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M Bader

Publications and source records attributed to M Bader.

At least 37 records · Page 2Linked to original sources
PubMed2000

Angiotensin peptides acting at rostral ventrolateral medulla contribute to hypertension of TGR(mREN2)27 rats.

We have previously demonstrated that microinjections of the selective angiotensin-(1-7) [ANG-(1-7)] antagonist, A-779, into the rostral ventrolateral medulla (RVLM) produces a significant fall in mean arterial pressure (MAP) and heart rate (HR) in both anesthetized and conscious rats. In contrast, microinjection of angiotensin II (ANG II) AT(1) receptor antagonists did not change MAP in anesthetized rats and produced dose-dependent increases in MAP when microinjected into the RVLM of conscious rats. In the present study, we evaluated whether endogenous ANG-(1-7) and ANG II acting at the RVLM contribute to the hypertension of transgenic rats harboring the mouse renin Ren-2 gene, TGR(mREN2)27. Unilateral microinjection of A-779 (0.1 nmol) produced a significant fall in MAP (-25 +/- 5 mmHg) and HR (-57 +/- 20 beats/min) of awake TGR rats. The hypotensive effect was greater than that observed in Sprague-Dawley (SD) rats (-9 +/- 2 mmHg). Microinjection of the AT(1) antagonist CV-11974 (0.2 nmol) produced a fall in MAP in TGR rats (-14 +/- 4 mmHg), contrasting with the pressor effect observed in SD rats (33 +/- 9 mmHg). These results indicate that endogenous ANG-(1-7) exerts a significant pressor action in the RVLM, contributing to the hypertension of TGR(mREN2)27 transgenic rats. The role of ANG II at the RVLM seems to be dependent on its endogenous level in this area.

Angiotensin I↗
PubMed2000

Regulation of renin: new evidence from cultured cells and genetically modified mice.

Renin, as the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II, has been studied for more than 100 years. Transgenic and knockout mice for renin and other proteins involved in renin regulation and function have recently revealed new evidence that can improve our understanding of its biological relevance. Furthermore, transgenic mice have been the source of the novel cell line As4.1. This cell line has been effective in the analysis of renin secretion and regulation because of its similarity with renin-producing juxtaglomerular (JG) cells. Renin secretion and synthesis by the JG cells of the kidney is upregulated by cAMP and downregulated by intracellular calcium. The effect of cGMP, once elevated by nitric oxide, depends on the present level of cAMP in the cells, which can be stimulatory in the presence of and inhibitory in the absence of the other cyclic nucleotides. All known effectors of renin regulation affect one of these molecules. Adenosine and ATP, released by macula densa cells in response to high salt load in the distal tubule and stretch of the JG cell by renal perfusion pressure, increase calcium. Furthermore, noradrenaline, derived from sympathetic nerve endings, and prostaglandins, generated by macula densa cells under low-salt conditions, increase cAMP. In addition to its stimulatory effect on secretion, cAMP also effectively augments renin mRNA levels by acting at the transcriptional and posttranscriptional levels. Several DNA elements in the distal and proximal promoter regions as well as in intron I have been implicated in cAMP regulation and in tissue specificity of renin gene expression. A second intracellular renin isoform, coded by the same gene but applying a different promoter located in intron I, has recently been detected. Transgenic technology will help to clarify the function of this isoform as well as some of the other unresolved aspects of renin regulation and function and may become the motor of the second century in renin research.

Animals↗
PubMed2000

Sex specific behavioural alterations in Mas-deficient mice.

Male mice lacking the Mas protooncogene have been shown to exhibit an increased anxiety in the Elevated Plus Maze Task and sustained long-term potentiation in the hippocampus without effect on spatial learning in the Morris Water Maze Task. Here, we report behavioural studies in female mice lacking the Mas protooncogene. As for the males, we analysed the learning and anxiety behaviour using both behavioural tasks. With the exception of a trend to a better performance in the Morris Water Maze no differences were found in both tests between control and Mas-deficient females. This implicates that the lack of Mas protein influences spatial learning and anxiety in a sex-specific manner.

Animals↗
PubMed2000

Case and reanalysis.

In this paper we discuss an asymmetry in the Case system of German and its implications for human sentence processing: the asymmetry between nominative/accusative and dative case. Starting from the assumption that dative case has a distinct grammatical representation--dative DPs are embedded into an extra structural layer KP--the results of two experiments will be presented, which show that dative assignment during reanalysis is accompanied by additional processing operations that are not needed when accusative or nominative are assigned. In particular, we show that dative assignment during reanalysis triggers reaccess to the mental lexicon, giving rise to greater processing difficulty. We conclude with a discussion of empirical and theoretical consequences of our findings.

Humans↗
PubMed2000

Smooth-muscle contraction without smooth-muscle myosin.

Here we have used gene-targeting to eliminate expression of smooth-muscle myosin heavy chain. Elimination of this gene does not affect expression of non-muscle myosin heavy chain, and knockout individuals typically survive for three days. Prolonged activation, by KCl depolarisation, of intact bladder preparations from wild-type neonatal mice produces an initial transient state (phase 1) of high force generation and maximal shortening velocity, which is followed by a sustained state (phase 2) characterized by low force generation and maximal shortening velocity. Similar preparations from knockout neonatal mice do not undergo phase 1, but exhibit a normal phase 2. We propose that, in neonatal smooth muscle phase 1 is generated by recruitment of smooth-muscle myosin heavy chain, whereas phase 2 can be generated by activation of non-muscle myosin heavy chain. We conclude that phase 1 becomes indispensable for survival and normal growth soon after birth, particularly for functions such as homeostasis and circulation.

Animals↗
PubMed2000

Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat.

Gluco- and mineralocorticoid receptors (GR and MR) act via common promoter elements but may exert different effects on gene regulation in various regions of the forebrain. In order to separately analyse the role of GR and MR in the regulation of neurotrophic factor genes and their receptors, we used adrenalectomy and subsequent hormone injections in the rat as a model system. Twenty-four hours after adrenalectomy rats were injected with a single dose of corticosterone (2 and 10 mg/kg), aldosterone (0.5 mg/kg) or the synthetic glucocorticoid agonist RU 28362 (4 mg/kg). Gene expression of basic fibroblast growth factor (bFGF) and its high-affinity receptors [fibroblast growth factor receptor subtypes 1-3 (FGF-R1, FGF-R2, FGF-R3)], as well as brain-derived growth factor (BDNF) and neurotrophin-3 (NT-3) was analysed at 4 h after the hormone injection in CA1-CA4 (cornus of Ammon areas of the hippocampus) and dentate gyrus of the dorsal hippocampus and in neocortex by means of in situ hybridization. We found that bFGF is regulated in CA2, CA3 and dentate gyrus by GR and MR together, and in CA1, CA4 and neocortex by GR alone. FGF-R2 expression in the hippocampus seems to be regulated only by MR, while BDNF expression appears to depend on both receptors. FGF-R1, FGF-R3 and NT-3 were only moderately affected by the hormone activation of GR and MR acting in concert or alone in the various regions. Thus, the present findings suggest that the adrenal cortical system through GR and MR participate in the control of neurotrophic factor signalling in a highly subregion- and cellular-dependent manner.

Adrenalectomy↗
PubMed2000

Inhibition of pressure natriuresis in mice lacking the AT2 receptor.

UNLABELLED: Inhibition of pressure natriuresis in mice lacking the AT2 receptor. BACKGROUND: Angiotensin II type 2 (AT2) receptor knockout mice have higher blood pressures than wild-type mice; however, the hypertension is imperfectly defined. We tested the hypothesis that renal mechanisms could be contributory. METHODS: We conducted pressure-natriuresis-diuresis experiments, measured renal cortical and medullary blood flow by laser Doppler methods, and explored cytochrome P450-dependent arachidonic acid metabolism by means of reverse transcription-polymerase chain reaction. RESULTS: Blood pressure was 15 mm Hg higher in AT2 receptor knockout mice than in controls, and pressure diuresis and natriuresis curves were shifted rightward. At similar renal perfusion pressures (113 to 118 mm Hg), wild-type mice excreted threefold more sodium and water than AT2 receptor knockout mice. Fractional sodium and water excretion curves were shifted rightward in parallel. Renal blood flow ranged between 6.72 and 7.88 mL/min/g kidney wet weight (kwt) in wild-type and between 5.84 and 6.15 mL/min/g kwt in AT2 receptor knockout mice. Renal vascular resistance was increased in AT2A receptor knockout mice. Cortical blood flow readings leveled at 2.5 V in wild-type and 1.5 V in AT2 receptor knockout mice. Medullary blood flow readings ranged between 0.8 and 1.0 V and increased 116% in wild-type mice as renal perfusion pressure was increased. This increase did not occur in AT2 receptor knockout mice. The glomerular filtration rate (GFR) was similar in both groups at approximately 1 mL/min/g kwt. Renal microsomes from AT2 receptor knockout mice had less activity in hydroxylating arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-meter) than controls, whereas renal AT1 receptor gene expression was increased in AT2 receptor knockout mice. CONCLUSIONS: Hemodynamic and tubular factors modify renal sodium handling in AT2 receptor knockout mice and may cause hypertension. AT2 receptor disruption induces alterations of other regulatory systems, including altered arachidonic acid metabolism, that may contribute to the intrarenal differences observed between AT2 receptor knockout and wild-type mice.

Angiotensin II↗
PubMed2000

[Magnetic resonance tomography of the brain in workers with chronic occupational manganese dioxide exposure].

AIM: Changes within the brain detected by MRI after chronic manganese poisoning raised the question whether morphological changes of the basal ganglia, particularly of the globus pallidus, could be detected after chronic occupational exposure to manganese dioxide. METHOD: In a cross-sectional study, healthy workers (48 male and 27 female) at a dry cell battery factory were examined. Actual internal exposure was quantified by the analysis of manganese in the blood using atomic absorption spectrometry. Chronic exposure was defined as a cumulative index (CBI) including duration of exposure, individual workplace factors, and previously measured concentrations of MnO2 in dust samples. A Philips Gyroscan T5-II (0.5 T) was used for the MRI of the brain. The following indicators were taken to ascertain possible manganese-induced changes; Pallidum-Index (PI), width of 3rd ventricle and cella media index in addition to clinical examinations. RESULTS: No cases of parkinsonism were detected in clinical examinations or by other means. The mean manganese concentration in blood was 12 micrograms/l (range: 3.9-23.3 micrograms/l). In comparison to the upper reference value of 10 micrograms/l, 42 workers (56%) had a higher body burden. A significant positive correlation between manganese levels in blood and the PI (indicated by T1-shortening) was observed as well as between the CBI and workplace-specific exposure. Brain atrophy was not detected in any of the observed cases. CONCLUSIONS: Long-term exposure to manganese dioxide dust correlates with the Pallidum-Index in MRI scans. Although the MRI findings have no current clinical relevance for individuals, further studies are necessary to evaluate specificity and potential prognostic value.

Adult↗
PubMed2000

Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene.

To evaluate the cardiovascular actions of kinins, we established a transgenic rat line harboring the human tissue kallikrein gene, TGR(hKLK1). Under the control of the zinc-inducible metallothionein promoter, the transgene was expressed in most tissues including the heart, kidney, lung, and brain, and human kallikrein was detected in the urine of transgenic animals. Transgenic rats had a lower 24-h mean arterial pressure in comparison with control rats, which was further decreased when their diet was supplemented with zinc. The day/night rhythm of blood pressure was significantly diminished in TGR(hKLK1) animals, whereas the circadian rhythms of heart rate and locomotor activity were unaffected. Induction of cardiac hypertrophy by isoproterenol treatment revealed a marked protective effect of the kallikrein transgene because the cardiac weight of TGR(hKLK1) increased significantly less, and the expression of atrial natriuretic peptide and collagen III as markers for hypertrophy and fibrosis, respectively, were less enhanced. The specific kinin-B2 receptor antagonist, icatibant, abolished this cardioprotective effect. In conclusion, the kallikrein-kinin system is an important determinant in the regulation of blood pressure and its circadian rhythmicity. It also exerts antihypertrophic and antifibrotic actions in the heart.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Increased kallikrein expression protects against cardiac ischemia.

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.

Animals↗
PubMed2000

Myocardial bradykinin B2-receptor expression at different time points after induction of myocardial infarction.

OBJECTIVE: To characterize the regulation of the myocardial bradykinin B2 receptor after induction of myocardial infarction (MI), we studied its expression at different time points in the left ventricle (LV), right ventricle (RV) and interventricular septum (S) of the heart. DESIGN: Male Sprague-Dawley rats were submitted to permanent occlusion of the left descending coronary artery. Six hours, 24 h or 6 days after MI induction or a sham operation, a Millar-tip catheter was placed in the LV. Left ventricular pressure (LVP) and contractility [(dP/dt)max] were measured. The LV, RV and S of all animals were isolated, and total RNA was extracted. B2-receptor expression was analysed by an RNase-protection assay. In addition, Western blot analysis was used to determine protein levels of the B2 receptor in the infarcted area of the LV. RESULTS: We observed a decrease in LVP and contractility at all time points after MI in comparison with sham-operated animals. Basal B2-receptor expression was detected in the LV and RV, but not in the S of sham-operated rats. In the LV of infarcted hearts, we found a time-dependent up-regulation of the B2-receptor expression, which was increased twofold and fivefold, respectively, 6 h and 24 h after induction of MI compared with controls. This increase was maintained for at least 6 days. Similarly, we also found an up-regulation of the B2-receptor expression in the RV and S. Both reached a peak 24 h after induction of MI. The protein level of the receptor gradually increased up to day 6. CONCLUSION: We conclude that myocardial ischaemia triggers B2-receptor up-regulation in both the infarcted and non-infarcted areas of the heart.

Animals↗
PubMed2000

Interaction between Mas and the angiotensin AT1 receptor in the amygdala.

The Mas-protooncogene is a maternally imprinted gene encoding an orphan G protein-coupled receptor expressed mainly in limbic structures of the rodent CNS. Because Mas and the product of the Mas-related gene enhance the effects of angiotensins on cells expressing angiotensin receptors of the AT1 subtype, we first compared the distribution of cells expressing AT1 receptors in different limbic and thalamic brain structures in Mas-knockout mice and in wildtype mice by an immunohistochemical approach. No significant differences could be found between the two strains. The Mas-protooncogene seems to be implicated in the signal transduction of angiotensin receptors and is expressed in the amygdala. Therefore we then analyzed whether field potentials are altered by angiotensin II in brain slices of the basolateral amygdala. An opposite action of angiotensin II was obtained in mice lacking the Mas-protooncogene in comparison to wildtype mice. The use of different angiotensin receptor antagonists provides the first in vitro evidence for a functional interaction between the Mas-protooncogene and the AT1 receptor.

Action Potentials↗
PubMed2000

The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy.

The potential involvement of the brain renin-angiotensin system in the hypertension induced by subpressor doses of angiotensin II was tested by the use of newly developed transgenic rats with permanent inhibition of brain angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague-Dawley rats (parent strain) (122.5+/-1.5 versus 128.9+/-1.9 mm Hg, respectively; P<0.05). The increase in systolic blood pressure induced by 7 days of chronic angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in comparison with control rats (29.8+/-4.2 versus 46. 3+/-2.5 mm Hg, respectively; P<0.005). Moreover, an increase in heart/body weight ratio was evident only in Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle measured by ribonuclease protection assay were similarly increased in both TGR(ASrAOGEN) (ANP, x2.5; collagen III, x1.8) and Sprague-Dawley rats (ANP, x2.4; collagen III, x2) as a consequence of angiotensin II infusion. Thus, the expression of these genes in the left ventricle seems to be directly stimulated by angiotensin II. However, the hypertensive and hypertrophic effects of subpressor angiotensin II are at least in part mediated by the brain renin-angiotensin system.

Angiotensin II↗
PubMed2000

Blood pressure-independent effects in rats with human renin and angiotensinogen genes.

The blood pressure-independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight. Although triple-drug therapy delayed the onset of renal damage, severe albuminuria nevertheless occurred. Semiquantitative scoring of ED-1-positive and MIB-5-positive (nuclear cell proliferation-associated antigen Ki-67) cells showed profound perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a minimal effect on local inflammatory response or vascular cell proliferation. In contrast, a novel orally active human renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks, normalized blood pressure and coronary resistance and also prevented cardiac hypertrophy and albuminuria. ED-1-positive cells and MIB-5-positive cells were decreased by HRI in hearts and kidneys almost to levels observed in normotensive Sprague-Dawley rats. The renoprotective effects of HRI were at least in part due to improved renal hemodynamics and distal tubular function, since HRI shifted renal pressure-diuresis/natriuresis curves leftward by approximately 35 mm Hg, increased glomerular filtration rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased by 400% and renal Ang II level was increased by 300% compared with Sprague-Dawley rats. HRI decreased plasma human renin activity by 95% and normalized Ang II levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinogen genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure.

Albuminuria↗
PubMed2000

Transgenic animal models for neuropharmacology.

The establishment of novel animal models using gene targeting and transgenic technology has opened a new area of neuropharmacological research. For the first time, it became possible to alter the expression of a gene in a specific cell type of an intact animal by either overexpression, inhibition or ablation. This review describes the technology and lists the relevant tools, such as reporter genes, suicide genes, immortalizing genes, and promoters, necessary for the targeted expression of these and other genes in specific cells of the central nervous system. In addition, the problem is discussed that the mouse is the species in which this technology is by far the most developed, while the rat has been used as the model species for neuropharmacology during the last century.

Animals↗
PubMed2000

From genotype to phenotype--behavior of the transgenic rat TGR(mRen2)27 as an example.

Transgenic techniques provide a tool to generate animals that differ from the wild-type by one or more genes, either by introducing foreign genes (transgenic animals) or by specific mutations of genes (knock-out animals). Most transgenic and knock-out animals are mice and not rats. The frequent use of rat models in the behavioral laboratory, however, will require the increasing application of transgenic techniques in this species. This paper reviews behavioral data from our laboratory as an example of characterizing the behavioral phenotype of a particular transgenic rat, the TGR(mRen2)27 rat. By describing the anxiogenic profile of this rat we also consider some problems associated with such an analysis, with the intention to raise issues that may also apply to studies of behavior in transgenic animals in general.

Animals↗