2016) reveal a potential central nervous system mechanism involving leptin affecting neural regulation of respiration. They review how leptin normally stimulates breathing and sensitises the peripheral chemoreceptor reflex through excitatory actions on melanocortin type 4 receptors on pro-opiomelanocortin neurones in the arcuate nucleus. The authors propose how obesity-induced leptin resistance deactivates this excitatory system, contributing to respiratory impairment and suppression.