Experimental physiology
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Experimental physiology · Jan 2019
ReviewEndocrine regulation of gut function - a role for glucagon-like peptide-1 in the pathophysiology of irritable bowel syndrome.
What is the topic of this review? Pathophysiological changes linked to irritable bowel syndrome (IBS) include stress and immune activation, changes in gastrointestinal microbial and bile acid profiles and sensitization of extrinsic and intrinsic gut neurons. This review explores the potential role for L-cells in these pathophysiological changes. What advances does it highlight? L-cells, which secrete glucagon-like peptide-1 in response to nutrients, microbial factors, bile acids and short-chain fatty acids, may sense IBS-related changes in the luminal environment. Glucagon-like peptide-1 can act as a hormone, a paracrine factor or a neuromodulatory factor and, through its actions on central or peripheral neurons, may play a role in gastrointestinal dysfunction. ⋯ The prevalent and debilitating functional bowel disorder, irritable bowel syndrome (IBS), is characterized by symptoms that include abdominal pain, bloating, diarrhoea and/or constipation. The heterogeneity of IBS underscores a complex multifactorial pathophysiology, which is not completely understood but involves dysfunction of the bi-directional signalling axis between the brain and the gut. This axis incorporates efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurocrine factors and microbial metabolites. L-cells, which are electrically excitable biosensors embedded in the gastrointestinal epithelium, secrete glucagon-like peptide-1 (GLP-1) in response to nutrients in the small intestine. However, they appear to function in a different manner more distally in the gastrointestinal tract, where they are activated by luminal factors including short-chain fatty acids, bile acids and microbial metabolic products, all of which are altered in IBS patients. Glucagon-like peptide-1 can also interact with the hypothalamic-pituitary-adrenal stress axis and the immune system, both of which are activated in IBS. Given that a GLP-1 mimetic has been found to alleviate acute pain symptoms in IBS patients, GLP-1 might be important in the manifestation of IBS symptoms. This review assesses the current knowledge about the role of GLP-1 in IBS pathophysiology and its potential role as a signal transducer in the microbiome-gut-brain signalling axis.
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Experimental physiology · Jul 2017
ReviewImpact of obstructive sleep apnoea and intermittent hypoxia on cardiovascular and cerebrovascular regulation.
What is the topic of this review? This review examines the notion that obstructive sleep apnoea (OSA) and intermittent hypoxia (IH) have hormetic effects on vascular health. What advances does it highlight? Clinical (OSA patient) and experimental animal and human models report that IH is detrimental to vascular regulation. However, mild IH and, by extension, mild OSA also have physiological and clinical benefits. ⋯ In general, data support an independent causal link between OSA and vascular disease, particularly for patients with severe OSA. However, the data are equivocal for older OSA patients and patients with mild OSA, because advanced age and short-duration, low-intensity IH have been reported to provide a degree of protection against IH and ischaemic events such as myocardial infarction and stroke, respectively. Overall, additional studies are needed to investigate the beneficial/detrimental effects of mild OSA on the various vascular beds.
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What is the topic of this review? Pain in infancy. What advances does it highlight? New neurophysiological research on pain processing in the human infant brain. Increased awareness of pain in the newborn has led to the development of numerous assessment tools for use in neonatal intensive care units. ⋯ This review focuses upon two interconnected nociceptive circuits, the spinal cord dorsal horn and the somatosensory cortex in the brain, to highlight what we know and what we do not know about infant pain. The effectiveness of oral sucrose, widely used in clinical practice to relieve infant pain, is discussed as a specific example of what we do not know. This 'hot topic review' highlights the importance of new laboratory-based neurophysiological research for the treatment of newborn infant pain.
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Experimental physiology · Sep 2014
ReviewIntestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4.
The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper-reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper-reabsorption and growth. The endogenous tone of the glucagon-like peptide 1 (GLP-1)/GLP-1 receptor (GLP-1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. ⋯ The GLP-1R agonist exendin-4 induces natriuresis via activation of the GLP-1R. In contrast, DPP4 inhibition increases circulating GLP-1, but drives a GLP-1R-independent natriuretic response, implying a role for other DPP-4 substrates. The extent to which the intrarenal DPP-4/GLP-1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation.
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Experimental physiology · Jan 2014
ReviewStructure and function of voltage-gated sodium channels at atomic resolution.
Voltage-gated sodium channels initiate action potentials in nerve, muscle and other excitable cells. Early physiological studies described sodium selectivity, voltage-dependent activation and fast inactivation, and developed conceptual models for sodium channel function. ⋯ Structural models for voltage-dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function and the opportunity for structure-based discovery of novel therapeutics.