ORCID Profile
0000-0002-1188-8960
Current Organisations
University of Calgary
,
James Cook University
,
University of Glasgow
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Publisher: MDPI AG
Date: 04-06-2019
DOI: 10.3390/JCDD6020022
Abstract: Ischemic preconditioning (IPC) and activation of ATP-sensitive potassium channels (KATP) protect cardiac myocytes from ischemia reperfusion (IR) injury. We investigated the influence of IR injury, IPC and KATP in isolated rat cardiac fibroblasts. Hearts were removed under isoflurane anesthesia. IR was simulated in vitro by application and removal of paraffin oil over pelleted cells. Ischemia (30, 60 and 120 min) followed by 60 min reperfusion resulted in significant differentiation of fibroblasts into myofibroblasts in culture (mean % fibroblasts ± SEM in IR vs. time control: 12 ± 1% vs. 63 ± 2%, 30 min ischemia 15 ± 3% vs. 71 ± 4%, 60 min ischemia 8 ± 1% vs. 55 ± 2%, 120 min ischemia). IPC (15 min ischemia, 30 min reperfusion) significantly attenuated IR-induced fibroblast differentiation (52 ± 3%) compared to 60 min IR. IPC was mimicked by opening KATP with pinacidil (50 μM 43 ± 6%) and by selectively opening mitochondrial KATP (mKATP) with diazoxide (100 μM 53 ± 3%). Furthermore, IPC was attenuated by inhibiting KATP with glibenclamide (10 μM 23 ± 5%) and by selectively blocking mKATP with 5-hydroxydecanoate (100 μM 22 ± 9%). These results suggest that (a) IR injury evoked cardiac fibroblast to myofibroblast differentiation, (b) IPC attenuated IR-induced fibroblast differentiation, (c) KATP were involved in IPC and (d) this protection involved selective activation of mKATP.
Publisher: Informa UK Limited
Date: 25-08-2016
Publisher: Oxford University Press (OUP)
Date: 22-06-2011
DOI: 10.1093/CVR/CVR179
Abstract: We investigated the role of the inward rectifier K(+) channel (K(IR)) in the renal interlobular artery (ILA). The ILA supplies the afferent arteriole and ranges in diameter from >100 µm near its origin at the arcuate artery to intermediate > proximal) mirrors the distribution of I(KIR) reported in the present study, further supporting a role for I(KIR). Our findings indicate differences in the magnitude of I(KIR) along the ILA and suggest that the influence of K(IR) on reactivity increases as vessel diameter decreases from proximal to distal regions.
Publisher: MDPI AG
Date: 21-09-2021
Abstract: Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation.
Publisher: Public Library of Science (PLoS)
Date: 22-09-2015
Publisher: Springer International Publishing
Date: 2015
Publisher: Elsevier BV
Date: 06-2007
Publisher: Portland Press Ltd.
Date: 06-2015
DOI: 10.1042/BST20150035
Abstract: Gap junctions are channels which allow electrical signals to propagate through the heart from the sinoatrial node and through the atria, conduction system and onwards to the ventricles, and hence are essential for co-ordinated cardiac contraction. Twelve connexin (Cx) proteins make up one gap junction channel, of which there are three main subtypes in the heart Cx40, Cx43 and Cx45. In the cardiac myocyte, gap junctions are present mainly at the intercalated discs between neighbouring myocytes, and assist in rapid electrical conduction throughout the ventricular myocardium. Fibroblasts provide the structural skeleton of the myocardium and fibroblast numbers significantly increase in heart disease. Fibroblasts also express connexins and this may facilitate heterocellular electrical coupling between myocytes and fibroblasts in the setting of cardiac disease. Interestingly, cardiac fibroblasts have been demonstrated to increase Cx43 expression in experimental models of myocardial infarction and functional gap junctions between myocytes and fibroblasts have been reported. Therefore, in the setting of heart disease enhanced cardiac myocyte: fibroblast coupling may influence the electrical activity of the myocyte and contribute to arrhythmias.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1992
Abstract: To explore a possible role for adenosine in the pathogenesis of the splanchnic hyperemia of cirrhosis, we administered 8-phenyltheophylline, a specific adenosine receptor antagonist, to rats with biliary cirrhosis caused by bile duct ligation and to control sham-operated rats. Micro-Doppler flow studies showed that a 10-mumol/kg dose of 8-phenyltheophylline completely abolished the superior mesenteric hyperemic response to infusions of exogenous adenosine in both cirrhotic and control rats. Analysis of regional blood flows by radioactive microspheres demonstrated that this dose of 8-phenyltheophylline in cirrhotic rats significantly increased portal tributary vascular resistance by 60% and decreased portal tributary blood flow by 26%. This decrease was entirely the result of a 42% reduction in the intestinal blood flow. 8-phenyltheophylline did not affect cardiac output, arterial pressure or any other extrasplanchnic hemodynamic variables in cirrhotic rats. No detectable effect of 8-phenyltheophylline was seen in sham-operated rats. These results suggest that adenosine may be involved in the genesis of splanchnic hyperemia in cirrhotic rats.
Publisher: MDPI AG
Date: 05-07-2022
DOI: 10.3390/JCDD9070217
Abstract: Cardiovascular diseases (CVDs) are a significant burden globally and are especially prevalent in obese and/or diabetic populations. Epicardial adipose tissue (EAT) surrounding the heart has been implicated in the development of CVDs as EAT can shift from a protective to a maladaptive phenotype in diseased states. In diabetic and obese patients, an elevated EAT mass both secretes pro-fibrotic ro-inflammatory adipokines and forms intramyocardial fibrofatty infiltrates. This narrative review considers the proposed pathophysiological roles of EAT in CVDs. Diabetes is associated with a disordered energy utilization in the heart, which promotes intramyocardial fat and structural remodeling. Fibrofatty infiltrates are associated with abnormal cardiomyocyte calcium handling and repolarization, increasing the probability of afterdepolarizations. The inflammatory phenotype also promotes lateralization of connexin (Cx) proteins, undermining unidirectional conduction. These changes are associated with conduction heterogeneity, together creating a substrate for atrial fibrillation (AF). EAT is also strongly implicated in coronary artery disease (CAD) inflammatory adipokines from peri-vascular fat can modulate intra-luminal homeostasis through an “outside-to-inside” mechanism. EAT is also a significant source of sympathetic neurotransmitters, which promote progressive diastolic dysfunction with eventual cardiac failure. Further investigations on the behavior of EAT in diabetic/obese patients with CVD could help elucidate the pathogenesis and uncover potential therapeutic targets.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2008
Publisher: Wiley
Date: 08-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-06-2002
DOI: 10.1161/01.RES.0000024262.11534.18
Abstract: The kinetic attributes of the afferent arteriole myogenic response were investigated using the in vitro perfused hydronephrotic rat kidney. Equations describing the time course for pressure-dependent vasoconstriction and vasodilation, and steady-state changes in diameter were combined to develop a mathematical model of autoregulation. Transfer functions were constructed by passing sinusoidal pressure waves through the model. These findings were compared with results derived using data from instrumented conscious rats. In each case, a reduction in gain and increase in phase were observed at frequencies of 0.2 to 0.3 Hz. We then examined the impact of oscillating pressure signals. The model predicted that pressure signals oscillating at frequencies above the myogenic operating range would elicit a sustained vasoconstriction the magnitude of which was dependent on peak pressure. These predictions were directly confirmed in the hydronephrotic kidney. Pressure oscillations presented at frequencies of 1 to 6 Hz elicited sustained afferent vasoconstrictions and the magnitude of the response depended exclusively on the peak pressure. Elevated systolic pressure elicited vasoconstriction even if mean pressure was reduced. These findings challenge the view that the renal myogenic response exists to maintain glomerular capillary pressure constant, but rather imply a primary role in protecting against elevated systolic pressures. Thus, the kinetic features of the afferent arteriole allow this vessel to adjust tone in response to changes in systolic pressures presented at the pulse rate. We suggest that the primary function of this mechanism is to protect the glomerulus from the blood pressure power that is normally present at the pulse frequency.
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.VASCN.2019.106601
Abstract: A volume-pressure sensor and tail-cuff method for monitoring blood pressure is non-invasive and inexpensive. This method requires animals to be restrained or subjected to anesthesia, but comparative effects of these manipulations on hemodynamic parameters have not been documented. Using a volume-pressure sensor and tail-cuff, we serially measured blood pressure and heart rate in normotensive adult male Lewis rats after light isoflurane-induced anesthesia (5% induction, 1% maintenance) and, following untrained restraint. Blood pressure was recorded until the acquisition of three complete measurements without the range of replicate mean arterial pressures exceeding 15 mmHg (steady-state). Averages for the entire series of consecutive measurements indicated that restraint yielded significantly higher systolic and diastolic blood pressure than anesthesia (P < .05), but heart rate was not affected. Following stabilization at steady-state, there were no significant differences in intra- or inter-day hemodynamic values between the restraint and isoflurane groups. The inter-day coefficient of variation for systolic pressure was 13-23% for isoflurane and 9-14% for restraint. Bland-Altman analysis showed wide limits of agreement (±59 mmHg systolic ±49 mmHg diastolic pressure) between restraint and isoflurane measurements. Isoflurane caused more variability but there was agreement in BP evaluation by the isoflurane and restraint methods. Using the VPR system, light isoflurane-induced anesthesia and restraint could effectively be used to screen and quantify overt changes in hemodynamic parameters for cardiovascular research utilizing laboratory rodents.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1111/J.1600-6143.2009.02553.X
Abstract: Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation. Although several therapies can be used to prevent leukocyte recruitment to ischemic vessels (e.g. antiadhesion molecule antibodies), there have been no clinical treatments reported that can prevent initial immediate neutrophil recruitment upon reperfusion. Using intravital microscopy, we describe abrogation of immediate neutrophil recruitment to ischemic microvessels by the K(ATP) antagonist glibenclamide (Glyburide). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (K(ATP)) are important in the control of cell membrane polarization. Here we describe profound hyperpolarization of endothelial cells during hypoxia, and the reduction of this hyperpolarization using glibenclamide. These findings suggest that control of endothelial membrane potential during ischemia may be an important therapeutic tool in avoiding ischemia/reperfusion injury, and therefore, enhancing transplant long-term function.
Publisher: Elsevier BV
Date: 06-2005
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPHEART.01041.2010
Abstract: Chemotactic movement of myofibroblasts is recognized as a common means for their sequestration to the site of tissue injury. Following myocardial infarction (MI), recruitment of cardiac myofibroblasts to the infarct scar is a critical step in wound healing. Contractile myofibroblasts express embryonic smooth muscle myosin, α-smooth muscle actin, as well as collagens I and III. We examined the effects of cardiotrophin-1 (CT-1) in the induction of primary rat ventricular myofibroblast motility. Changes in membrane potential (E m ) and Ca 2+ entry were studied to reveal the mechanisms for induction of myofibroblast migration. CT-1-induced cardiac myofibroblast cell migration, which was attenuated through the inhibition of JAK2 (25 μM AG490), and myosin light chain kinase (20 μM ML-7). Inhibition of K + channels (1 mM tetraethylammonium or 100 μM 4-aminopyridine) and nonselective cation channels by 10 μM gadolinium (Gd 3+ ) significantly reduced migration in the presence of CT-1. CT-1 treatment caused a significant increase in myosin light chain phosphorylation, which could be inhibited by incubation in Ca 2+ -free conditions or by application of AG490, ML-7, and W7 (100 μM calmodulin inhibitor). Monitoring myofibroblast membrane potential with potentiometric fluorescent DiBAC 4 ( 3 ) dye revealed a biphasic response to CT-1 consisting of an initial depolarization followed by hyperpolarization. Increased intracellular Ca 2+ , as assessed by fluo 3, occurred immediately after membrane depolarization and attenuated at the time of maximal hyperpolarization. CT-1 exerts chemotactic effects via multiple parallel signaling modalities in ventricular myofibroblasts, including changes in membrane potential, alterations in intracellular calcium, and activation of a number of intracellular signaling pathways. Further study is warranted to determine the precise role of K + currents in this process.
Publisher: American Physiological Society
Date: 06-2005
DOI: 10.1152/AJPHEART.01220.2004
Abstract: Despite the important roles played by ventricular fibroblasts and myofibroblasts in the formation and maintenance of the extracellular matrix, neither the ionic basis for membrane potential nor the effect of modulating membrane potential on function has been analyzed in detail. In this study, whole cell patch-cl experiments were done using ventricular fibroblasts and myofibroblasts. Time- and voltage-dependent outward K + currents were recorded at depolarized potentials, and an inwardly rectifying K + (Kir) current was recorded near the resting membrane potential (RMP) and at more hyperpolarized potentials. The apparent reversal potential of Kir currents shifted to more positive potentials as the external K + concentration ([K + ] o ) was raised, and this Kir current was blocked by 100–300 μM Ba 2+ . RT-PCR measurements showed that mRNA for Kir2.1 was expressed. Accordingly, we conclude that Kir current is a primary determinant of RMP in both fibroblasts and myofibroblasts. Changes in [K + ] o influenced fibroblast membrane potential as well as proliferation and contractile functions. Recordings made with a voltage-sensitive dye, DiBAC 3 (4), showed that 1.5 mM [K + ] o resulted in a hyperpolarization, whereas 20 mM [K + ] o produced a depolarization. Low [K + ] o (1.5 mM) enhanced myofibroblast number relative to control (5.4 mM [K + ] o ). In contrast, 20 mM [K + ] o resulted in a significant reduction in myofibroblast number. In separate assays, 20 mM [K + ] o significantly enhanced contraction of collagen I gels seeded with myofibroblasts compared with control mechanical activity in 5.4 mM [K + ] o . In combination, these results show that ventricular fibroblasts and myofibroblasts express a variety of K + channel α-subunits and demonstrate that Kir current can modulate RMP and alter essential physiological functions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Lisa Chilton.