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Taylor D.,University of Hull | Bhandari S.,Hull and East Yorkshire Hospital NHS Trust | Seymour A.-M.L.,University of Hull
American Journal of Physiology - Renal Physiology | Year: 2015

Uremic cardiomyopathy (UCM) is characterized by metabolic remodelling, compromised energetics, and loss of insulin-mediated cardioprotection, which result in unsustainable adaptations and heart failure. However, the role of mitochondria and the susceptibility of mitochondrial permeability transition pore (mPTP) formation in ischemiareperfusion injury (IRI) in UCM are unknown. Using a rat model of chronic uremia, we investigated the oxidative capacity of mitochondria in UCM and their sensitivity to ischemia-reperfusion mimetic oxidant and calcium stressors to assess the susceptibility to mPTP formation. Uremic animals exhibited a 45% reduction in creatinine clearance (P < 0.01), and cardiac mitochondria demonstrated uncoupling with increased state 4 respiration. Following IRI, uremic mitochondria exhibited a 58% increase in state 4 respiration (P < 0.05), with an overall reduction in respiratory control ratio (P < 0.01). Cardiomyocytes from uremic animals displayed a 30% greater vulnerability to oxidant-induced cell death determined by FAD autofluorescence (P < 0.05) and reduced mitochondrial redox state on exposure to 200 µM H2O2 (P < 0.01). The susceptibility to calciuminduced permeability transition showed that maximum rates of depolarization were enhanced in uremia by 79%. These results demonstrate that mitochondrial respiration in the uremic heart is chronically uncoupled. Cardiomyocytes in UCM are characterized by a more oxidized mitochondrial network, with greater susceptibility to oxidant-induced cell death and enhanced vulnerability to calcium-induced mPTP formation. Collectively, these findings indicate that mitochondrial function is compromised in UCM with increased vulnerability to calcium and oxidant-induced stressors, which may underpin the enhanced predisposition to IRI in the uremic heart. © 2015 the American Physiological Society.

Semple D.J.,University of Hull | Bhandari S.,Hull and East Yorkshire Hospital NHS Trust | Seymour A.-M.L.,University of Hull
American Journal of Physiology - Renal Physiology | Year: 2012

Chronic kidney disease is associated with a unique cardiomyopathy, characterized by a combination of structural and cellular remodeling, and an enhanced susceptibility to ischemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway due to insulin resistance. The susceptibility of the uremic heart to ischemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Uremia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischemia was investigated in vitro in control and uremic hearts ± insulin ± rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C-NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immunoprecipitation. Insulin improved postischemic rate pressure product in control but not uremic hearts, [recovered rate pressure product (%), control 59.6 ± 10.7 vs. 88.9 ± 8.5, P < 0.05; uremic 19.3 ± 4.6 vs. 28.5 ± 10.4, P = ns]. Rosiglitazone resensitized uremic hearts to insulin-mediated cardioprotection [recovered rate pressure product (%) 12.7 ± 7.0 vs. 61.8 ± 15.9, P < 0.05]. Myocardial carbohydrate metabolism remained responsive to insulin in uremic hearts. Uremia was associated with increased phosphorylation of Akt (1.00 ± 0.08 vs. 1.31 ± 0.11, P < 0.05) in normoxia, but no change in postischemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased postischemia in uremic hearts (P < 0.05). Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uremic hearts post-ischemia-reperfusion and impaired activation of the reperfusion injury salvage kinase pathway may underlie these findings. © 2012 the American Physiological Society.

Seymour A.-M.L.,University of Hull | Reddy V.,University of Hull | Bhandari S.,Hull and East Yorkshire Hospital NHS Trust
Frontiers in Bioscience - Elite | Year: 2013

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease. The uraemic heart undergoes remodelling and changes in metabolic function. Experimental uraemia produces a reduction in the myocardial energy reserve phosphocreatine in parallel with left ventricular hypertrophy and depletion of serum carnitine. This study investigated the effects of chronic L-carnitine supplementation on myocardial substrate metabolism and function in the experimental uraemia. Experimental uraemia was induced surgically in male Sprague-Dawley rats via a subtotal nephrectomy. Carnitine was administered continuously via subcutaneous mini-osmotic pumps. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C NMR, at 3 and 6 weeks. Uraemic animals exhibited anaemia, kidney dysfunction and systemic carnitine deficiency but no myocardial tissue carnitine deficiency. Myocardial hypertrophy was abolished following carnitine supplementation. This was associated with a reduction in glucose utilisation. In summary carnitine supplementation prevents cardiac hypertrophy, and this effect is amplified with the duration of treatment. This is associated with a reduction in myocardial glucose utilisation but no significant modulation of myocardial function.

Smith K.,University of Hull | Semple D.,University of Hull | Aksentijevic D.,University of Oxford | Bhandari S.,Hull and East Yorkshire Hospital NHS Trust | Seymour A.-M.L.,University of Hull
Frontiers in Bioscience - Elite | Year: 2010

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). The uraemic heart undergoes substantial remodelling, including left ventricular hypertrophy (LVH), an important determinant of heart failure. LVH results in a shift in myocardial substrate oxidation from fatty acids towards carbohydrates however, whether this metabolic adaptation occurs in the uraemic heart is unknown. The aim of this study was to investigate the progression of kidney dysfunction in parallel with cardiac remodelling in experimental uraemia. Experimental uraemia was induced surgically via a subtotal nephrectomy. At 3, 6 and 12 weeks post-surgery, renal function, LVH, in vitro cardiac function and metabolic remodelling using 13C-NMR were assessed. Uraemic animals exhibited anaemia and kidney dysfunction at 3 weeks, with further deterioration as uraemia progressed. By 12 weeks, uraemic hearts showed marked LVH, preserved cardiac function and markedly reduced fatty acid oxidation. This change in substrate preference may contribute to the deterioration of cardiac function in the uraemic heart and ultimately failure.

Scott A.R.,Sheffield Teaching Hospitals NHS Trust | Allan B.,Hull and East Yorkshire Hospital NHS Trust | Dhatariya K.,Norwich University | Flanagan D.,Plymouth Hospitals NHS Trust | And 19 more authors.
Diabetic Medicine | Year: 2015

Hyperglycaemic hyperosmolar state (HHS) is a medical emergency, which differs from diabetic ketoacidosis (DKA) and requires a different approach. The present article summarizes the recent guidance on HHS that has been produced by the Joint British Diabetes Societies for Inpatient Care, available in full at http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_HHS_Adults.pdf. HHS has a higher mortality rate than DKA and may be complicated by myocardial infarction, stroke, seizures, cerebral oedema and central pontine myelinolysis and there is some evidence that rapid changes in osmolality during treatment may be the precipitant of central pontine myelinolysis. Whilst DKA presents within hours of onset, HHS comes on over many days, and the dehydration and metabolic disturbances are more extreme. The key points in these HHS guidelines include: (1) monitoring of the response to treatment: (i) measure or calculate the serum osmolality regularly to monitor the response to treatment and (ii) aim to reduce osmolality by 3-8 mOsm/kg/h; (2) fluid and insulin administration: (i) use i.v. 0.9% sodium chloride solution as the principal fluid to restore circulating volume and reverse dehydration, (ii) fluid replacement alone will cause a fall in blood glucose (BG) level, (iii) withhold insulin until the BG level is no longer falling with i.v. fluids alone (unless ketonaemic), (iv) an initial rise in sodium level is expected and is not itself an indication for hypotonic fluids and (v) early use of insulin (before fluids) may be detrimental; and (3) delivery of care: (i) The diabetes specialist team should be involved as soon as possible and (ii) patients should be nursed in areas where staff are experienced in the management of HHS. © 2015 Diabetes UK.

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