Clinical Science
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Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects 1. In this study an acute anti-hypertensive effect of three anti-oxidant agents (vitamin C, thiopronine and glutathione) in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported.
2. The anti-oxidants had no effect on blood pressure in healthy normal subjects at a dose of 6 mmol, but thiopronine and glutathione produced a significant hypotensive effect at a dose of 12 mmol.
3. These data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.
Clinical Science - Tập 81 Số 6 - Trang 739-742 - 1991
Resolution of acute inflammation and the role of apoptosis in the tissue fate of granulocytes
Clinical Science - Tập 83 Số 6 - Trang 639-648 - 1992
Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease.
Clinical Science - Tập 130 Số 8 - Trang 565-574 - 2016
Activation of haemostasis by exercise, mental stress and adrenaline: effects on platelet sensitivity to thrombin and thrombin generation
Clinical Science - Tập 97 Số 1 - Trang 27 - 1999
Relationship between overnight neuroendocrine activity and morning haemostasis in working men Sustained effects of SNS (sympathetic nervous system) and HPAA (hypothalamic–pituitary–adrenal axis) hyperactivity on haemostasis have not been investigated. In the present study, we tested for an association of overnight urinary catecholamine and cortisol excretion with morning plasma levels of fibrinogen, PAI-1 (plasminogen activator inhibitor-1) and D-dimer. Participants (639 male industrial employees) with a complete dataset were studied (age, 41±11 years; mean±S.D.). Subjects collected overnight urinary samples and had a fasting morning blood sample drawn. Measurement of urinary adrenaline (epinephrine), noradrenaline (norepinephrine) and cortisol were dichotomized to perform multivariate analyses of (co)variance. Haemostatic parameters were measured by ELISA. Fibrinogen was higher in men with high adrenaline (F7,631=5.68, P=0.018; where the subscripted value represents the degrees of freedom) and high noradrenaline (F7,631=4.19, P=0.041) compared with men with low excretion of the respective hormones. PAI-1 was higher in men with high cortisol than in men with low cortisol (F7,631=4.77, P=0.029). Interaction revealed that subjects with high cortisol/low noradrenaline had higher PAI-1 than subjects with low cortisol/high noradrenaline (P=0.038). Subjects with high adrenaline/high noradrenaline had higher D-dimer than subjects with high adrenaline/low noradrenaline (P=0.029), low adrenaline/high noradrenaline (P=0.022) and low adrenaline/low noradrenaline (not significant). When covariance for several confounders of haemostatic function was determined, the main effect of adrenaline on fibrinogen and the interaction between adrenaline and noradrenaline for D-dimer maintained significance. Although overnight SNS hyperactivity was associated independently with morning hypercoagulability, the relationship between the activity of HPAA and haemostasis was mediated by traditional cardiovascular risk factors.
Clinical Science - Tập 107 Số 1 - Trang 89-95 - 2004
Phenolic Content of Various Beverages Determines the Extent of Inhibition of Human Serum and Low-Density Lipoprotein Oxidation <i>in Vitro</i>: Identification and Mechanism of Action of Some Cinnamic Acid Derivatives from Red Wine 1. An antioxidant effect of phenolic substances in red wine to reduce oxidizability of low-density lipoprotein has been proposed as the basis for a relatively lower incidence of coronary disease in populations with high red wine intake. We have now investigated the possible antioxidant effects of various beverages, including red wines, white wines, beers and red grape juices (diluted 1:500), on metal ion-dependent (copper) and -independent (aqueous peroxyl radicals) oxidation of isolated human low-density lipoprotein. We also tested the effects of these beverages on copper-initiated oxidation of lipoproteins in serum.
2. The higher the polyphenolic content of a beverage, the greater was its antioxidative effect measured as change in lag time in the different oxidation systems. Upon stripping the polyphenolics from the drinks, the lag times returned to control levels in isolated low-density lipoprotein; however, the low concentrations of phenolics remaining after stripping had a lesser but still significant effect on oxidation of lipoproteins in serum. The inhibitory effect of these phenolics appeared to be more pronounced for metal ion (copper)-induced oxidation than for those induced by aqueous peroxyl radicals, suggesting that both copper-binding and free radical-trapping activities may be involved. A mixture of the carboxylic acids representative of those present in red wine exhibited no significant effect on lag time of metal iondependent and -independent low-density lipoprotein oxidations. Ethanol, at concentrations of 0.1–0.5%, had no effect on either copper-induced or aqueous peroxyl radical oxidations.
3. Extracts of acid-hydrolysed red wine were separated by thin-layer chromatography and the most active antioxidant fractions identified. GC-MS and HPLC analysis of these fractions resulted in the identification of several cinnamic acid derivatives, such as coumaric acid, caffeic acid and protocatechuic acid. Dose—response studies using the pure compounds indicated that caffeic acid was the most active antioxidant with an IC50 < l μmol/l for copper-initiated low-density lipoprotein oxidation. Caffeic acid (1 μmol/l) significantly inhibited lipid hydroperoxide formation while sparing α-tocopherol consumption. Caffeic acid at the same concentration also inhibits aqueous peroxyl radical-induced oxidation of low-density lipoprotein, sparing α-tocopherol. There was no evidence of caffeic acid preventing the binding of copper to low-density lipoprotein.
4. We conclude that phenolics in both alcoholic and non-alcoholic beverages can give dose-dependent protection against oxidation of low-density lipoprotein. Caffeic acid and protocatechuic acid are two compounds likely to contribute to these effects. These findings may be relevant to the putative cardiovascular-protective effects of high phenolic content alcoholic beverages such as red wine; however, the widespread occurrence of antioxidants such as caffeic acid in fruits and vegetables suggests that these protective principles are not limited to red wine.
Clinical Science - Tập 91 Số 4 - Trang 449-458 - 1996
Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22±1 years) and 11 older (O: 71±3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O=82±3 vs Y=96±1, P=0.002) and NO-dependent vasodilatation (%CVCmax: O=26±6% vs Y=49±5, P=0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax=91±2, P=0.03) and NO-dependent (%CVCmax=43±9%, P=0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O=31±8 vs Y=44±5, P=0.001) and NO-dependent (%CVCmax: O=9±2 vs Y=21±2, P=0.003) vasodilatation. Folic acid increased CVC (%CVCmax=47±5%, P=0.001) and NO-dependent vasodilatation (20±3%, P=0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.
Clinical Science - Tập 129 Số 2 - Trang 159-167 - 2015
Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In the present study, we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative reverse transcription-PCR (RT-PCR), immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors (OXR). In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11, d-Leu15]-Orexin B) exerted similar effects as OR-B, whereas a specific orexin receptor-1 (OX1R) antagonist (SB-408124) did not alter the responsiveness of OR-B. Treatment of the same model with OR-B resulted in a dose-dependent increase in myosin light chain and troponin-I (TnI) phosphorylation. Following ischaemia/reperfusion in the isolated Langendorff perfused rat heart model, OR-B, but not OR-A, exerts a cardioprotective effect; mirrored in an in vivo model as well. Unlike OR-A, OR-B was also able to induce extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2) and Akt phosphorylation in rat myocardial tissue and ERK1/2 phosphorylation in human heart samples. These findings were further corroborated in an in vivo rat model. In human subjects with heart failure, there is a significant negative correlation between the expression of OX2R and the severity of the disease clinical symptoms, as assessed by the New York Heart Association (NYHA) functional classification. Collectively, we provide evidence of a distinct orexin system in the heart that exerts a cardioprotective role via an OR-B/OX2R pathway.
Clinical Science - Tập 132 Số 24 - Trang 2547-2564 - 2018
Role of Orexin-B/Orexin 2 receptor in myocardial protection Abstract
Emerging evidence attributes to orexins/hypocretins (ORs) a protective function in the regulation of cardiovascular responses, heart rate, and hypertension. However, little is known about any direct effect of orexins in the heart function. This is of special relevance considering that cardiovascular diseases, including myocardial infarction and heart failure, are one of the major causes of mortality in the world. In the article published in Clinical Science (2018) (vol. 132, 2547–2564), Patel and colleagues investigated the role of orexins in myocardial protection. Intriguingly, they revealed a source of orexin-A (OR-A) and orexin-B (OR-B) in the heart and cardiomyocytes of the rat. More interestingly, these peptides exert a direct effect on the heart rate by acting in an autocrine/paracrine manner on their respective receptors (OXRs). Indeed, OR-B, but not OR-A, by acting through orexin receptor-2 (OX2R), exerts direct cardioprotective effects in heart failure models. OR-B/OX2R signalling enhances myosin light chain (MLC) and troponin-I (TnI) phosphorylation in a dose-dependent manner, leading to an increase in the strength of their twitch contraction. This effect is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation, both in the rat myocardial tissue and human heart samples. A negative correlation between OX2R expression and clinical severity of symptoms has been found in patients with heart failure. Thus, in addition to the known central effects of orexins/OX2R, the work of Patel and colleagues (Clinical Science (2018) 132, 2547–2564) reports a direct action of OR-B on the heart rate pinpointing to OX2R as a potential therapeutic target for prevention and treatment of cardiovascular disease.
Clinical Science - Tập 133 Số 7 - Trang 853-857 - 2019
Influence of Leucine on Arterial Concentrations and Regional Exchange of Amino Acids in Healthy Subjects 1. l-Leucine was given to healthy, post-absorptive subjects as a continuous intravenous infusion (300 μmol/min) during 2 1/2 h. Arterial blood concentrations and regional exchange of amino acids were measured across the splanchnic region, the brain and a leg, by the catheter technique. Renal clearance of amino acids was also determined.
2. During the infusion of leucine its concentration rose four- to six-fold, while the concentrations of several other amino acids declined continually, the effect being most pronounced for isoleucine (−55% of initial value), methionine (−55%), valine (−40%), tyrosine (−35%) and phenylalanine (−35%).
3. The infused leucine was taken up by muscle tissue (55%), by the splanchnic region (25%) and by the brain (10%). Neither leg-muscle release nor splanchnic uptake of aromatic amino acids was affected. Renal clearance and tubular reabsorption of amino acids were uninfluenced by leucine infusion. The uptake of isoleucine and methionine by the brain, seen in the basal state, was inhibited during leucine infusion.
4. The marked reduction in the concentrations of the aromatic amino acids, the uptake of leucine by the brain and the inhibition of brain methionine uptake, which accompany leucine infusion in healthy subjects,-5-be of relevance for the treatment of patients with portal-systemic encephalopathy.
Clinical Science - Tập 59 Số 3 - Trang 173-181 - 1980
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