145 research outputs found

    Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels

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    Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels. The contractile properties of recombinant human erythropoietin (rHuEPO) on isolated resistance vessels of renal and mesenteric vascular beds were studied in an in vitro model using a small vessel myograph. Under isometric conditions, rHuEPO caused a contraction of this vasculature in a concentration range between 10 U/ml and 200 U/ml. A maximal active wall tension of 1.52 ± 0.19 mN/mm was obtained under a rHuEPO dose of 200 U/ml. In Ca2+ free solution, the pressor response to high rHuEPO-concentrations was attenuated, and the response to low rHuEPO concentrations was abolished. In the presence of verapamil, phentolamine and saralasin, rHuEPO-induced contractions were not affected significantly. A dose-dependent vasodilatation of mounted vasculature to acetylcholine (ACh) indicated that endothelium remained intact in our preparations rHuEPO-induced vessel contraction was not abrogated after an enzymatical removal of endothelium by collagenase, confirming that the described contractile responses are endothelial independent. These findings suggest that a direct vasopressor effect of rHuEPO on proximal resistance vessels may contribute to development of hypertension seen in rHuEPO-treated hemodialysis patients

    Transdermal β-Blocker Therapy in Essential Hypertension

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    Transdermal drug delivery has been applied to various agents in an effort to decrease the frequency of drug administration and increase the patients compliance. In our study, we demonstrated that transdermal application of a ß-blocker (20 mg mepindolol) in patients with essential hypertension led to effective blood pressure lowering effect within 1 week (160.1 ±6.1 mm Hg/95.8 ± 8.3 mm Hg vs 136.8 ± 7.2 mm Hg/84.3 ± 5.0 mm Hg; Ρ < 0.05). A controlled study of transdermal versus oral ß-blocker administration in hypertensives is necessary before this new therapeutic system is introduced in antihypertensive treatment. Am J Hypertens 1988; 1:199S-200

    Interaction of Human Serum Albumin with short Polyelectrolytes: A study by Calorimetry and Computer Simulation

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    We present a comprehensive study of the interaction of human serum albumin (HSA) with poly(acrylic acid) (PAA; number average degree of polymerization: 25) in aqueous solution. The interaction of HSA with PAA is studied in dilute solution as the function of the concentration of added salt (20 - 100 mM) and temperature (25 - 37^{\circ}C). Isothermal titration calorimetry (ITC) is used to analyze the interaction and to determine the binding constant and related thermodynamic data. It is found that only one PAA chain is bound per HSA molecule. The free energy of binding ΔGb\Delta G_b increases with temperature significantly. ΔGb\Delta G_b decreases with increasing salt concentration and is dominated by entropic contributions due to the release of bound counterions. Coarse-grained Langevin computer simulations treating the counterions in an explicit manner are used study the process of binding in detail. These simulations demonstrate that the PAA chains are bound in the Sudlow II site of the HSA. Moreover, ΔGb\Delta G_b is calculated from the simulations and found to be in very good agreement with the measured data. The simulations demonstrate clearly that the driving force of binding is the release of counterions in full agreement with the ITC-data

    Blood pressure control and components of the metabolic syndrome: the GOOD survey

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    <p>Abstract</p> <p>Background</p> <p>The GOOD (Global Cardiometabolic Risk Profile in Patients with Hypertension Disease) survey showed that blood pressure control was significantly worse in hypertensive patients with metabolic syndrome and/or diabetes mellitus than in those with essential hypertension only. This analysis aimed to investigate which components of the metabolic syndrome are primarily associated with poor blood pressure control.</p> <p>Methods</p> <p>The GOOD survey was designed as an observational cross-sectional survey in 12 European countries to assess the cardiometabolic risk profile in patients with essential hypertension. Investigators were randomly selected from a list of general practitioners (70% of investigators) and a list of specialists such as internists, cardiologists and hypertension specialists (30% of investigators). Data from 3,280 outpatients with hypertension, aged at least 30 years who were receiving antihypertensive treatment or had newly diagnosed hypertension according to the European Society of Hypertension and the European Society of Cardiology criteria, were included in the analyses. Blood pressure control, body mass index (BMI), waist circumference, serum triglycerides, total and high density lipoprotein (HDL) cholesterol measurements were compared in patients with diabetes mellitus and metabolic syndrome, with diabetes mellitus only, with metabolic syndrome only, and with neither metabolic syndrome nor diabetes mellitus.</p> <p>Results</p> <p>The highest blood pressure values were found in patients with metabolic syndrome with or without diabetes mellitus. Blood pressure was significantly lower in patients with diabetes mellitus only. The highest BMI, waist circumference and serum triglycerides, and the lowest HDL cholesterol levels among the groups studied occurred in patients with metabolic syndrome, either with or without diabetes mellitus.</p> <p>Conclusion</p> <p>Among the components of the metabolic syndrome, it is not impaired glucose tolerance which is associated with the poor response to antihypertensive treatment. Instead, visceral obesity and dyslipidemia components of the metabolic syndrome, i.e. hypertriglyceridemia and low HDL cholesterol levels, are associated with resistance to antihypertensive treatment.</p

    Induction of Mineralization

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    Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans- differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis

    A Novel Long-Term ex vivo Model for Studying Vascular Calcification Pathogenesis: The Rat Isolated-Perfused Aorta

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    The investigation of vascular calcification and its underlying cellular and molecular pathways is of great interest in current research efforts. Therefore, suitable assays are needed to allow examination of the complex calcification process under controlled conditions. The current study describes a new ex vivo model of isolated-perfused rat aortic tissue with subsequent quantification and vessel staining to analyze the calcium content of the aortic wall. A rat aorta was perfused ex vivo with control and calcification media for 14 days, respectively. The calcification medium was luminally perfused and induced a significant increase in calcium deposition within the media of the vessel wall detected alongside the elastic laminae. Perfusion with control medium induced no calcification. In addition, the mRNA expression of the osteogenic marker bone morphogenetic protein 2 (BMP-2) increased in aortic tissue after perfusion, while SM22α as smooth muscle marker decreased. This newly developed ex vivo model of isolated-perfused rat aorta is suitable for vascular calcification studies testing inducers and inhibitors of vessel calcification and studying signaling pathways within calcification progression

    First-line antihypertensive treatment in patients with pre-diabetes: Rationale, design and baseline results of the ADaPT investigation

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    <p>Abstract</p> <p>Background</p> <p>Recent clinical trials reported conflicting results on the reduction of new-onset diabetes using RAS blocking agents. Therefore the role of these agents in preventing diabetes is still not well defined. Ramipril is an ACE inhibitor (ACEi), that has been shown to reduce cardiovascular events in high risk patients and post-hoc analyses of the HOPE trial have provided evidence for its beneficial action in the prevention of diabetes.</p> <p>Methods</p> <p>The ADaPT investigation ("ACE inhibitor-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes") is a 4-year open, prospective, parallel group phase IV study. It compares an antihypertensive treatment regimen based on ramipril versus a treatment based on diuretics or betablockers. The primary evaluation criterion is the first manifestation of type 2 diabetes. The study is conducted in primary care to allow the broadest possible application of its results. The present article provides an outline of the rationale, the design and baseline characteristics of AdaPT and compares these to previous studies including ASCOT-BLPA, VALUE and DREAM.</p> <p>Results</p> <p>Until March 2006 a total of 2,015 patients in 150 general practices (general physicians and internists) throughout Germany were enrolled. The average age of patients enrolled was 67.1 ± 10.3 years, with 47% being male and a BMI of 29.9 ± 5.0 kg/m<sup>2</sup>. Dyslipidemia was present in 56.5%. 37.8% reported a family history of diabetes, 57.8% were previously diagnosed with hypertension (usually long standing). The HbA1c value at baseline was 5.6 %. Compared to the DREAM study patients were older, had more frequently hypertension and patients with cardiovascular disease were not excluded.</p> <p>Conclusion</p> <p>Comparing the ADaPT design and baseline data to previous randomized controlled trial it can be acknowledged that AdaPT included patients with a high risk for diabetes development. Results are expected to be available in 2010. Data will be highly valuable for clinical practice due to the observational study design.</p

    Proteomic-biostatistic integrated approach for finding the underlying molecular determinants of hypertension in human plasma

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    Despite advancements in lowering blood pressure, the best approach to lower it remains controversial because of the lack of information on the molecular basis of hypertension. We, therefore, performed plasma proteomics of plasma from patients with hypertension to identify molecular determinants detectable in these subjects but not in controls and vice versa. Plasma samples from hypertensive subjects (cases; n=118) and controls (n=85) from the InGenious HyperCare cohort were used for this study and performed mass spectrometric analysis. Using biostatistical methods, plasma peptides specific for hypertension were identified, and a model was developed using least absolute shrinkage and selection operator logistic regression. The underlying peptides were identified and sequenced off-line using matrix-assisted laser desorption ionization orbitrap mass spectrometry. By comparison of the molecular composition of the plasma samples, 27 molecular determinants were identified differently expressed in cases from controls. Seventy percent of the molecular determinants selected were found to occur less likely in hypertensive patients. In cross-validation, the overall R(2) was 0.434, and the area under the curve was 0.891 with 95% confidence interval 0.8482 to 0.9349, P&lt;0.0001. The mean values of the cross-validated proteomic score of normotensive and hypertensive patients were found to be -2.007±0.3568 and 3.383±0.2643, respectively, P&lt;0.0001. The molecular determinants were successfully identified, and the proteomic model developed shows an excellent discriminatory ability between hypertensives and normotensives. The identified molecular determinants may be the starting point for further studies to clarify the molecular causes of hypertension

    Ramipril-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes (ADaPT) study

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    <p>Abstract</p> <p>Background</p> <p>Previous randomized controlled trials demonstrated a protective effect of renin angiotensin system blocking agents for the development of type-2 diabetes in patients with pre-diabetes. However, there are no real-world data available to illustrate the relevance for clinical practice.</p> <p>Methods</p> <p>Open, prospective, parallel group study comparing patients with an ACE inhibitor versus a diuretic based treatment. The principal aim was to document the first manifestation of type-2 diabetes in either group.</p> <p>Results</p> <p>A total of 2,011 patients were enrolled (mean age 69.1 ± 10.3 years; 51.6% female). 1,507 patients were available for the per-protocol analysis (1,029 ramipril, 478 diuretic group). New-onset diabetes was less frequent in the ramipril than in the diuretic group over 4 years. Differences were statistically different at a median duration of 3 years (24.4% vs 29.5%; p < 0.05). Both treatments were equally effective in reducing BP (14.7 ± 18.0/8.5 ± 8.2 mmHg and 12.7 ± 18.1/7.0 ± 8.3 mmHg) at the 4 year follow-up (p < 0.001 vs. baseline; p = n.s. between groups). In 38.6% and 39.7% of patients BP was below 130/80 mmHg (median time-to-target 3 months). There was a significant reduction of cardiovascular morbidity and mortality in favour of ramipril (p = 0.033). No significant differences were found for a change in HbA1c as well as for fasting blood glucose levels during follow-up. The rate of adverse events was higher in diuretic treated patients (SAE 15.4 vs. 12.4%; p < 0.05; AE 26.6 vs. 25.6%; p = n.s).</p> <p>Conclusions</p> <p>Ramipril treatment is preferable over diuretic based treatment regimens for the treatment of hypertension in pre-diabetic patients, because new-onset diabetes is delayed.</p