Carnevali L.,University of Parma |
Bondarenko E.,University of Newcastle |
Sgoifo A.,University of Parma |
Walker F.R.,University of Newcastle |
And 4 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011
In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= -23 ± 3 beats per minute (bpm)] and light/inactive (Δ= -20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= -54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methylscopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= -16 ±3 bpm, inactive phase Δ= -19 ±2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosteroneindependent. © 2011 the American Physiological Society. Source
Burke S.L.,Baker IDI Heart and Diabetes Institute |
Prior L.J.,Baker IDI Heart and Diabetes Institute |
Lukoshkova E.V.,National Cardiology Research Center |
Lim K.,Baker IDI Heart and Diabetes Institute |
And 6 more authors.
Chronobiology International | Year: 2013
Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk. BP, HR, and RSNA were measured daily in the home cage via implanted telemeters. Baseline BP, HR, and RSNA over 24 h were 71 ± 1 mm Hg, 205 ± 4 beats/min and 7 ± 1 normalized units (nu). The 24-h pattern was entrained to the feeding cycle and values increased from preprandial minimum to postprandial maximum by 4 ± 1 mm Hg, 51 ± 6 beats/min, and 1.6 ± .6 nu each day. Feeding of a HFD markedly diminished the preprandial dip after 2 d (79-125% of control; p < 0.05) and this reduction lasted for 3 wks of HFD. Twenty-four-hour BP, HR, and RSNA concurrently increased by 2%, 18%, and 22%, respectively. Loss of preprandial dipping accounted for all of the BP increase and 50% of the RSNA increase over 3 wks and the 24-h rhythm became entrained to the light-dark cycle. Resumption of a NFD did not alter the BP preprandial dip. Thus, elevated BP induced by a HFD and mediated by increased sympathetic nerve activity results from a reduction in preprandial dipping, from the first day. Increased calories, glucose, insulin, and leptin may account for early changes, whereas long-term loss of dipping may be related to increased sensitivity of sympathetic pathways. © Informa Healthcare USA, Inc. Source
Danilov S.M.,University of Illinois at Chicago |
Danilov S.M.,National Cardiology Research Center |
Kalinin S.,University of Illinois at Chicago |
Chen Z.,University of Illinois at Chicago |
And 6 more authors.
PLoS ONE | Year: 2010
Background: Angiotensin-converting enzyme (ACE; Kininase II; CD143) hydrolyzes small peptides such as angiotensin I, bradykinin, substance P, LH-RH and several others and thus plays a key role in blood pressure regulation and vascular remodeling. Complete absence of ACE in humans leads to renal tubular dysgenesis (RTD), a severe disorder of renal tubule development characterized by persistent fetal anuria and perinatal death. Methodology/Principal Findings: Patient with RTD in Lisbon, Portugal, maintained by peritoneal dialysis since birth, was found to have a homozygous substitution of Arg for Glu at position 1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of plasma ACE activity; both parents and a brother who are heterozygous carriers of this mutation had exactly half-normal plasma ACE activity compared to healthy individuals. We hypothesized that the Q1069R substitution impaired ACE trafficking to the cell surface and led to accumulation of catalytically inactive ACE in the cell cytoplasm. CHO cells expressing wild-type (WT) vs. Q1069R-ACE demonstrated the mutant accumulates intracellularly and also that it is significantly degraded by intracellular proteases. Q1069R-ACE retained catalytic and immunological characteristics of WT-ACE N domain whereas it had 10-20% of the nativity of the WT-ACE C domain. A combination of chemical (sodium butyrate) or pharmacological (ACE inhibitor) chaperones with proteasome inhibitors (MG 132 or bortezomib) significantly restored trafficking of Q1069R-ACE to the cell surface and increased ACE activity in the cell culture media 4-fold. Conclusions/Significance: Homozygous Q1069R substitution results in an ACE trafficking and processing defect which can be rescued, at least in cell culture, by a combination of chaperones and proteasome inhibitors. Further studies are required to determine whether similar treatment of individuals with this ACE mutation would provide therapeutic benefits such as concentration of primary urine. © 2010 Danilov et al. Source
Morecroft I.,University of Glasgow |
White K.,University of Glasgow |
Caruso P.,University of Glasgow |
Nilsen M.,University of Glasgow |
And 7 more authors.
Molecular Therapy | Year: 2012
Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of a gene therapy approach to PAH using selective inhibition of PAEC-Tph1 in vivo in a hypoxic model of PAH. We exposed cultured bovine pulmonary arterial smooth muscle cells (bPASMCs) to conditioned media from human PAECs (hPAECs) before and after hypoxic exposure. Serotonin levels were increased in hypoxic PAEC media. Conditioned media evoked bPASMC proliferation, which was greater with hypoxic PAEC media, via a serotonin-dependent mechanism. In vivo, adenoviral vectors targeted to PAECs (utilizing bispecific antibody to angiotensin-converting enzyme (ACE) as the selective targeting system) were used to deliver small hairpin Tph1 RNA sequences in rats. Hypoxic rats developed PAH and increased lung Tph1. PAEC-Tph1 expression and development of PAH were attenuated by our PAEC-Tph1 gene knockdown strategy. These results demonstrate that hypoxia induces Tph1 activity and selective knockdown of PAEC-Tph1 attenuates hypoxia-induced PAH in rats. Further investigation of pulmonary endothelial-specific Tph1 inhibition via gene interventions is warranted. © The American Society of Gene & Cell Therapy. Source
Metzger R.,University of Leipzig |
Franke F.E.,Justus Liebig University |
Bohle R.M.,Saarland University |
Alhenc-Gelas F.,University of Paris Descartes |
And 2 more authors.
Microvascular Research | Year: 2011
Angiotensin I-converting enzyme (kininase II, ACE, CD143) availability is a determinant of local angiotensin and kinin concentrations and physiological actions. Limited information is available on ACE synthesis in peripheral vascular beds. We studied the distribution of ACE along the human and rat vascular tree, and determined whether the enzyme was uniformly distributed in all endothelial cells (EC) or if differences occurred among vessels and organs.The distribution of ACE was assessed by using a panel of anti-human ACE monoclonal antibodies and serial sections of the entire vascular tree of humans. Comparison was made with other EC markers. EC of small muscular arteries and arterioles displayed high ACE immunoreactivity in all organs studied except the kidney, while EC of large arteries and of veins were poorly reactive or completely negative. Only 20% on average of capillary EC in each organ, including the heart, stained for ACE, with the remarkable exception of the lung and kidney. In the lung all capillary EC were labeled intensively for ACE, whereas in the kidney the entire vasculature was devoid of detectable enzyme. In contrast to the man, the rat showed homogeneous endothelial expression of ACE in all large and middle-sized arteries, and in veins, but in renal vessels ACE expression was reduced.This study documents a vessel, organ and species specific pattern of distribution of endothelial ACE. The markedly reduced ACE content of the renal vasculature may protect the renal circulation against excess angiotensin II formation and kinin depletion, and maintain high renal blood flow. © 2010 Elsevier Inc. Source