Julian F R Paton

University of Bristol, Bristol, England, United Kingdom

Are you Julian F R Paton?

Claim your profile

Publications (370)1346.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: We sought to determine the prevalence of asymmetric hypertensive heart disease (HHD) overlapping morphologically with hypertrophic cardiomyopathy (HCM) and to determine predictors of this pattern of hypertensive remodelling. Methods and results: One hundred and fifty hypertensive patients underwent 1.5 T cardiovascular magnetic resonance imaging. Twenty-one patients were excluded due to concomitant cardiac pathology that may confound the hypertrophic response, e.g. myocardial infarction, moderate-severe valvular disease, or other cardiomyopathy. Asymmetric HHD was defined as a segmental wall thickness of ≥15 mm and >1.5-fold the opposing wall in ≥1 myocardial segments, measured from short-axis cine stack at end-diastole. Ambulatory blood pressure, myocardial replacement fibrosis, aortic distensibility and aortoseptal angle were investigated as predictors of asymmetric HHD by multivariate logistic regression. Out of 129 hypertensive subjects (age: 51 ± 15 years, 50% male, systolic blood pressure: 170 ± 30 mmHg, diastolic blood pressure: 97 ± 16 mmHg), asymmetric HHD occurred in 21%. Where present, maximal end-diastolic wall thickness (EDWT) was 17.8 ± 1.9 mm and located exclusively in the basal or mid septum. In asymmetric HHD, aortoseptal angle (114 ± 10° vs. 125 ± 9° vs. 123 ± 12°, P < 0.05, respectively) was significantly reduced compared to concentric left ventricular hypertrophy (LVH) and compared to no LVH, respectively. Aortic distensibility in asymmetric HHD (1.01 ± 0.60 vs. 1.83 ± 1.65 mm(2)/mmHg × 10(3), P < 0.05, respectively) was significantly reduced compared to subjects with no LVH. Age (odds ratio [95th confidence interval]: 1.10 [1.02-1.18], P < 0.05) and indexed LV mass (1.09 [0.98-1.28], P < 0.0001) were significant, independent predictors of asymmetric HDD. Conclusions: Asymmetric HHD morphologically overlapping with HCM, according to the current ESC guidelines, is common. Postulating a diagnosis of HCM on the basis of EDWT of ≥15 mm should be made with caution in the presence of arterial hypertension particular in male subjects with elevated LV mass.
    No preview · Article · Dec 2015 · European Heart Journal Cardiovascular Imaging
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In response to an osmotic challenge, the synthesis of the antidiuretic hormone arginine vasopressin (AVP) increases in the hypothalamus, and this is accompanied by extension of the 3′ poly(A) tail of the AVP mRNA, and the up-regulation of the expression of RNA binding protein Caprin-2. Here we show that Caprin-2 binds to AVP mRNAs, and that lentiviral mediated shRNA knockdown of Caprin-2 in the osmotically stimulated hypothalamus shortens the AVP mRNA poly(A) tail at the same time as reducing transcript abundance. In a recapitulated in vitro system, we confirm that Caprin-2 over-expression enhances AVP mRNA abundance and poly(A) tail length. Importantly, we show that Caprin-2 knockdown in the hypothalamus decreases urine output and fluid intake, and increases urine osmolality, urine sodium concentration, and plasma AVP levels. Thus Caprin-2 controls physiological mechanisms that are essential for the body's response to osmotic stress. DOI: http://dx.doi.org/10.7554/eLife.09656.001
    Full-text · Article · Nov 2015 · eLife Sciences
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The rat Caprin-2 gene. (a) The sequence of full-length rat brain Caprin-2 cDNA. (b) The predicted amino acid sequence of full-length rat brain Caprin-2 protein. (c) Alternatively spliced isoforms of rat brain Caprin-2. (d) Hypothetical functional domains of the rat brain Caprin-2 protein based on alignment to the Xenopus RNG105 protein sequence, a paralogue of the well-analyzed rat Caprin-1 protein, which is highly homologous to Caprin-2. DOI: http://dx.doi.org/10.7554/eLife.09656.014
    Full-text · Dataset · Nov 2015
  • Aihua Li · Eugene Nattie · Julian Paton

    No preview · Article · Nov 2015

  • No preview · Article · Nov 2015

  • No preview · Article · Nov 2015
  • Source
    W. Pijacka · F. McBryde · A.P. Ford · J.F.R. Paton

    Full-text · Article · Nov 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sympathetic nerve activity (SNA) exhibits respiratory modulation. This component of SNA is important - being recruited under cardiorespiratory reflex conditions and elevated in the spontaneously hypertensive (SH) rat - and yet, the exact influence of this modulation on vascular tone is not understood, even in normotensive conditions. We constructed a mathematical model of the sympathetic innervation of an arteriole, and used it to test the hypothesis that respiratory modulation of SNA preferentially increases vasoconstriction compared to a frequency-matched tonic pattern. Simulations supported the hypothesis, where respiratory modulated increases in vasoconstriction were mediated by a noradrenergic mechanism. These predictions were tested in vivo in adult Wistar rats. Stimulation of the sympathetic chain (L3) with respiratory-modulated bursting patterns, revealed that bursting increases vascular resistance (VR) more than tonic stimulation (57.8 ± 3.3% vs 44.8 ± 4.2%; P < 0.001; n = 8). The onset of the VR response was also quicker for bursting stimulation (rise time-constant = 1.98 ± 0.09 s vs 2.35 ± 0.20 s; P < 0.01). In adult SH rats (n = 8), the VR response to bursting (44.6 ± 3.9%) was not different to tonic (37.4 ± 3.5%; P = 0.57). Using both mathematical modelling and in vivo techniques, we have shown that VR depends critically on respiratory modulation and revealed that this pattern-dependency in Wistar rats is due to a noradrenergic mechanism. This respiratory component may therefore contribute to the ontogenesis of hypertension in the pre-hypertensive SH rat - raising VR and driving vascular remodelling. Why adult SH rats do not exhibit a pattern-dependent response is not known, but further modelling revealed that this may be due to dysfunctional NA reuptake. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · The Journal of Physiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post-inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since the pontine Kölliker-Fuse area (KF) drives post-inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) Mecp2 heterozygous mice showed deficiency of GABA perisomatic bouton-like puncta and processes in the KF nucleus; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABAA receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post-inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT.
    No preview · Article · Oct 2015 · The Journal of Physiology

  • No preview · Article · Oct 2015 · Journal of Human Hypertension

  • No preview · Article · Oct 2015 · Journal of Human Hypertension

  • No preview · Article · Oct 2015 · Journal of Human Hypertension

  • No preview · Article · Oct 2015 · Journal of Human Hypertension

  • No preview · Article · Sep 2015 · European Respiratory Journal
  • David J Paterson · Julian F R Paton

    No preview · Article · Jul 2015 · The Journal of Physiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Healthy ageing and alterations in respiratory-sympathetic coupling have been independently linked with heightened sympathetic neural vasoconstrictor activity. We investigated how age influences the respiratory related modulation of muscle sympathetic nerve activity (MSNA), and the association between the rhythmic fluctuations in MSNA and blood pressure that occur with respiration (Traube-Hering Waves; THW). Ten young (22 ± 2 years, mean±SD) and ten older (58 ± 6 years) healthy men were studied while resting supine and breathing spontaneously. MSNA, blood pressure and respiration were simultaneously recorded. Resting values were ascertained and respiratory cycle triggered averaging of MSNA and blood pressure measurements performed. MSNA burst incidence was higher in older individuals (22.7 ± 9.2 vs. 42.2 ± 13.7 bursts·100 heartbeats(-1) P<0.05), and was similarly reduced in the inspiratory to post-inspiratory period in young and older subjects (by ∼25% compared to mid-to-late expiration). A similar attenuation of MSNA burst frequency (bursts per minute), amplitude and total activity (burst frequency × mean burst amplitude) was also observed in the inspiratory to post-inspiratory period in both groups. A significant positive correlation between respiratory related MSNA and THW magnitude was observed in all young (100%) and most older (80%) subjects. These data suggest that the strength of the cyclical inhibition of MSNA during respiration is similar between young and older individuals and thus alterations in respiratory-sympathetic coupling appear not to contribute to the age-related elevation in MSNA. Furthermore, central respiratory-sympathetic coupling plays a role in the generation of THW in both healthy young and older humans. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Experimental physiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold-standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0±15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow-Lyon voltage and product, Cornell voltage and product, Gubner-Ungerleidger voltage and Romhilt-Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2±5.7 vs 26.4±9.4 mm, P<0.05), Cornell product (2540±942 vs 3023±1185 mm • ms, P<0.05) and for Gubner-Ungerleider voltage (18.2±7.1 vs 23.3±1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow-Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension.Journal of Human Hypertension advance online publication, 4 June 2015; doi:10.1038/jhh.2015.58.
    Full-text · Article · Jun 2015 · Journal of human hypertension
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypertensive patients and experimental models of hypertension showed a marked sympatho-excitation. The mechanisms responsible for this sympathetic activation in arterial hypertension (AHT) are not completely elucidated.Our working hypothesis is that the increased sympathetic activity observed in AHT is a result from an elevated sympathetic drive from the rostroventrolateral medulla (RVLM) and the paraventricular nucleus of the hypothalamus (PVN). Both areas are included in the autonomic network and have an increased neuronal activity in hypertensive conditions. A decrease in neuronal excitability in PVN and RVLM was promoted to modulate the central sympathetic activity in spontaneously hypertensive rats (SHR) by the over-expression of a potassium-channel induced by a lentivirus. Telemetry blood pressure (BP) values, autonomic output, baro- and chemoreceptor function and molecular signalling in hypertensive target organ were evaluated. Chronic over-expression of potassium-channels in the PVN and RVLM caused a sustained decrease in systolic (26mmHg, 39mmHg), diastolic (22mmHg, 40mmHg) and mean BP (22mmHg,40mmHg) in conscious unrestrained SHR. This BP decrease were accompanied by a decrease in sympathetic-output as revealed indirectly by a decrease in the low frequencies band of systolic BP (from 0.79 ± 0.13 to 0.42 ± 0.09mmHg2 and from 0.69 ± 0.11 to 0.42 ± 0.10mmHg2,p < 0.05) in PVN and RVLM, respectively, at 60 days post-microinjection.In the PVN the baro- and chemoreceptor function were restored but no changes were observed in the RVLM. Signalling changes occurred in heart, kidney and vessels, mainly through the up-regulation of angiotensinogen and AT-2 genes in the kidney and down-regulation of AT-1 receptors in the heart. These results give support to PVN and RVLM role as powerful sites to control BP in neurogenic hypertension and we expect, by identifying the role of these central areas, to provide realistic targets for therapeutic interventions.
    No preview · Article · Jun 2015 · Journal of Hypertension
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The polyamines spermidine and spermine are small cations present in all living cells. In the brain, these cations are particularly abundant in the neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, which synthesise the neuropeptide hormones arginine vasopressin (AVP) and oxytocin (OT). We recently reported increased mRNA expression of antizyme inhibitor 1 (Azin1), an important regulator of polyamine synthesis, in rat SON and PVN as a consequence of 3 days of dehydration (DH). Here, we show that Azin1 protein is highly expressed in both AVP and OT positive magnocellular neurons of the SON and PVN, together with antizyme 1 (AZ1), ornithine decarboxylase (ODC) and polyamines. Azin1 mRNA expression increased in the SON and PVN as a consequence of DH, salt loading (SL) and by acute hypertonic stress. In organotypic hypothalamic cultures, addition of the irreversible ODC inhibitor DL-2-(Difluoromethyl)-ornithine hydrochloride (DFMO) significantly increased the abundance of heteronuclear AVP (hnAVP), but not hnOT. To identify the function of Azin1 in vivo, lentiviral vectors that either over-express or knockdown Azin1 were stereotaxically delivered into the SON and/or PVN. Azin1 shRNA delivery resulted in decreased plasma osmolality and had a significant effect on food intake. The expression of AVP mRNA was also significantly increased in the SON by Azin1 shRNA. In contrast, Azin1 overexpression in the SON decreased AVP mRNA expression. We have therefore identified Azin1, and hence by inference polyamines, as novel regulators of the expression of the AVP gene.
    Full-text · Article · May 2015 · Endocrinology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Arginine vasopressin (AVP) is synthesised in magnocellular neurons (MCNs) of supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In response to the hyperosmotic stressors of dehydration (complete fluid deprivation, DH) or salt loading (drinking 2% salt solution, SL), AVP synthesis increases in MCNs, which over-burdens the protein folding machinery in the endoplasmic reticulum (ER). ER stress and the unfolded protein response (UPR) are signaling pathways that improve ER function in response to the accumulation of misfold/unfold protein. We asked whether an ER stress response was activated in the SON and PVN of DH and SL rats. We observed increased mRNA expression for the immunoglobulin heavy chain binding protein (BiP), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), and cAMP responsive element binding protein 3 like 1 (Creb3l1) in both SON and PVN of DH and SL rats. Although we found no changes in the splicing pattern of X box-binding protein 1 (Xbp1), an increase in the level of the unspliced form of Xbp1 (Xbp1U) was observed in DH and SL rats. CREB3L1, a novel ER stress inducer, has been shown to be activated by ER stress to regulate the expression of target genes. We have previously shown that CREB3L1 is a transcriptional regulator of the AVP gene; however, a role for CREB3L1 in the response to ER stress has yet to be investigated in MCNs. Here, we used lentiviral vectors to introduce a dominant negative form of CREB3L1 (CREB3L1DN) in the rat SON. Expression of CREB3L1DN in the SON decreased Chop and Xbp1U mRNA levels, but not BiP and Atf4 transcript expression. CREB3L1 is thus implicated as a transcriptional mediator of the ER stress response in the osmotically stimulated SON.
    Full-text · Article · Apr 2015 · PLoS ONE

Publication Stats

9k Citations
1,346.95 Total Impact Points

Institutions

  • 1995-2015
    • University of Bristol
      • School of Physiology and Pharmacology
      Bristol, England, United Kingdom
  • 2014
    • University of Auckland
      • Faculty of Medical and Health Sciences
      Окленд, Auckland, New Zealand
  • 2010
    • Drexel University College of Medicine
      • Department of Neurobiology & Anatomy
      Philadelphia, PA, United States
  • 2007
    • Geisel School of Medicine at Dartmouth
      • Department of Physiology and Neurobiology
      Hanover, New Hampshire, United States
  • 2005
    • Wayne State University
      • Department of Physiology
      Detroit, MI, United States
  • 2003
    • McKnight Brain Institute
      Gainesville, Florida, United States
  • 2002
    • Dartmouth–Hitchcock Medical Center
      LEB, New Hampshire, United States
  • 2001
    • Drexel University
      • School of Biomedical Engineering, Science and Health Systems
      Filadelfia, Pennsylvania, United States
  • 1994
    • Georg-August-Universität Göttingen
      • III. Physical Institute
      Göttingen, Lower Saxony, Germany