Abstract-Short-term treatment of the endothelium with dihydropyridine calcium antagonists resulted in an increased release in NO that is not due to a modulation of L-type calcium channels, because macrovascular endothelial cells do not express this channel. We investigated whether long-term (48 hours) treatment of porcine endothelial cell cultures with the dihydropyridine calcium antagonist nifedipine resulted in a similar enhanced NO liberation. Regarding to the underlying mechanism, we examined whether (1) nifedipine changed the mRNA and protein levels of the constitutive endothelial NO synthase (NOS) in endothelial cell cultures or (2) nifedipine exerts an NO protective effect via its antioxidative properties, as revealed in a cell culture model and with native endothelium from porcine coronary arteries. ihydropyridine (DHP)-type calcium antagonists are important drugs in the treatment of hypertension and coronary heart disease. They induce their specific pharmacological effects by binding to L-type calcium channels, 1,2 which results in a reduced calcium influx with impaired electromechanical coupling both in vascular smooth muscle cells and in the heart. 3 A few years ago, however, it was observed that removal of the endothelium or blockade of the guanylate cyclase of the vessel wall reduced the efficacy of the DHP-induced vasorelaxation, 4 which indicated an endothelium-responsive cGMP-mediated process as part of the DHP action. Because macrovascular endothelial cells lack voltage-operated L-type calcium channels, 5,6 the DHPs must exert these effects via other mechanisms. In this context, it is worth mentioning that DHPs may also exert antihrombotic 7,8 and antiatherosclerotic 9,10 effects in different experimental and clinical settings, of which the underlying signal transduction remains obscure.With this background, it is tempting to speculate that NO, one of the most prominent endothelium-derived factors, 11,12 which relaxes smooth muscle cells via the cGMP signal cascade, 13 might be involved in these DHP actions. In fact, in various models, evidence has accumulated that DHPs stimulate the endothelial NO release, 14 -19 which may mediate or at least contribute to the abovementioned calcium channel-independent effects.Up to now, however, all of these findings were obtained only after acute exposure to DHPs (lasting minutes to hours). Because patients usually take calcium antagonists for a longer period of time, we investigated whether long-term treatment of endothelial cell cultures with nifedipine may alter the basal endothelial NO release as well as the expression of the constitutive endothelial NO synthase (ecNOS) mRNA and protein. Furthermore, because NO is rapidly deactivated by reactive oxygen species (ROS) 20 and the DHPs may act as scavengers as known from different in vitro models, [21][22][23] we also determined the antioxidative potency of nifedipine in endothelial cell cultures as well as in native cells to reveal a potential NO-protection effect as an underlying mechanism of the increased ...

Background & aims: Protein-energy wasting (PEW) is increasingly becoming a clinical problem in maintenance hemodialysis patients and guidelines call for nutritional interventions. Serum prealbumin (transthyretin) represents a critical nutritional marker positively correlated with patient survival and negatively correlated with morbidity. Nutritional counseling, oral supplementation as well as intradialytic parenteral nutrition (IDPN) are recommended to fight PEW, however clinical trials on their use are scarce. Methods: We conducted a prospective, multicenter, randomized, open-label, controlled, parallel-group Phase IV clinical trial in 107 maintenance hemodialysis patients suffering from PEW to assess the impact of IDPN on prealbumin and other biochemical and clinical parameters reflecting nutritional status. Patients randomized to the intervention group received standardized nutritional counseling plus IDPN three times weekly over 16 weeks followed by a treatment-free period of 12 weeks. The control group received standardized nutritional counseling only. Main trial inclusion criteria included moderate to severe malnutrition (SGA score B or C), maintenance hemodialysis therapy (3 times per week) for more than six months, and presence of two out of the following three criteria: albumin <35 g/L, prealbumin <250 mg/L, phase angle alpha <4.5 assessed by bioelectrical impedance analysis (BIA). Changes in serum prealbumin, albumin, transferrin, phase angle alpha, subjective global assessment (SGA) score and health-related quality of life using the 12-item short form health survey (SF-12) were investigated. Results: IDPN significantly increased prealbumin (p < 0.05), showing rapid rise within 16 weeks of treatment and sustained response thereafter. In the full analysis set (n ¼ 83), 41.0% of 39 patients receiving IDPN achieved a relevant (i.e., at least !15%) increase in prealbumin over baseline at week 4 compared to 20.5% of 44 patients in the control group. Considerably more patients with IDPN therapy achieved an increment of prealbumin >30 mg/L at week 16 (48.7% vs. 31.8%). Prealbumin response to IDPN therapy was more prominent in patients suffering from moderate malnutrition (SGA score B) compared to patients with severe malnutrition (SGA score C). Conclusions: The results of this trial demonstrate for the first time that IDPN therapy, given three times weekly in a 16-week short-term intervention, results in a statistically significant and clinically relevant

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Background. The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods. FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400–600 µg/L) or lower (100–200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results. The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions. These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD.