The Journal of physiology
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The Journal of physiology · Feb 2011
Comparative StudyAngiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor.
The renin–angiotensin system (RAS) regulates blood pressure mainly via the actions of angiotensin (Ang)II, generated via angiotensin converting enzyme (ACE). The ACE homologue ACE2 metabolises AngII to Ang1-7, decreasing AngII and increasing Ang1-7, which counteracts AngII activity via the Mas receptor. However, ACE2 also converts AngI to Ang1-9, a poorly characterised peptide which can be further converted to Ang1-7 via ACE. ⋯ Radioligand binding assays demonstrated that Ang1-9 was able to bind the AT2R (pKi = 6.28 ± 0.1). In summary, we ascribe a direct biological role for Ang1-9 acting via the AT2R. This has implications for RAS function and identifying new therapeutic targets in cardiovascular disease.
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The Journal of physiology · Feb 2011
Randomized Controlled Trial Comparative StudyChronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans.
We have previously shown that insulin increases muscle total carnitine (TC) content during acute i.v. l-carnitine infusion. Here we determined the effects of chronic l-carnitine and carbohydrate (CHO; to elevate serum insulin) ingestion on muscle TC content and exercise metabolism and performance in humans. On three visits, each separated by 12 weeks, 14 healthy male volunteers (age 25.9 ± 2.1 years, BMI 23.0 ± 0.8 kg m−2) performed an exercise test comprising 30 min cycling at 50% , 30 min at 80% , then a 30 min work output performance trial. ⋯ The Carnitine group increased work output 11% from baseline in the performance trial, while Control showed no change. This is the first demonstration that human muscle TC can be increased by dietary means and results in muscle glycogen sparing during low intensity exercise (consistent with an increase in lipid utilisation) and a better matching of glycolytic, PDC and mitochondrial flux during high intensity exercise, thereby reducing muscle anaerobic ATP production. Furthermore, these changes were associated with an improvement in exercise performance.
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The Journal of physiology · Feb 2011
Comparative StudyRegulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents.
The ventrolateral pons contains the A5 group of noradrenergic neurons which regulate the circulation and probably breathing. The present experiments were designed to identify these neurons definitively in vivo, to examine their response to chemoreceptor stimuli (carotid body stimulation and changes in brain pH) and to determine their effects on sympathetic outflow. Bulbospinal A5 neurons, identified by juxtacellular labelling in anaesthetized rats, had a slow regular discharge, were vigorously activated by peripheral chemoreceptor stimulation with cyanide, but only mildly activated by hyperoxic hypercapnia (central chemoreceptor stimulation). ⋯ In summary, adult A5 noradrenergic neurons are vigorously activated by carotid body stimulation. This effect presumably contributes to the increase in visceral sympathetic nerve activity elicited by acute hypoxia. A5 neurons respond weakly to hypercapnia in vivo or to changes in pH in slices suggesting that their ability to sense local variations in brain pH or Pco₂ is limited.
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The Journal of physiology · Feb 2011
Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated resurgent sodium currents.
Abnormal pain sensitivity associated with inherited and acquired pain disorders occurs through increased excitability of peripheral sensory neurons in part due to changes in the properties of voltage-gated sodium channels (Navs). Resurgent sodium currents (I(NaR)) are atypical currents believed to be associated with increased excitability of neurons and may have implications in pain. ⋯ We show that changes in Nav1.7 function due to mutations associated with PEPD, but not IEM, are important in I(NaR) generation, suggesting that I(NaR) may play a role in pain associated with PEPD. This knowledge provides us with a better understanding of the mechanism of I(NaR) generation and may lead to the development of specialized treatment for pain disorders associated with I(NaR).