Experimental physiology
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Experimental physiology · Aug 2008
Comparative StudyIontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.
With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed to restore CFTR function in CF. ⋯ Thus, the electrochemical driving forces generated by beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-adrenergic agonists, isoproprenaline and salbutamol, induced sweat secretion only when applied in combination with an adenylyl cyclase activator (forskolin) or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, aminophylline or theophylline). We surmise that to obtain consistent beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are essential. beta-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects.
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Experimental physiology · May 2008
ReviewThe discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice.
During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world, causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS), which is the severe form of acute lung injury (ALI). Interestingly, a novel homologue of angiotensin-converting enzyme, termed angiotensin-converting enzyme 2 (ACE2), has been identified as a receptor for SARS-CoV. Angiotensin-converting enzyme and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (RAS). ⋯ Importantly, our recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo, which can be attenuated by blocking the renin-angiotensin pathway, suggesting that the activation of the pulmonary RAS influences the pathogenesis of ALI/ARDS and SARS.
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Experimental physiology · Sep 2007
Sertraline, a selective serotonin reuptake inhibitor, affects thirst, salt appetite and plasma levels of oxytocin and vasopressin in rats.
We investigated the effects of chronic administration of sertraline (SERT; approximately 20 mg kg(-1) day(-1) in drinking water), a selective serotonin reuptake inhibitor, on water and sodium intake and on plasma levels of oxytocin (OT) and vasopressin (AVP) in basal and stimulated conditions. Basal water intake was reduced in SERT-treated rats. After 24 h of water deprivation, rats treated with SERT for 21 days ingested less water than the control rats (9.7 +/- 0.5 versus 20.0 +/- 0.9 ml, respectively, at 300 min after water presentation, P < 0.0001). ⋯ Sertraline also increased plasma levels of vasopressin and oxytocin (AVP, 2.65 +/- 0.36 versus 1.31 +/- 0.16 pg ml(-1), P < 0.005; OT, 17.16 +/- 1.06 versus 11.3 +/- 1.03 pg ml(-1), P < 0.0009, at the third week post-treatment). These data constitute the first evidence that chronic SERT treatment affects water and sodium intake in rats. These effects seem to be related to the hyponatraemia caused by the higher plasma levels of AVP and OT.
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Experimental physiology · Mar 2007
ReviewGlucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?
A fuller understanding of the central mechanisms involved in controlling food intake and metabolism is likely to be crucial for developing treatments to combat the growing problem of obesity in Westernised societies. Within the hypothalamus, specialized neurones respond to both appetite-regulating hormones and circulating metabolites to regulate feeding behaviour accordingly. Thus, the activity of hypothalamic glucose-excited and glucose-inhibited neurones is increased or decreased, respectively, by an increase in local glucose concentration. ⋯ Whilst the intracellular signalling mechanisms through which glucose-sensing neurones detect changes in the concentration of the sugar have been investigated quite extensively, many elements remain poorly understood. Furthermore, the similarities, or otherwise, with other nutrient-sensing cells, including pancreatic islet cells, are not completely resolved. In this review, we discuss recent advances in this field and explore the potential involvement of AMP-activated protein kinase and other nutrient-regulated protein kinases.
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Experimental physiology · Mar 2007
Differential sensitivity of excitatory and inhibitory synaptic transmission to modulation by nitric oxide in rat nucleus tractus solitarii.
The nucleus tractus solitarii (NTS) is a key central link in control of multiple homeostatic reflexes. A number of studies have demonstrated that exogenous and endogenous nitric oxide (NO) within NTS regulates visceral function, but further understanding of the role of NO in the NTS is hampered by the lack of information about its intracellular actions. We studied effects of NO in acute rat brainstem slices. ⋯ The effects of NO on EPSPs and IPSPs persisted in cells where postsynaptic sGC was blocked by ODQ and therefore were presynaptic, owing to a direct modulation of transmitter release combined with depolarization of presynaptic neurones. Therefore, while lower concentrations of NO may be important for fine tuning of glutamatergic transmission, higher concentrations are required to directly engage GABAergic inhibition. This differential sensitivity of excitatory and inhibitory connections to NO may be important for determining the specificity of the effects of this freely diffusible gaseous messenger.