| 1. |
- De Basso, Rachel, et al.
(author)
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Increased carotid plaque burden in men with the fibrillin-1 2/3 genotype
- 2014
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In: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 41:9, s. 637-642
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Journal article (peer-reviewed)abstract
- Fibrillin-1 (FBN1) is an important constituent of the vascular wall and earlier studies have indicated an effect of the FBN1 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim of the present study was to determine whether the FBN1 2/3 genotype was associated with the presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects. The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; age 45-69years) recruited from the Malmo Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima-media thickness (IMT) of the carotid artery were assessed by ultrasound. The incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality were monitored over a mean follow-up period of 13.2years. The most common FBN1 genotypes were 2/2, 2/3 and 2/4, which accounted for 92.2% (n=5317) of subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, common carotid artery diameter and intima-media thickness in men and women. The presence of plaque in the carotid artery was higher in men with the 2/3 genotype compared with the 2/2 and 2/4 genotypes (55% vs 46% and 50%, respectively; P=0.007). No similar differences were observed in women. No significant relationship was observed between FBN1 genotypes and the incidence of cardiovascular disease or all-cause mortality. The increased prevalence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates pathological arterial wall remodelling with a more pronounced atherosclerotic burden.
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| 2. |
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| 3. |
- Gnjidic, Danijela, et al.
(author)
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Clinical implications from drug-drug and drug-disease interactions in older people
- 2013
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 40:5, s. 320-325
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Journal article (peer-reviewed)abstract
- This clinical review summarizes the evidence in relation to clinical outcomes from drugdrug and drugdisease interactions in older people. Exposure to drugdrug interactions is associated with increased risk of hospitalization-related outcomes in older people. Drugdisease interactions have been linked with adverse drug interactions and adverse drug events in studies of older people. Although the prevalence of drugdrug and drugdisease interactions is common in older people, there are very limited empirical data on important clinical outcomes from drugdrug and drugdisease interactions. Clinical implications of interactions between drugs and geriatric syndromes such as frailty, falls, cognitive impairment, immobility and urinary incontinence should also be considered in older people.
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| 4. |
- Hansell, Peter, et al.
(author)
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Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension
- 2013
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In: Clinical and experimental pharmacology & physiology. - : Blackwell Publishing. - 0305-1870 .- 1440-1681. ; 40:2, s. 123-137
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Research review (peer-reviewed)abstract
- The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (Qo2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension. The metabolic efficiency for solute transport (Qo2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction. Sustained hyperglycaemia results in increased kidney Qo2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased Qo2 is not matched by a similar increase in O2 delivery. Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function. Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.
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| 5. |
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| 6. |
- Killi, Uday Kumar, et al.
(author)
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Invitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat.
- 2014
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 41:2, s. 139-46
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Journal article (peer-reviewed)abstract
- Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the invitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (<5μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (<5μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (>5μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
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| 7. |
- Liss, Per, et al.
(author)
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Imaging of intrarenal haemodynamics and oxygen metabolism
- 2013
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 40:2, s. 158-167
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Research review (peer-reviewed)abstract
- The interruption of blood flow results in impaired oxygenation and metabolism. This can lead to electrophysiological changes, functional impairment and symptoms in quick succession. Quantitative measures of organ perfusion, perfusion reserve and tissue oxygenation are crucial to assess normal tissue metabolism and function. Magnetic resonance imaging (MRI) provides a number of quantitative methods to assess physiology in the kidney. Blood oxygenation level-dependent (BOLD) MRI provides a method for the assessment of oxygenation. Blood flow to the kidney can be assessed using phase contrast MRI. Dynamic contrast-enhanced MRI and arterial spin labelling (ASL) provide methods to assess tissue perfusion, ASL using the magnetization of endogenous water protons and thus providing a non-invasive method to assess perfusion. The application of diffusion-weighted MRI allows molecular motion in the kidney to be measured. Novel techniques can also be used to assess oxygenation in the renal arteries and veins and, combined with flow measures, provide an estimation of oxygen metabolism. Magnetic resonance imaging provides a synergy of non-invasive techniques to study renal function and the demand for these techniques is likely to be driven by the incentive to avoid the use of contrast media, to avoid radiation and to avoid complications with intervention procedures.
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| 8. |
- Singh, P., et al.
(author)
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Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease
- 2013
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In: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 40:2, s. 138-147
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Journal article (peer-reviewed)abstract
- Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.
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| 9. |
- Carlström, Mattias
(author)
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Causal link between neonatal hydronephrosis and later development of hypertension
- 2010
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 37:2, s. E14-E23
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Journal article (peer-reviewed)abstract
- 1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non-symptomatic hydronephrosis in children has become more conservative, but the long-term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin-angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hypertension. 4. In view of the new knowledge regarding the long-term effects of partial ureteral obstruction, today's non-operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.
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| 10. |
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| 11. |
- Nitescu, Nicoletta, 1974, et al.
(author)
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Urotensin II receptor antagonism does not improve renal hemodynamics or function in rats with endotoxin-induced acute kidney injury.
- 2010
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 37:12, s. 1170-1175
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Journal article (peer-reviewed)abstract
- 1.Urotensin II (U-II) is a vasoactive peptide that influences renal hemodynamics and kidney function. The aim was to examine the effects of the selective U-II receptor antagonist urantide, on renal hemodynamics, oxygenation and function in endotoxemic rats. 2.Endotoxemia was induced in Sprague-Dawley rats by an intraperitoneal dose of lipopolysaccharide (LPS; E Coli O127:B8, 7.5 mg/kg). At 16 h after endotoxin administration, renal clearance experiments were performed in thiobutabarbital anesthetized rats. Groups (1) sham-saline, (2) sham-urantide, (3) LPS-saline and (4) LPS-urantide, received isotonic saline, or urantide (0.2 mg/kg bolus intravenously, followed by an infusion of 1.2 mg/kg/h throughout), after baseline measurements. Kidney function, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark-type microelectrodes) were analyzed during 2 h of drug administration. 3.At baseline, endotoxemic rats showed approximate 50% reductions in glomerular filtration rate (GFR) and RBF (p<0.05), a decline in cortical and outer medullary perfusion and pO(2) (p<0.05), and a significant increase in mean arterial pressure (MAP; p<0.05), compared to saline-injected controls. In sham animals, urantide in a dose that did not significantly influence MAP or RBF, increased GFR (p<0.05 time x treatment interaction) and filtration fraction (p<0.05 treatment effect). However, urantide had no statistically significant effects on any of the investigated variables in endotoxemic rats. 4.These findings indicate that U-II, via the UT receptor, does not contribute to abnormalities in renal hemodynamics and function in endotoxemic rats.
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| 12. |
- Palm, Fredrik, et al.
(author)
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Renal tubulointerstitial hypoxia : Cause and consequence of kidney dysfunction
- 2011
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In: Clinical and experimental pharmacology & physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 38:7, s. 424-430
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Journal article (peer-reviewed)abstract
- 1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia.2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption.3. Tubulointerstitial hypoxia stimulates the production of collagen I and alpha-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction.4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia.5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease.
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| 13. |
- Wang, Ming-De, et al.
(author)
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Agonist function of the recombinant alpha 4 beta 3 delta GABAA receptor is dependent on the human and rat variants of the alpha 4-subunit
- 2010
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In: Clinical and experimental pharmacology & physiology. - : Blackwell Publishing. - 0305-1870 .- 1440-1681. ; 37:7, s. 662-669
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Journal article (peer-reviewed)abstract
- 1. It is known that the alpha(4)-subunit is likely to occur in the brain predominantly in alpha(4)beta(3)delta receptors at extrasynaptic sites. Recent studies have revealed that the alpha(1)-, alpha(4)-, gamma(2)- and delta-subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA(A) receptors containing human (H) and rat (R) alpha(1)/alpha(4)-, beta(2)/beta(3)- and gamma(2S)/delta-subunits in Xenopus oocytes using the two-electrode voltage-clamp technique. 2. Both H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the alpha(4)beta(3)delta combination was more sensitive to agonist action than the alpha(4)beta(3)gamma(2S) receptor, we observed extremely small GABA- and pentobarbital-activated currents at the wild-type H alpha(4)beta(3)delta receptor. However, GABA and pentobarbital activated the wild-type R alpha(4)beta(3)delta receptor with high potency (EC(50) = 0.5 +/- 0.7 and 294 +/- 5 micromol/L, respectively). 3. Substituting the H alpha(4) subunit with R alpha(4) conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC(50) and increased I(max). When the H alpha(4) subunit was combined with the R beta(3) and R delta subunit in a heteropentameric form, the amplitude of GABA- and pentobarbital-activated currents increased significantly compared with the wild-type H alpha(4)beta(3)delta receptor. 4. Thus, the results indicate that the R alpha(4)beta(3)delta, H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) combinations may contribute to functions of extrasynaptic GABA(A) receptors. The presence of the R alpha(4) subunit at recombinant GABA(A) receptors containing the delta-subunit is a strong determinant of agonist action. The recombinant H alpha(4)beta(3)delta receptor is a less sensitive subunit composition in terms of agonist activation.
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