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Publication Record


Association of Vitamin D Metabolites With Arterial Function in the Hemodialysis Fistula Maturation Study.
van Ballegooijen AJ, Zelnick L, Hoofnagle AN, Hamburg NM, Robinson-Cohen C, Roy-Chaudhury P, Cheung AK, Shiu YT, de Boer IH, Himmelfarb J, Beck G, Imrey PB, Kusek JW, Kestenbaum B, Hemodialysis Fistula Maturation (HFM) Study Group
(2017) Am J Kidney Dis 69: 805-814
MeSH Terms: 25-Hydroxyvitamin D 2, Adult, Aged, Anastomosis, Surgical, Arteries, Brachial Artery, Calcifediol, Carotid Arteries, Chromatography, Liquid, Cohort Studies, Cross-Sectional Studies, Ergocalciferols, Female, Femoral Artery, Humans, Kidney Failure, Chronic, Male, Middle Aged, Nitroglycerin, Prospective Studies, Pulse Wave Analysis, Radial Artery, Renal Dialysis, Tandem Mass Spectrometry, Vascular Stiffness, Vasodilation, Vasodilator Agents, Veins, Vitamin D
Show Abstract · Added September 19, 2017
BACKGROUND - Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction.
STUDY DESIGN - Cross-sectional.
SETTING & PARTICIPANTS - We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery.
FACTOR - 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery.
OUTCOMES - Vasodilator functions and measurements of arterial stiffness.
MEASUREMENTS - Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use.
RESULTS - Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses.
LIMITATIONS - Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease.
CONCLUSIONS - Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.
Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.
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29 MeSH Terms
Treatment initiation in paediatric pulmonary hypertension: insights from a multinational registry.
Humpl T, Berger RMF, Austin ED, Fasnacht Boillat MS, Bonnet D, Ivy DD, Zuk M, Beghetti M, Schulze-Neick I
(2017) Cardiol Young 27: 1123-1132
MeSH Terms: Adolescent, Antihypertensive Agents, Calcium Channel Blockers, Cardiac Catheterization, Child, Child, Preschool, Female, Humans, Hypertension, Pulmonary, Infant, Male, Phosphodiesterase 5 Inhibitors, Prognosis, Pulmonary Circulation, Pulmonary Wedge Pressure, Registries, Vasodilator Agents
Show Abstract · Added February 21, 2017
Different treatment options for pulmonary hypertension have emerged in recent years, and evidence-based management strategies have improved quality of life and survival in adults. In children with pulmonary vascular disease, therapeutic algorithms are not so clearly defined; this study determined current treatment initiation in children with pulmonary hypertension in participating centres of a registry. Through the multinational Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension registry, patient demographics, diagnosis, and treatment as judged and executed by the local physician were collected. Inclusion criteria were >3 months and <18 years of age and diagnostic cardiac catheterisation consistent with pulmonary hypertension (mean pulmonary arterial pressure ⩾25 mmHg, pulmonary vascular resistance index ⩾3 Wood units×m2, and mean pulmonary capillary wedge pressure ⩽12 mmHg). At diagnostic catheterisation, 217/244 patients (88.9%) were treatment naïve for pulmonary hypertension-targeted therapy. Targeted therapy was initiated after catheterisation in 170 (78.3%) treatment-naïve patients. A total of 19 patients received supportive therapy, 28 patients were not started on therapy, and 26 patients (10.7%) were on targeted treatment before catheterisation. Among treatment-naïve subjects, treatment was initiated with one targeted drug (n=112, 51.6%), dual therapy (n=39, 18%) or triple-therapy (n=5, 2.3%), and calcium channel blockers with one targeted medication in one patient (0.5%). Phosphodiesterase inhibitors type 5 were used frequently; some patients with pulmonary hypertension related to lung disease received targeted therapy. There is a diverse therapeutic approach for children with pulmonary hypertension with a need of better-defined treatment algorithms based on paediatric consensus for different aetiologies including the best possible diagnostic workup.
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17 MeSH Terms
Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration.
Aamodt KI, Aramandla R, Brown JJ, Fiaschi-Taesch N, Wang P, Stewart AF, Brissova M, Powers AC
(2016) Am J Physiol Endocrinol Metab 311: E859-E868
MeSH Terms: Activins, Adenosine, Adenosine A2 Receptor Agonists, Adenosine-5'-(N-ethylcarboxamide), Adult, Automation, Cell Culture Techniques, Cell Proliferation, Drug Evaluation, Preclinical, Erythropoietin, Exenatide, Female, GABA Agents, Harmine, Humans, Incretins, Insulin-Secreting Cells, Male, Middle Aged, Monoamine Oxidase Inhibitors, Myostatin, Nucleosides, Peptides, Platelet-Derived Growth Factor, Prolactin, Regeneration, Serotonin, Serotonin Receptor Agonists, Vasodilator Agents, Venoms, Young Adult, gamma-Aminobutyric Acid
Show Abstract · Added April 26, 2017
Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers. β-Cells from each donor were assessed for their function and ability to enter the cell cycle by cotransduction with adenoviruses encoding cell cycle regulators cdk6 and cyclin D3. Using this approach, we tested 12 previously identified mitogens, including neurotransmitters, hormones, growth factors, and molecules, involved in adenosine and Tgf-1β signaling. Each compound was tested in a wide concentration range either in the presence of basal (5 mM) or high (11 mM) glucose. Treatment with the control compound harmine, a Dyrk1a inhibitor, led to a significant increase in Ki-67 β-cells, whereas treatment with other compounds had limited to no effect on human β-cell proliferation. This new scalable approach reduces the time and effort required for sensitive and specific evaluation of human β-cell proliferation, thus allowing for increased testing of candidate human β-cell mitogens.
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2 Members
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32 MeSH Terms
Vasodilator-responsive idiopathic pulmonary arterial hypertension: evidence for a new disease?
Brittain EL, Hemnes AR
(2015) Ann Intern Med 162: 148-9
MeSH Terms: Capillaries, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Microcirculation, Vasodilator Agents
Added February 10, 2015
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7 MeSH Terms
Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress.
Nazarewicz RR, Dikalova AE, Bikineyeva A, Dikalov SI
(2013) Am J Physiol Heart Circ Physiol 305: H1131-40
MeSH Terms: Animals, Aorta, Blood Pressure, Cell Respiration, Cells, Cultured, Diazoxide, Electron Transport Complex I, Electron Transport Complex II, Endothelial Cells, Humans, Membrane Glycoproteins, Membrane Potential, Mitochondrial, Mice, Mitochondria, NADPH Oxidase 2, NADPH Oxidases, Oxidative Stress, Potassium Channels, Superoxides, Vasodilator Agents
Show Abstract · Added March 30, 2014
Superoxide (O2(·-)) production by the NADPH oxidases is implicated in the pathogenesis of many cardiovascular diseases, including hypertension. We have previously shown that activation of NADPH oxidases increases mitochondrial O2(·-) which is inhibited by the ATP-sensitive K(+) channel (mitoKATP) inhibitor 5-hydroxydecanoic acid and that scavenging of mitochondrial or cytoplasmic O2(·-) inhibits hypertension. We hypothesized that mitoKATP-mediated mitochondrial O2(·-) potentiates cytoplasmic O2(·-) by stimulation of NADPH oxidases. In this work we studied Nox isoforms as a potential target of mitochondrial O2(·-). We tested contribution of reverse electron transfer (RET) from complex II to complex I in mitochondrial O2(·-) production and NADPH oxidase activation in human aortic endothelial cells. Activation of mitoKATP with low dose of diazoxide (100 nM) decreased mitochondrial membrane potential (tetramethylrhodamine methyl ester probe) and increased production of mitochondrial and cytoplasmic O2(·-) measured by site-specific probes and mitoSOX. Inhibition of RET with complex II inhibitor (malonate) or complex I inhibitor (rotenone) attenuated the production of mitochondrial and cytoplasmic O2(·-). Supplementation with a mitochondria-targeted SOD mimetic (mitoTEMPO) or a mitochondria-targeted glutathione peroxidase mimetic (mitoEbselen) inhibited production of mitochondrial and cytoplasmic O2(·-). Inhibition of Nox2 (gp91ds) or Nox2 depletion with small interfering RNA but not Nox1, Nox4, or Nox5 abolished diazoxide-induced O2(·-) production in the cytoplasm. Treatment of angiotensin II-infused mice with RET inhibitor dihydroethidium (malate) significantly reduced blood pressure. Our study suggests that mitoKATP-mediated mitochondrial O2(·-) stimulates cytoplasmic Nox2, contributing to the development of endothelial oxidative stress and hypertension.
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20 MeSH Terms
Safety and feasibility of adjunctive regadenoson injection at peak exercise during exercise myocardial perfusion imaging: The Both Exercise and Regadenoson Stress Test (BERST) trial.
Ross MI, Wu E, Wilkins JT, Gupta D, Shen S, Aulwes D, Montero K, Holly TA
(2013) J Nucl Cardiol 20: 197-204
MeSH Terms: Adenosine A2 Receptor Agonists, Adult, Coronary Artery Disease, Exercise Test, Female, Humans, Image Enhancement, Male, Myocardial Perfusion Imaging, Physical Endurance, Physical Exertion, Purines, Pyrazoles, Reproducibility of Results, Sensitivity and Specificity, Tomography, Emission-Computed, Single-Photon, Vasodilator Agents
Show Abstract · Added February 28, 2014
BACKGROUND - The data existing in the literature regarding the safety of using regadenoson with symptom-limited exercise are limited, which motivated the authors to undertake this randomized study.
METHODS - We offered patients scheduled to undergo vasodilator stress nuclear myocardial perfusion imaging the opportunity to exercise instead. Patients who failed to reach target heart rate (THR) were randomized to (1) receive regadenoson at peak exercise or (2) stop exercise and receive regadenoson at rest. Patients who reached THR received a standard Tc-99m sestamibi injection with no regadenoson.
RESULTS - 200 patients were included (66% male, mean age 52.5 ± 13.6). 125 patients (62%) reached THR with exercise alone. All stress protocols were well tolerated, and there were no significant adverse events. There were no statistically significant differences in the extent of perfusion abnormalities, image quality, or rate of referral to cardiac catheterization within 60 days between the groups. In fully adjusted logistic regression models, beta-blocker use and diabetes remained significant univariate predictors of failure to reach THR (OR 0.21, 95% CI 0.1-0.5, P < .0001, OR 0.34, 95% CI 0.2-0.7, P = .004, respectively).
CONCLUSIONS - A protocol combining regadenoson at peak exercise in patients unable to reach THR with exercise is feasible, well-tolerated, and yields comparable imaging results to a standard regadenoson injection at rest. In addition, pharmacologic stress testing may be over-ordered in current clinical practice, as patients referred for such testing were often able to exercise.
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17 MeSH Terms
Arginase II inhibition prevents nitrate tolerance.
Khong SM, Andrews KL, Huynh NN, Venardos K, Aprico A, Michell DL, Zarei M, Moe KT, Dusting GJ, Kaye DM, Chin-Dusting JP
(2012) Br J Pharmacol 166: 2015-23
MeSH Terms: Animals, Aorta, Thoracic, Arginase, Arginine, Boronic Acids, Drug Tolerance, Human Umbilical Vein Endothelial Cells, Humans, In Vitro Techniques, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type III, Nitroglycerin, Reactive Oxygen Species, Vasodilator Agents
Show Abstract · Added July 21, 2014
BACKGROUND AND PURPOSE - Nitrate tolerance, the loss of vascular responsiveness with continued use of nitrates, remains incompletely understood and is a limitation of these therapeutic agents. Vascular superoxide, generated by uncoupled endothelial NOS (eNOS), may play a role. As arginase competes with eNOS for L-arginine and may exacerbate the production of reactive oxygen species (ROS), we hypothesized that arginase inhibition might reduce nitrate tolerance.
EXPERIMENTAL APPROACH - Vasodilator responses were measured in aorta from C57Bl/6 and arginase II knockout (argII -/-) mice using myography. Uncoupling of eNOS, determined as eNOS monomer : dimer ratio, was assessed using low-temperature SDS-PAGE and ROS levels were measured using L-012 and lucigenin-enhanced chemiluminescence.
KEY RESULTS - Repeated application of glyceryl trinitrate (GTN) on aorta isolated from C57Bl/6 mice produced a 32-fold rightward shift of the concentration-response curve. However this rightward shift (or resultant tolerance) was not observed in the presence of the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC; 100 µM) nor in aorta isolated from argII -/- mice. Similar findings were obtained after inducing nitrate tolerance in vivo. Repeated administration of GTN in human umbilical vein endothelial cells induced uncoupling of eNOS from its dimeric state and increased ROS levels, which were reduced with arginase inhibition and exogenous L-arginine. Aortae from GTN tolerant C57Bl/6 mice exhibited increased arginase activity and ROS production, whereas vessels from argII -/- mice did not.
CONCLUSION AND IMPLICATIONS - Arginase II removal prevents nitrate tolerance. This may be due to decreased uncoupling of eNOS and consequent ROS production.
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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16 MeSH Terms
Oral iloprost improves endobronchial dysplasia in former smokers.
Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, Franklin WA, Mao J, Wilson DO, Merrick DT, Hirsch FR, Kennedy TC, Bunn PA, Geraci MW, Miller YE
(2011) Cancer Prev Res (Phila) 4: 793-802
MeSH Terms: Biopsy, Bronchi, Bronchoscopy, Double-Blind Method, Female, Follow-Up Studies, Humans, Hyperplasia, Iloprost, Lung Neoplasms, Male, Middle Aged, Smoking, Sputum, Treatment Outcome, United States, Vasodilator Agents
Show Abstract · Added March 10, 2014
There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.
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17 MeSH Terms
Inhibition of human cytochrome P450 3A4 by cholesterol.
Shinkyo R, Guengerich FP
(2011) J Biol Chem 286: 18426-33
MeSH Terms: Anti-Arrhythmia Agents, Cells, Cultured, Cholesterol, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Enzyme Inhibitors, Hepatocytes, Humans, Microsomes, Liver, Models, Biological, Nifedipine, Oxidation-Reduction, Quinidine, Vasodilator Agents
Show Abstract · Added March 7, 2014
If cholesterol is a substrate of P450 3A4, then it follows that it should also be an inhibitor, particularly in light of the high concentrations found in liver. Heme perturbation spectra indicated a K(d) value of 8 μM for the P450 3A4-cholesterol complex. Cholesterol inhibited the P450 3A4-catalyzed oxidations of nifedipine and quinidine, two prototypic substrates, in liver microsomes and a reconstituted enzyme system with K(i) ∼ 10 μM in an apparently non-competitive manner. The concentration of cholesterol could be elevated 4-6-fold in cultured human hepatocytes by incubation with cholesterol; the level of P450 3A4 and cell viability were not altered under the conditions used. Nifedipine oxidation was inhibited when the cholesterol level was increased. We conclude that cholesterol is both a substrate and an inhibitor of P450 3A4, and a model is presented to explain the kinetic behavior. We propose that the endogenous cholesterol in hepatocytes should be considered in models of prediction of metabolism of drugs and steroids, even in the absence of changes in the concentrations of free cholesterol.
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14 MeSH Terms
Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans.
Lee CR, Pretorius M, Schuck RN, Burch LH, Bartlett J, Williams SM, Zeldin DC, Brown NJ
(2011) Hypertension 57: 116-22
MeSH Terms: Adult, African Continental Ancestry Group, Blood Pressure, Bradykinin, Cohort Studies, Epoxide Hydrolases, European Continental Ancestry Group, Female, Forearm, Genetic Variation, Humans, Male, Methacholine Chloride, Nitroprusside, Smoking, Vascular Resistance, Vasodilation, Vasodilator Agents, Young Adult
Show Abstract · Added December 10, 2013
Cytochrome P450-derived epoxyeicosatrienoic acids are potent vasodilators in preclinical models and are hydrolyzed by soluble epoxide hydrolase (EPHX2). Associations between the EPHX2 Lys55Arg and Arg287Gln polymorphisms and cardiovascular disease risk have been reported; however, their impact on vascular function in humans has not been investigated. In 265 volunteers (198 white, 67 black American), forearm blood flow was measured by strain-gauge venous occlusion plethysmography at baseline and in response to bradykinin, methacholine, and sodium nitroprusside. Forearm vascular resistance was calculated as mean arterial pressure/forearm blood flow. In white Americans, Lys55Arg genotype was associated with vasodilator response to bradykinin, such that forearm blood flow was significantly lower (P = 0.043) and forearm vascular resistance was significantly higher (P = 0.013) in Arg55 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In contrast, no relationship was observed in black Americans. In black Americans, Arg287Gln genotype was associated with vasodilator response to bradykinin. Although the difference in forearm blood flow did not reach statistical significance (P = 0.058), forearm vascular resistance was significantly lower (P = 0.037) in Gln287 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In white Americans, Gln287 variant allele carriers did not exhibit significantly higher forearm blood flow (P = 0.128) or lower forearm vascular resistance (P = 0.080). Genetic variation in EPHX2 is associated with forearm vasodilator responses in a bradykinin receptor- and endothelium-independent manner, suggesting an important role for soluble epoxide hydrolase in the regulation of vascular function in humans.
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19 MeSH Terms