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ABSTRACT: Recent studies have shown that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] exerts important vasoactive actions and can act as an endogenous physiological antagonist of angiotensin II (Ang II) within the renin-angiotensin system (RAS). The present study was performed to evaluate the effects, first, of chronic increases of Ang-(1-7) levels, second, of [7-D-Ala], an Ang-(1-7) receptor antagonist, and, third, of an angiotensin-converting enzyme 2 (ACE2) inhibitor on the course of hypertension and of renal function of the nonclipped kidney in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats.
Blood pressure (BP) was monitored by radiotelemetry. Elevation of the effect of circulating Ang-(1-7) levels was achieved either by chronic subcutaneous infusion of Ang-(1-7) through osmotic minipumps or by employing transgenic rats that express an Ang-(1-7)-producing fusion protein [Ang-(1-7)TGR+/+] (and its control Ang-(1-7)TGR-/-). [7-D-Ala] was also infused subcutaneously and the ACE2 inhibitor was administrated in drinking water. On day 25 after clipping, rats were anesthetized and renal function was evaluated.
Chronic infusion of Ang-(1-7) did not modify the course of 2K1C hypertension and did not alter renal function as compared with saline vehicle-infused 2K1C rats. Chronic infusion of [7-D-Ala] or treatment with the ACE2 inhibitor worsened the course of hypertension and elicited decreases in renal hemodynamics. [Ang-(1-7)TGR+/+] and [Ang-(1-7)TGR-/-] rats exhibited a similar course of hypertension.
The present data support the notion that Ang-(1-7) serves as an important endogenous vasodilator and natriuretic agent and its deficiency might contribute to the acceleration of 2K1C Goldblatt hypertension.
Journal of hypertension 08/2009; 27(10):1988-2000. · 4.02 Impact Factor
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ABSTRACT: Results of our previous studies have suggested that enhanced generation of superoxide (O2(-)) may contribute to the pathophysiology of hypertension in Ren-2 transgenic rats (TGR). The present study was performed to evaluate in TGR the effects of chronic treatment with the O2(-) scavenger tempol and the antioxidant apocynin on the development of hypertension. Systolic blood pressure (SBP) was monitored from 30 to 99 days of age in TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats. At the end of the experiment, urinary protein and 8-isoprostane excretion were determined and angiotensin II (ANG II) and malondialdehyde (MDA) levels were measured in kidney and cardiac tissues. Cardiac hypertrophy was assessed as the ratio of left heart ventricle weight to tibia length (LVW/TL). Although tempol and apocynin treatment in TGR significantly decreased 8-isoprostane excretion and MAD tissue concentrations as compared with untreated TGR, it did not alter the course of SBP, LVW/TL ratio, proteinuria or ANG II levels that were enhanced as compared with HanSD rats. Our data suggest that the development of hypertension in TGR is clearly ANG II-dependent but the contribution of oxidative stress to the development of hypertension in this model appears to be negligible.
Vascular Pharmacology 07/2009; 51(2-3):175-81. · 1.99 Impact Factor
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ABSTRACT: Hypertension is a frequent complication in children after renal transplantation and the control of post-transplant hypertension is unsatisfactorily low. The aim of this prospective interventional study was to improve the control of hypertension in children after renal transplantation. Thirty-six children fulfilled the inclusion criteria (> or =6 months after transplantation and no acute rejection in the last three months). BP was measured using ABPM. Hypertension was defined as mean ambulatory BP > or =95th-centile for healthy children and/or using antihypertensive drugs. The study intervention consisted of using intensified antihypertensive drug therapy - in children with uncontrolled hypertension (i.e., mean ambulatory BP was > or =95th centile in treated children), antihypertensive therapy was intensified by adding new antihypertensive drugs to reach goal BP <95th centile. ABPM was repeated after 12 and 24 months. Daytime BP did not change significantly after 12 or 24 months. Night-time BP decreased from 1.57 +/- 1.33 to 0.88 +/- 0.84 SDS for systolic and from 1.10 +/- 1.51 to 0.35 +/- 1.18 SDS for diastolic BP after 24 months (p < 0.05). The number of antihypertensive drugs increased from 2.1 +/- 0.9 to 2.7 +/- 0.8 drugs per patient (p < 0.05), this was especially seen with the use of ACE-inhibitors (increase from 19% to 40% of children, p < 0.05). In conclusion, this interventional trial demonstrated that, in children after renal transplantation, the control of hypertension, especially at night-time, can be improved by increasing the number of antihypertensive drugs, especially ACE-inhibitors.
Pediatric Transplantation 09/2007; 11(5):491-7. · 1.48 Impact Factor
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ABSTRACT: Male heterozygous Ren-2 transgenic rats and Hannover Sprague-Dawley rats fed a normal or high-salt diet were either untreated or treated with the nonselective receptor ET(A)/ET(B) receptor blocker bosentan or the selective ET(A) receptor blocker, ABT-627, known as atrasentan. Survival rate was partly increased by bosentan and fully normalized by atrasentan. Bosentan did not significantly influence the course of hypertension in TGR, whereas atrasentan significantly decreased BP on both diets. Atrasentan substantially reduced proteinuria, cardiac hypertrophy, glomerulosclerosis and left ventricular ET-1 tissue concentration on both diets. Our data indicate that ET(A) receptor blockade is superior to nonselective blockade in attenuating hypertension, end-organ damage and improving survival rate.
Vascular Pharmacology 10/2006; 45(3):163-70. · 1.99 Impact Factor
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ABSTRACT: The aim of this cross-sectional single-center study was to investigate the efficacy of hypertension control in children who underwent transplantation using ambulatory blood pressure (BP) monitoring, and to determine the risk factors associated with poor control of hypertension. Thirty-six children fulfilled the inclusion criteria. The mean age was 13.9+/-4.4 yr; the mean time after renal transplantation was 2.7+/-2.4 yr (0.5-10.1). Hypertension was defined as a mean ambulatory BP > or =95th centile for healthy children and/or requiring antihypertensive drugs. Hypertension was regarded as controlled if the mean ambulatory BP was <95th centile in children already on antihypertensive drugs, or uncontrolled if the mean ambulatory BP was > or =95th centile in treated children. Hypertension was present in 89% of children. Seventeen children (47%) had controlled hypertension, and 14 (39%) had uncontrolled hypertension. One child (3%) had untreated hypertension, and only four children (11%) showed normal BP without antihypertensive drugs. The efficacy of hypertensive control was 55% (17 of 31 children on antihypertensive drugs had a BP<95th centile), i.e. 45% of treated children still had hypertension. Children with uncontrolled hypertension had significantly higher cyclosporine doses (6.1 vs. 4.3 mg/kg/day, p=0.01) and tacrolimus levels (9.2 vs. 6.1 microg/L, p<0.05), and there was a tendency toward use of lower number of antihypertensive drugs (2.0 vs. 1.5 drugs/patient, p=0.06) and lower use of angiotensin-converting enzyme (ACE) inhibitors (7 vs. 35%, p=0.09) and diuretics (29 vs. 59%, p=0.14) than in children with controlled hypertension. In conclusion, nearly 90% of our children after renal transplantation are hypertensive and the control of hypertension is unsatisfactorily low. The control of hypertension could be improved by increasing the number of prescribed antihypertensive drugs, especially ACE inhibitors, and diuretics, or by using higher doses of currently used antihypertensives.
Pediatric Transplantation 05/2006; 10(3):316-22. · 1.48 Impact Factor
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Pavel Dvorák,
Herbert J Kramer,
Angela Bäcker,
Jan Malý,
Libor Kopkan,
Ivana Vanecková,
Zdena Vernerová,
Martin Opocenský,
Vladimír Tesar,
Michael Bader,
Detlev Ganten,
Jan Janda,
Ludek Cervenka
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ABSTRACT: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake.
Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET(A/B) receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination.
All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR.
Our data show that nonselective ET(A/B) receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.
Kidney and Blood Pressure Research 02/2004; 27(4):248-58. · 1.46 Impact Factor
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ABSTRACT: The purpose of this study was to investigate the use of a polymer gel-based dosimeter for the evaluation of geometric and dosimetric inaccuracies during gamma knife radiosurgery and during the irradiation of an experimental animal.
A polymer gel dosimeter, based on acrylic monomers, was used for experiments conducted in this study. The accuracy of the dosimeter was evaluated on a Siemens EXPERT 1-tesla scanner in the transmitter/receiver head coil with the use of a multiecho sequence with 16 echoes, TE 22.5 to 360 msec, TR 2000 msec, slice thickness 2 mm, field of view 255 mm, and a pixel size of 0.5 x 0.5 mm2. Two experiments were conducted. First, the head phantom containing the polymer gel dosimeter was irradiated using 4-, 8-, 14-, and 18-mm isocenters. Second, a specially designed rat phantom was irradiated by four 4-mm isocenters. The dose profiles in the x, y, and z axes were calculated in the treatment planning system and measured with the polymer gel dosimeter and the results were compared. There was good agreement between the measured and calculated dose profiles. The maximum deviation in the spatial position of the center of measured and calculated dose profiles was 0.5 mm in the head phantom and 1 mm in the rat phantom. The maximum deviation in the width of the selected reference isodose of measured profiles was 1.2 mm in the head phantom and 1.1 mm in the rat phantom.
The use of the polymer gel-based dosimeter for the verification of stereotactic procedures has advantages compared with other dosimetric systems. The dosimeter itself is tissue equivalent. Three-dimensional dose distributions can be measured and the dosimeter allows simulation of the therapeutic procedures.
Journal of Neurosurgery 01/2003; 97(5 Suppl):556-62. · 2.96 Impact Factor
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ABSTRACT: To assess the entire geometric and dosimetric (relative) uncertainties of the radiosurgery procedure with the Leksell gamma knife.
The entire Leksell gamma knife stereotactic radiosurgery treatment procedure was simulated with the use of a special water filled head phantom and polymer-gel dosimeter evaluated by nuclear magnetic resonance (NMR). A test vessel filled with the polymer-gel dosimeter was fixed in the head phantom. The phantom underwent stereotactic NMR imaging, treatment planning and then irradiation according to the treatment plan prepared exactly the same way as in the ordinary treatment procedure for a patient. The treatment plan was represented by one isocenter positioned approximately centrally in the head phantom. This procedure was subsequently repeated for all four collimators (4, 8, 14, 18mm) used on the Leksell gamma knife. Evaluation of dosimeters was performed on a Siemens EXPERT 1T NMR scanner. Dose profiles in X, Y and Z axes through the ellipsoidal shaped dose distribution were obtained to compare experimental results from the irradiated phantom with the treatment planning system calculations.
Reasonable agreement was observed between the treatment planning system calculations of relative dose distribution and the measured data. The maximum observed deviation in the spatial position between the center of the measured and calculated dose profiles was 0.6mm. The maximum observed difference in full width of half maximum between calculated and measured profiles was 1.2mm.
The use of polymer-gel dosimetry for a verification of stereotactic procedures has some unique advantages that can be summarized as follows: the dosimeter itself is tissue equivalent, three-dimensional dose distributions can be measured and the dosimeter allows simulation of the patient's procedures without any limitations.
Radiotherapy and Oncology 06/2002; 63(2):223-30. · 5.58 Impact Factor
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ABSTRACT: To evaluate geometric and dosimetric inaccuracies in the irradiation of the rat brain with the Leksell Gamma Knife.
Altogether three types of dosimeters were employed for these measurements: (a) a thermoluminescent dosimeter, (b) a semiconductor detector and (c) a polymer gel dosimeter. The thermoluminescent dosimeter and the semiconductor detector were calibrated using an ion chamber and then implanted in the brain of a rat cadaver and used for absolute dose determination. A special glass phantom mimicking exactly the shape of the rat body filled with the polymer gel was used for measurements of the relative dose distribution and evaluation of geometric inaccuracies during the stereotactic irradiation in the rat brain.
Both thermoluminescent and semiconductor detectors, due to their size, measured mean doses. The observed results demonstrated that the Leksell GammaPlan can be employed for the calculation of absorbed doses in irradiation of experimental animals. In our case, it was necessary to apply a correction factor of 1.078 for the absolute absorbed dose to obtain reliable results. A comparison of calculated dose profiles using the treatment planning system in all three axes with those measured by the polymer gel dosimeter demonstrated a very good geometric agreement with the mean deviation in profile position of 0.5 mm.
The results indicate that this technique can effectively check the geometric and dosimetric accuracy of stereotactic irradiation in the rat brain. The Leksell GammaPlan can be employed for the calculation of absorbed doses, but the correction factor of 1.078 had to be applied for the absolute dose calculations in our irradiation geometry.
Stereotactic and Functional Neurosurgery 02/2002; 79(2):57-74. · 1.85 Impact Factor
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Zdenka Vanourková,
Herbert J Kramer,
Michaela Erbanová,
Angela Bäcker,
Ludek Cervenka,
Zuzana Husková,
Vera Certíková Chábová,
Vladimír Tesar, Pavel Dvorák,
Jan Malý,
Ivana Vanecková
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ABSTRACT: We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET(A)/ET(B) in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET(A)/ET(B), or with atrasentan, a selective ET(A) receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (13C; 03% in rat chow), a natural xenobiotic which activates the Cyplal promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of 13C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.
Vascular Pharmacology 50(5-6):194-9. · 1.99 Impact Factor
