Publications (290) View all
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Article: Role of Endogenous Vascular Endothelial Growth Factor in Endothelium-Dependent Vasodilation in Humans.
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ABSTRACT: Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. Hypertension is the most reported side effect of angiogenesis inhibitors interfering with vascular endothelial growth factor signaling. In this study, we test the hypothesis that circulating vascular endothelial growth factor at physiological concentrations is essential to preserve normal endothelial control of vasomotor tone. In 7 healthy male volunteers, infusion of bevacizumab (monoclonal vascular endothelial growth factor antibody) into the brachial artery for 15 minutes (144 μg/dL forearm volume per minute) did not affect forearm vasodilator tone as measured with venous occlusion strain gauge plethysmography. In a separate group of 12 male volunteers, a similar bevacizumab infusion reduced the vasodilator response to 2 dosages of acetylcholine from (mean±SE) 440±157% and 926±252% to 169±40% and 612±154% (P<0.05). Finally, in a third group of 12 volunteers, bevacizumab did not alter the percentage increase in forearm blood flow during infusion of sodium nitroprusside at dosages equipotent to acetylcholine. Bevacizumab acutely and specifically reduced endothelium-mediated vasodilation at local concentrations that resemble plasma concentrations after systemic exposure to bevacizumab. This observation suggests a physiological role for vascular endothelial growth factor in maintaining normal endothelial control of vasomotor tone. The role of the endothelium in the mechanism of bevacizumab-induced hypertension deserves further exploration.Hypertension 03/2013; · 6.21 Impact Factor -
Article: Improved resistance to ischemia and reperfusion, but impaired protection by ischemic preconditioning in patients with type 1 diabetes mellitus: a pilot study.
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ABSTRACT: BACKGROUND: In patients with type 1 diabetes mellitus (T1DM), cardiovascular events are more common, and the outcome following a myocardial infarction is worse than in nondiabetic subjects. Ischemic or pharmacological preconditioning are powerful interventions to reduce ischemia reperfusion (IR)-injury. However, animal studies have shown that the presence of T1DM can limit these protective effects. Therefore, we aimed to study the protective effect of ischemic preconditioning in patients with T1DM, and to explore the role of plasma insulin and glucose on this effect. METHODS: 99mTechnetium-annexin A5 scintigraphy was used as a model of IR-injury. IR-injury was induced by unilateral forearm ischemic exercise. At reperfusion, Tc-annexin A5 was administered, and IR-injury was expressed as the percentage difference in radioactivity in the thenar muscle between the experimental and control arm 4 hours after reperfusion. 15 patients with T1DM were compared to 21 nondiabetic controls. The patients were studied twice, with or without ischemic preconditioning (10 minutes of forearm ischemia and reperfusion). Patients were studied in either normoglycemic hyperinsulinemic conditions (n = 8) or during hyperglycemic normoinsulinemia (n = 7). The controls were studied once either with (n = 8) or without (n = 13) ischemic preconditioning. RESULTS: Patients with diabetes were less vulnerable to IR-injury than nondiabetic healthy controls (12.8 +/- 2.4 and 11.0 +/- 5.1% versus 27.5 +/- 4.5% in controls; p < 0.05). The efficacy of ischemic preconditioning to reduce IR-injury, however, was lower in the patients and was even completely abolished during hyperglycemia. CONCLUSIONS: Patients with T1DM are more tolerant to forearm IR than healthy controls in our experimental model. The efficacy of ischemic preconditioning to limit IR-injury, however, is reduced by acute hyperglycemia.Trial RegistrationThe study is registered at www.clinicaltrials.gov (NCT00184821).Cardiovascular Diabetology 10/2012; 11(1):124. · 3.35 Impact Factor -
Article: Adaptive changes of mesenteric arteries in pregnancy: a meta-analysis.
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ABSTRACT: The vascular response to pregnancy has been frequently studied in mesenteric artery models by investigating endothelial cell (EC)- and smooth muscle cell (SMC)-dependent responses to mechanical (flow-mediated vasodilation, myogenic reactivity, and vascular compliance) and pharmacological stimuli (G protein-coupled receptor responses: Gq(EC), Gs(SMC), Gq(SMC)). It is unclear to what extent these pathways contribute to normal pregnancy-induced vasodilation across species, strains, and/or gestational age and at which receptor level pregnancy affects the pathways. We performed a meta-analysis on responses to mechanical and pharmacological stimuli associated with pregnancy-induced vasodilation of mesenteric arteries and included 55 (188 responses) out of 398 studies. Most included studies (84%) were performed in Wistar and Sprague-Dawley rats (SDRs) and compared late gestation versus nonpregnant controls (80%). Pregnancy promotes flow-mediated vasodilation in all investigated species. Only in SDRs, pregnancy additionally stimulates both vasodilator Gq(EC) sensitivity (EC(50) reduced by -0.76 [-0.92, -0.60] log[M]) and Gs(SMC) sensitivity (EC(50) reduced by -0.51 [-0.82, -0.20] log[M]), depresses vasopressor Gq(SMC) sensitivity (EC(50) increase in SDRs by 0.23 [0.16, 0.31] log[M]), and enhances arterial compliance. We conclude that 1) pregnancy facilitates flow-mediated vasodilation at term among all investigated species, and the contribution of additional vascular responses is species and strain specific, and 2) late pregnancy mediates vasodilation through changes at the receptor level for the substances tested. The initial steps of vasodilation in early pregnancy remain to be elucidated.AJP Heart and Circulatory Physiology 07/2012; 303(6):H639-57. · 3.71 Impact Factor -
Article: How systemic inflammation modulates adenosine metabolism and adenosine receptor expression in humans in vivo.
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ABSTRACT: Adenosine modulates inflammation and prevents associated organ injury by activation of its receptors. During sepsis, the extracellular adenosine concentration increases rapidly, but the underlying mechanism in humans is unknown. We aimed to determine the changes in adenosine metabolism and signaling both in vivo during experimental human endotoxemia and in vitro. We studied subjects participating in three different randomized double-blind placebo-controlled trials. In order to prevent confounding by the different pharmacological interventions in these trials, analyses were performed on data of placebo-treated subjects only. Intensive care research unit at the Radboud University Nijmegen Medical Center. In total, we used material of 24 healthy male subjects. Subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide) intravenously. Following experimental endotoxemia, endogenous adenosine concentrations increased. Expression of 5'ectonucleotidase messenger RNA was upregulated (p = .01), whereas adenosine deaminase messenger RNA was downregulated (p = .02). Furthermore, both adenosine deaminase and adenosine kinase activity was significantly diminished (both p ≤ .0001). A2a and A2b receptor messenger RNA expression was elevated (p = .02 and p = .04, respectively), whereas messenger RNA expression of A1 and A3 receptors was reduced (both, p = .03). In vitro, lipopolysaccharide dose-dependently attenuated the activity of both adenosine deaminase and adenosine kinase (both p ≤ .0001). Adenosine metabolism and signaling undergo adaptive changes during human experimental endotoxemia promoting higher levels of adenosine thereby facilitating its inflammatory signaling.Critical care medicine 06/2012; 40(9):2609-16. · 6.37 Impact Factor -
Article: Differential effects of sulfonylurea derivatives on vascular ATP-sensitive potassium channels.
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ABSTRACT: Sulfonylurea drugs exert their insulinotropic action by inhibiting ATP-sensitive potassium channels in the pancreas. However, these channels are also expressed in myocardial and vascular smooth muscle, implicating possible detrimental cardiovascular effects. Aim of the present study was to investigate the inhibitory potency of various widely used sulfonylurea drugs in resistance arteries. Isolated mesenteric and renal resistance arteries mounted in a myograph and isolated perfused kidneys were used to measure drug responses. Pinacidil induced a dose-dependent relaxation of phenylephrine preconstricted mesenteric and renal arteries (pEC(50)=6.10 ± 0.01 and 5.66 ± 0.03, respectively). Schild plot analysis of pinacidil relaxation curves in mesenteric arteries in the presence of sulfonylurea antagonists revealed the following order of potency: glimepiride (pA(2)=7.22) ≥ glibenclamide (pA(2)=7.05) > glipizide (pA(2)=5.25) > gliclazide (pA(2)=4.31). The effects of glibenclamide in renal arteries were comparable. Furthermore, glibenclamide produced similar constrictive properties in isolated renal arteries as in isolated perfused whole kidneys. We conclude that sulfonylurea drugs exert differential effects on vascular smooth muscle K(ATP) channels. Our results suggest that glibenclamide and glimepiride will interact with these channels at therapeutic concentrations.European journal of pharmacology 02/2012; 681(1-3):75-9. · 2.59 Impact Factor
