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M Bader

Publications and source records attributed to M Bader.

At least 91 records · Page 5Linked to original sources
PubMed1998

Local renin-angiotensin system in the pineal gland.

Besides the classical endocrine renin-angiotensin system (RAS), a local RAS has been described also in the brain. We attempted to clarify the existence of a local RAS in the pineal gland. Through the use of a ribonuclease protection assay, it proved possible to detect the mRNA for angiotensinogen (AOGEN), for the angiotensin receptor type 1A (AT1a) and 1B (AT1b) and for the angiotensin-converting enzyme (ACE) in pineal glands from rats. Renin mRNA, however, could not be found by this method. By in situ hybridization and immunocytochemistry, AOGEN mRNA was co-localized with the astrocyte marker glial fibrillary acidic protein. AT1b mRNA expression exceeded the expression of AT1a mRNA and was co-localized with the pinealocyte-specific tryptophan hydroxylase. Thus, in the mammalian pineal gland there is a local formation of the components of the RAS. The presence of angiotensin II receptors further substantiates a role for angiotensins and the pineal RAS in the physiology of this gland.

Angiotensinogen↗
PubMed1998

Ambient and biochemical effect monitoring of workers exposed to ethylene oxide.

OBJECTIVES: Ethylene oxide is an alkylating agent known to be a directly acting mutagen and carcinogen. This study describes the relationship between workplace ambient air concentrations of ethylene oxide and the concentration of N-2-hydroxyethylvaline in the globin of exposed workers. METHODS: During the sterilization of medical equipment, 12 workers were occupationally exposed to ethylene oxide. Personal and stationary ambient air measurements were carried out to monitor the external exposure. The determination of the protein adducts was based on the N-alkyl-Edman method, introducing a new commercially available dipeptide standard for calibration purposes. RESULTS: Ethylene oxide concentrations ranging from 0.2 to 8.5 ppm were found in the workplace air. The adduct concentrations ranged from 5,219 to 32,738 pmol N-2-hydroxyethylvaline/g globin in the case of regularly exposed workers (n = 9) and from 518 to 3,321 pmol N-2-hydroxyethylvaline/g globin for three persons with occasional contact with ethylene oxide. CONCLUSIONS: The Deutsche Forschungsgemeinschaft established in 1993 a relationship between the ethylene oxide concentration in ambient air and the amount of N-2-hydroxyethylvaline in human globin. By extrapolation, constant exposure to 1 ppm ethylene oxide should yield approximately 4,000 pmol N-2-hydroxyethylvaline/g globin. The ambient air concentrations of ethylene oxide and the amount of N-2-hydroxyethylvaline determined within the present study confirm this extrapolation in practice. In addition, the determination of adducts based on the use of commercially available dipeptide standards for calibration purposes turned out to be an advantageous alternative to the commonly used protein standards.

Air Pollution, Indoor↗
PubMed1998

Heat stress-induced B1 receptor synthesis in the rat: an ex vivo study.

1. This ex vivo study was performed to characterize B1 receptor induction in rats submitted to heat stress. Changes in aortic isometric tension were recorded after a 90 min in vitro incubation with [des-Arg9]-bradykinin. B1 receptor mRNA were detected in aorta and heart using RT-PCR technique. 2. Aortic rings from sham rats did not respond to [des-Arg9]-bradykinin. In contrast, this agonist induced a concentration-dependent relaxation of aortic rings from rats submitted to lipopolysaccharide (LPS) treatment or to heat stress 24 h earlier. 3. The concentration-dependent relaxation induced by [des-Arg9]-bradykinin on aortic rings from heat-stressed rats was abolished by [des-Arg10]-HOE 140, a selective B1 receptor antagonist. 4. In endothelium denuded aortic rings from heat-stress rats, [des-Arg9]-bradykinin induced a concentration-dependent constriction. 5. Pretreatment of intact aortic rings from heat-stress rats with the cyclo-oxygenase inhibitor, diclofenac (1 microM) did not prevent the concentration-dependent relaxation in response to [des-Arg9]-bradykinin. In contrast. NO synthase inhibition with N(omega)-nitro-L-arginine methyl ester (30 microM) totally prevented the vasorelaxant response. 6. B1 receptor mRNA were not detected in aorta and heart from sham animals but were present in tissue from heat-stressed and LPS-treated rats. 7. In conclusion, our results suggest that heat stress induces a transcriptional activation of the B1 receptor gene. The induction of B1 receptors leads to an endothelium- and NO-dependent vasorelaxant response to [des-Arg9]-bradykinin.

Animals↗
PubMed1998

Event-related brain potentials and case information in syntactic ambiguities.

In an ERP study, German sentences were investigated that contain a case-ambiguous NP that may be assigned accusative or dative case. Sentences were disambiguated by the verb in final position of the sentence. As our data show, sentences ending in a verb that assigns dative case to the ambiguous NP elicit a clear garden-path effect. The garden-path effect was indicated by a broad centro-posterior negative shift that occurred between 300 and 900 msec after the dative-assigning verb was presented. No enhanced P600 following the misanalysis was observed. Noun phrases whose case ambiguity was resolved in favor of accusative case and unambiguously dative-marked NPs did not trigger significant ERP differences. We will discuss the implications of our results for parsing and its neuropsychological correlates. The results of this study support a parser design according to which the so-called structural case (nominative or accusative) is assigned without any delay in the absence of morpho-lexical counterevidence. It is argued that the enhancement of a negative ERP component with a "classical" N400 topography reflects the difficulty of reanalysis due to reaccessing morpho-lexical information that lies outside the domain of the parsing module. Consequently, ERP responses to garden-path effects are not confined to a late positivity but vary depending on the level of processing involved in reanalysis. The fact that garden-path effects may also elicit an N400 can be linked to the nonhomogeneous linguistic properties of the constructions from which they arise.

Adult↗
PubMed1998

Transgenic animal models for the functional analysis of vasoactive peptides.

The interplay of vasoactive peptide systems is an essential determinant of blood pressure regulation in mammals. While the endothelin and the renin-angiotensin systems raise blood pressure by inducing vasoconstriction and sodium retention, the kallikrein-kinin and the natriuretic-peptide systems reduce arterial pressure by eliciting vasodilatation and natriuresis. Transgenic technology has proven to be very useful for the functional analysis of vasoactive peptide systems. As an outstanding example, transgenic rats overexpressing the mouse Ren-2 renin gene in several tissues become extremely hypertensive. Several other transgenic rat and mouse strains with genetic modifications of components of the renin-angiotensin system have been developed in the past decade. Moreover, in recent years gene-targeting technology was employed to produce mouse strains lacking these proteins. The established animal models as well as the main insights gained by their analysis are summarized in this review.

Angiotensinogen↗
PubMed1998

Molecular biology of the kallikrein-kinin system: from structure to function.

The participation of the kallikrein-kinin system, comprising the serine proteases kallikreins, the protein substrates kininogens and the effective peptides kinins, in some pathological processes like hypertension and cardiovascular diseases is still a matter of controversy. The use of different experimental set-ups in concert with the development of potent and specific inhibitors and antagonists for the system has highlighted its importance but the results still lack conclusivity. Over the last few years, transgenic and gene-targeting technologies associated with molecular biology tools have provided specific information about the elusive role of the kallikrein-kinin system in the control of blood pressure and electrolyte homeostasis. cDNA and genomic sequences for kinin receptors B2 and B1 from different species were isolated and shown to encode G-protein-coupled receptors and the structure and pharmacology of the receptors were characterized. Transgenic animals expressing an overactive kallikrein-kinin system were established to study the cardiovascular effects of these alterations and the results of these investigations further corroborate the importance of this system in the maintenance of normal blood pressure. Knockout animals for B2 and B1 receptors are available and their analysis also points to the role of these receptors in cardiovascular regulation and inflammatory processes. In this paper the most recent and relevant genetic animal models developed for the study of the kallikrein-kinin system are reviewed, and the advances they brought to the understanding of the biological role of this system are discussed.

Animals↗
PubMed1998

Cortical and medullary hemodynamics in deoxycorticosterone acetate-salt hypertensive mice.

The effect of acutely increasing renal perfusion pressure or extracellular fluid volume on renal medullary and cortical blood flow was examined in the low-renin deoxycorticosterone acetate (DOCA)-salt hypertension model in mice. A 50-mg DOCA tablet was implanted, and 1% saline was given as drinking water for 3 wk. Medullary and cortical blood flow were determined with laser-Doppler flowmetry, and whole-kidney blood flow was measured with a transit-time ultrasound flowprobe around the renal artery. In control mice, total renal blood flow ranged from 6.3 and 7.6 ml/min per g kidney weight and in DOCA-salt mice from 4.3 and 4.7 ml/min per g kidney weight, respectively, and was minimally affected as renal perfusion pressure was increased. Renal vascular resistance increased correspondingly. During stepwise increases in renal artery pressure from 90 to 140 mmHg, medullary blood flow progressively increased in control mice to 125% of baseline values, whereas cortical blood flow did not change. In DOCA-salt mice, increasing BP from 100 to 154 mmHg had no effect on either cortical or medullary blood flow. Urine flow and sodium excretion were lower in DOCA-salt mice than in controls and increased nearly to the same extent in both groups after volume expansion with isotonic saline. Total renal blood flow increased after saline loading, more in controls than in DOCA-salt mice. Increases in medullary blood flow after saline loading were up to 122% of baseline values in controls and demonstrated a significantly steeper slope than the 110% of baseline increases in DOCA-salt mice. Cortical blood flow, however, was not different between the groups. Thus, medullary blood flow is not as tightly autoregulated as cortical blood flow in normal mice. Natriuresis with acute volume loading is facilitated by increased medullary blood flow. In DOCA-salt mice, the medullary blood flow reaction to renal perfusion pressure increases is abolished, whereas flow increases with extracellular volume expansion are diminished. These results suggest that diminished pressure-natriuresis responses in DOCA-salt mice are related to perturbed medullary blood flow.

Angiotensinogen↗
PubMed1997

Effects of angiotensin II and IV on geniculate activity in nontransgenic and transgenic rats.

Microiontophoretic ejection of angiotensin II and angiotensin IV in the vicinity of geniculate neurons was used to study the effects of these peptides on the discharge rate and the discharge pattern of extracellularly recorded activity. The main aim of the experiments was to study the effects of angiotensins in different strains of rats anesthetized with urethane (normotensive Wistar, normotensive Sprague-Dawley and hypertensive, transgenic (TGR(mREN2)27) rats). Both angiotensins mostly increased the spontaneous activity of angiotensin-sensitive geniculate neurons in all strains. Angiotensin II reduced the number of bursts in most neurons, whereas angiotensin IV significantly enhanced it. Inhibitory effects of angiotensins on spontaneous as well as on light-evoked activity could be effectively blocked by GABA(A) or GABA(B) receptor antagonists. Therefore, it can be supposed that angiotensin-containing afferent fibers innervate both projection and local circuit neurons of the dorsal lateral geniculate nucleus. In addition, angiotensin II suppressed excitation induced by glutamate receptor agonists in most neurons tested. Angiotensin-induced effects could be blocked by specific receptor antagonists. There were no significant differences in the effects of angiotensins in the various strains of rats, except for the latencies of the neuronal responses to the iontophoretic ejection of angiotensins.

Angiotensin II↗
PubMed1997

Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro.

PURPOSE: Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), betamethasone (BM) and desoximetasone (DM) by evaluating their effects on epidermal and dermal cells. Synopsis of pharmacokinetic and pharmacodynamic studies, possibly explaining the improved benefit-risk ratio of prednicarbate. METHODS: Isolated foreskin keratinocytes were used to investigate the influence on epidermal inflammatory processes, dermal fibroblasts of the same origin to study antiproliferative activities of glucocorticoids. Interleukins were measured by ELISA-assay, the influence on II-1 alpha-production also on mRNA-level by RNAse protection assay. Proliferation was assessed by 3H thymidine incorporation and biodegradation by HPLC/UV-absorption. Cell viability was controlled by MTT assay. RESULTS: In keratinocytes, inflammation was induced by TNF alpha, resulting in an increased II-1 alpha synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p < or = 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1 alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation effects. In agreement with the previous experiment, the antiinflammatory potency of native PC was confirmed. In fibroblasts, II-1 alpha and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II-1 alpha and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p < or = 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymidine incorporation. More pronounced antiproliferative features were observed with BM, PEC and especially BMV. CONCLUSIONS: Correlating antiphlogistic effects in keratinocytes (suppression of II-1 alpha) with antiproliferative effects in fibroblasts (suppression of II-1 alpha and II-6), the improved benefit-risk ratio of PC compared to conventional glucocorticoids does not result only from distinct drug metabolism in the skin but also from a specific influence on the cytokine network.

Administration, Topical↗
PubMed1997

Less efficacy with alternating regimen as adjuvant chemotherapy in stage II node-positive breast cancer: results at 8 years (Pronacam 85).

A randomized trial to compare adjuvant treatment with an alternating regimen with conventional chemotherapy was performed. A total of 589 node-positive patients were included and stratified according to number of positive nodes (N1-3 and N > 4) and menopausal status. Premenopausal N1-3 patients were randomized to cyclophosphamide, methotrexate and fluorouracil (CMF) or CMF/4'-epirubicin, cyclophosphamide (EC), post-menopausal N1-3 patients to fluorouracil, 4 epirubicin, cyclophosphamide (FEC) or CMF/EC and pre- and post-menopausal patients with N > or = 4 to fluorouracil, 4' epirubicin, cyclophosphamide, methotrexate, prednisone (FECMP) or CMF/EC. In premenopausal patients, CMF was superior to CMF/EC in terms of disease-free survival (DFS) (65% vs 45%, P = 0.0149) and survival (72.3% vs 50.2%, P = 0.0220) whereas, for N > or = 4 patients, differences between FECMP and CMF/EC did not achieve statistical significance (DFS 35% vs 26.2%; survival 50% vs 38.1%, P = NS). For post-menopausal patients, FEC was superior to CMF/EC in DFS (58.6% vs 36.8%, P = 0.0215) and survival (66.2% vs 46%, P = 0.0155). In post-menopausal patients with N > 4, differences favouring CMF/EC were significant in DFS (40.4% vs 22%, P = 0.0371) but not in survival (47.4% vs 32.2%, P = 0.1185). Alternating regimens did not offer better results in premenopausal and post-menopausal N1-3 patients. Results regarding post-menopausal N > 4 women require further confirmation.

Adult↗
PubMed1997

Renovascular hypertension with low-to-normal plasma renin: clinical and angiographic features.

1. Low-to-normal renin renovascular hypertension (RVH) and the accuracy of renal vein renin ratios were investigated in 129 consecutive patients referred for suspected RVH. Forty-nine had essential hypertension, 24 unilateral renoparenchymal hypertension and 56 renal artery obstruction. Of the latter, 86% were diagnosed retrospectively as RVH, based on fall in blood pressure with correction of renal ischaemia. We measured baseline, captopril-stimulated and renal vein plasma renin activity (PRA) levels, as well as several other parameters. 2. PRA was low-to-normal in 37% of the RVH patients [low-to-normal renin (LNR-) RVH group] and elevated in the remaining 63% [high-renin (HR-) RVH group]. In the LNR-RVH group, low-to-normal renin levels, by immunoreactive active renin and plasma renin concentration measurements, and a blunted response of PRA to captopril, were seen. As compared with HR-RVH, LNR-RVH patients had a longer duration of hypertension (P < 0.05), higher serum K+ (P = 0.04) and lower diastolic blood pressure (P = 0.02). However, they did not differ for the other variables, including the fall in blood pressure after correction of renal ischaemia. Although the number of bilateral stenoses was similar in the two groups, no patient in the LNR-RVH group had total renal artery occlusion compared with 53% in the HR-RVH group (P = 0.00015). The accuracy of renal vein renin indices were high enough to justify their use only in the patients with total occlusion of a renal artery. 3. Thus LNR-RVH is common in patients with longstanding hypertension without a totally occluded renal artery. Since the sensitivity of renin measurements is low, cure of hypertension would be precluded for more than one third of RVH patients, if these tests were a prerequisite for identifying RVH.

Adolescent↗
PubMed1997

Nitric oxide synthase and renin-angiotensin system gene expression in salt-sensitive and salt-resistant Sabra rats.

The molecular mechanisms of salt sensitivity and the contribution of the kidney to salt-induced hypertension in Sabra rats are imperfectly defined. We investigated the expression of the nitric oxide (NO) system (endothelial, inducible, and neural NO synthases) and renin-angiotensin system (renin, angiotensinogen, and angiotensin II type 1A receptor) gene components in the kidneys of SBN/y (salt-resistant) and SBH/y (salt-sensitive) Sabra rat substrains, with and without deoxycorticosterone acetate (DOCA)-salt treatment. We also looked for immunocytochemical evidence of angiotensin II, the effector peptide of the renin-angiotensin system. Inducible and neural NO synthase gene expression values were lower in SBH/y than in SBN/y before and after DOCA-salt treatment. The gene expression level of endothelial NO synthase was not different in SBH/y and SBN/y, either with or without DOCA salt. Renin gene expression was significantly higher in kidneys of SBN/y than in kidneys of SBH/y rats, whereas angiotensinogen gene expression was significantly lower in SBN/y. After DOCA-salt treatment, renin gene expression was strongly suppressed in both strains but more so in SBH/y. Angiotensinogen gene expression, on the other hand, was increased by DOCA salt in SBN/y rats so that the two strains were no longer different. Angiotensin II immunoreactivity was significantly higher in SBN/y than in SBH/y; however, after DOCA salt, immunoreactivity in both strains was no longer detectable. Angiotensin II type 1A receptor gene expression was not different between the two strains, either before or after DOCA-salt administration. We conclude that DOCA salt induced a decrease in the activity of the renin-angiotensin system but did not change NO synthase gene expression in SBH/y and SBN/y. Inducible and neural NO synthase gene expression values were less in SBH/y than in SBN/y, independent of DOCA-salt administration. Thus, the NO system could explain, at least in part, the salt resistance of SBN/y.

Angiotensin II↗
PubMed1996

Behaviour of the transgenic (mREN2)27 rat.

The first model of genetically engineered hypertension, the transgenic rat TGR (mREN2)27, provides a unique opportunity to study the behavioural effects of an altered brain renin-angiotensin system. The TGR (mREN2)27 rats, characterised by fulminant hypertension, show differences in both the peripheral and central angiotensin systems. The behaviour of male transgenic TGR (mREN2)27 and male Sprague-Dawley rats were determined by 4 behavioural tests. While on the elevated X-maze the TGR (mREN2)27 rat showed a greater 'anxiogenic' profile (fewer open arm entries) than the control Sprague-Dawley rats, this 'anxiogenic' profile increased further during a second exposure to the elevated X-maze 24 h later. In comparison the behaviour of the male Sprague-Dawley rats was not different between the two exposures to the elevated X-maze. Locomotor activity did not differ between either the TGR (mREN2)27 or Sprague-Dawley rats when placed in a 1 m2 open-field for 10 min. A short period of fluid-deprivation (3 h) reversed the 'anxiogenic' profile of the TGR (mREN2)27 on the elevated X-maze. Administration of captopril (20 mg . kg-1 body weight) in the drinking water of the TGR (mREN2)27 rats and Sprague-Dawley rats reversed the anxiogenic profile of the TGR (mREN2)27 rat on the elevated X-maze but did not alter the behaviour of the Sprague-Dawley rats.

Animals↗
PubMed1996

Molecular cloning and functional characterization of a mouse bradykinin B1 receptor gene.

The gene encoding a putative mouse bradykinin B1 receptor was cloned from a genomic library by low stringency screening. Analysis of two isolated clones revealed a region which contains an open reading frame uninterrupted by introns and encodes a 334 amino acid protein, which exhibits seven potential transmembrane domains and is 68% identical to the human and rabbit bradykinin B1 receptors. Lipopolysaccharide-treatment induces B1 receptor transcripts in the heart, liver, and lung. Stable expression of the coding region in COS-7 cells resulted in high levels of binding sites for the specific B1 ligand des-ARG10 kallidin (Kd = 1.3 nM; Bmax = 51 fmol/mg protein). The rank order of affinity of the receptor for the agonists and antagonists was: des-Arg9BKdes-Arg9Leu8BKdes- Arg10kallidin >> Hoe-140=bradykinin. Functional coupling of the cloned receptor was demonstrated by the dose-dependent effects of des-Arg(9)BK on the extracellular acidification rate in stably transfected COS-7 cells. This effect was not produced by bradykinin and could be blocked by the B1 antagonist des-Arg9Leu8BK.

Amino Acid Sequence↗
PubMed1996

Transcriptional regulatory elements in the rat bradykinin B2 receptor gene.

In an attempt to elucidate the mechanisms underlying the regulation of bradykinin B2 receptor gene expression, the molecular structure of the rat gene including the 5'-flanking region was characterized (J. Biol. Chem. 269: 26920-26925, 1994). In this study we show that the gene spans about 32 kb, including a long first intron of 25 kb. The promoter region drives reporter gene expression in NG108-15 neuroglioma cells, and its expression is upregulated by cAMP, bradykinin, phorbol esters and by coexpression of an activated ras oncogene but not by dexamethasone.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27.

Transgenic techniques represent powerful tools for the study of gene-related mechanisms of diseases such as hypertension, which results from a complex interaction between genetic and environmental factors. The renin-angiotensin system, a biochemical cascade in which renin functions as the key enzyme in the formation of the effector peptide angiotensin II, plays a major role in the regulation of blood pressure. The renin gene, therefore, represents an important candidate gene for hypertension. Because rats are more suited than mice for a number of experimental settings often employed in cardiovascular research, we modified the transgenic technique to generate the transgenic rat strain TGR(mREN2)27 harboring the murine Ren-2 gene. These transgenic rats develop fulminant hypertension at an early age despite low levels of renin in plasma and kidney. In addition, high expression of the transgene in a number of extrarenal tissues is associated with increased local formation of angiotensin II. Thus the TGR(mREN2)27 rat represents a model of hypertension with a defined genetic background. Studies on the transgenic rat may not only provide new insights into pathophysiological mechanisms of hypertension in this animal model but also offer the unique possibility to investigate the function and regulation of renin-angiotensin systems in extrarenal tissues. The aim of this review is to compile the knowledge that has been accumulated to date on this transgenic rat and to discuss possible mechanisms responsible for its hypertensive phenotype.

Animals↗