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Biomedical subjects

D Ganten

Publications and source records attributed to D Ganten.

At least 199 records · Page 11Linked to original sources
PubMed1994

Effects of nephrectomy and adrenalectomy on the renin-angiotensin system of transgenic rats TGR(mRen2)27.

The transgenic rat TGR(mRen2) develops severe hypertension with high renin activity in the adrenal and low renin activity in the kidney. To clarify the role of the adrenal gland as a source of circulating renin in TGR rats, we investigated the effects of nephrectomy (NEPEX) and adrenalectomy (ADX) on the adrenal and plasma renin-angiotensin system. TGR rats had a high basal plasma renin concentration (PRC; 18.2 +/- 1.0 ng angiotensin-I (AngI)/ml.h) compared with Harlan Sprague-Dawley (SD) rats (7.4 +/- 0.5 ng AngI/ml.h; P < 0.01) and SD rats of the Hannover strain from which the TGR rat was derived (5.3 +/- 0.6 ng AngI/ml.h, P < 0.01); TGR rats also had high adrenal renin (83.3 +/- 8.9) compared with Harlan SD rats (5.5 +/- 0.7; P < 0.01) and Hanover SD rats (6.1 +/- 0.6 ng AngI/ml.h). NEPEX markedly increased PRC (82.4 +/- 18.8 ng AngI/ml.h, P < 0.01) and adrenal renin levels (386.3 +/- 43.9 ng AngI/adrenal.h; P < 0.01) in TGR rats. ADX significantly lowered control levels of PRC and plasma AngII in the TGR rats (19.0 +/- 1.2 to 7.7 +/- 1.2 ng AngI/ml.h and 33.5 +/- 5.6 to 12.8 +/- 2.1 pg/ml, respectively) and suppressed the increases in PRC (119.4 +/- 20.2 to 61.8 +/- 4.0 ng AngI/ml.h) and plasma AngII (95.8 +/- 9.8 to 55.1 +/- 4.3 pg/ml; P < 0.01) caused by NEPEX in TGR rats. However, the levels of PRC and plasma AngII remained high after NEPEX/ADX in TGR rats. Our results suggest that the adrenal gland is one of the main sources of circulating renin in the TGR rat, but other extrarenal sources of plasma renin also exist in these animals.

Adrenal Glands↗
PubMed1994

Effects of enalaprilat on circadian profiles in blood pressure and heart rate of spontaneously and transgenic hypertensive rats.

We investigated the dose-dependent cardiovascular effects of enalaprilat at different dosing times in two animal models of hypertension. Blood pressure (BP) and heart rate (HR) were measured telemetrically in 5 spontaneously hypertensive rats (SHR) and in 5 transgenic hypertensive rats (TGR) after intraperitoneal (i.p.) injection of enalaprilat either at 700 h or at 1900 h. In SHR, dosing of enalaprilat at the beginning of the resting period, i.e., at 700 h, significantly reduced BP but did not influence HR. After dosing at 1900 h, BP was unchanged, whereas HR increased, which might have resulted from reflexly increased sympathetic tone. In TGR, enalaprilat at either dosing time decreased BP dose dependently and to a higher extent than in SHR, but the effects were more pronounced after morning than after evening dosing. These findings demonstrate that in two animal models of hypertension the antihypertensive effects of enalaprilat depended on the time of drug dosing.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Genetics of primary hypertension.

New technologies in molecular biology and medicine have opened new avenues for the study of disease. As a result of this, the genetic basis of many diseases has been discovered and candidate genes that contribute to the underlying pathology have been identified. An important approach to test the function of these genes is the establishment of transgenic animal models. Candidate genes can be expressed in these animals to study their regulation in vivo. Furthermore, the pathophysiological consequences of the alteration in gene expression can be investigated in detail. Like many other diseases, primary hypertension is influenced by genetic factors. A number of candidate genes have been implicated in its pathogenesis, and current research efforts are directed toward testing these candidates. For this purpose, several transgenic animal models have been established. Most of this transgenic work has been carried out in mice, but recent efforts have focused on the development of transgenic rat models for hypertension, which may provide the better experimental system for the study of cardiovascular regulation.

Angiotensinogen↗
PubMed1994

Widespread tissue distribution of human chymase.

OBJECTIVE: Human chymase is a potent and specific angiotensin (Ang) II-forming serine proteinase. Although the histological localization of heart chymase indicated that this enzyme contributes to extracellular Ang II formation, the systemic distribution and the level of expression of chymase in various human tissues have not been clarified. This information is needed to elucidate the human tissue Ang II system. METHODS: Levels of immunoreactivity and enzymatic activity in various human tissues were evaluated respectively by Western blot analysis and by an enzymatic assay for Ang II-forming activity from Ang I. RESULTS: High levels of chymase-like immunoreactivity were found in alimentary tract tissue, uterus and tonsil; moderate levels were found in both cardiac ventricles, lung, adenoid and liver; low levels were found in the cardiac atria, coronary artery, aorta and skin; and almost undetectable levels were found in the spleen and kidney. High levels of chymase-like enzymatic activity were detected in skin, oesophagus, stomach and uterus; moderate levels were found in both cardiac ventricles, lung, colon, tonsil, adenoid and renal cortex; and low levels were found in the cardiac atria, coronary artery, aorta, spleen, renal medulla and liver. CONCLUSIONS: Our studies have revealed heterogeneous and widespread tissue distribution of human chymase throughout the human body and indicate that chymase probably has a significant influence not only in the heart but also in other tissues.

Angiotensin I↗
PubMed1993

Extra-hepatic transcription of plasma prekallikrein gene in human and rat tissues.

The expression of plasma prekallikrein (PPK) mRNA has been investigated applying reverse transcription, followed by polymerase chain reaction, of mRNA (RT-PCR) in various human and rat tissues. PPK gene transcripts were detected in liver and kidney in both species and, in addition, in human adrenal gland and placenta. No PPK mRNA was identified in rat adrenal gland, heart, aorta, lung, brain cortex and medulla, hypothalamus, and uterus. These results show that PPK gene expression is not restricted to the liver.

Adrenal Glands↗
PubMed1993

Antisense oligonucleotide to c-fos induces ipsilateral rotational behaviour to d-amphetamine.

The immediate-early genes, especially c-fos, have been suggested to have an important role in neuronal plasticity and memory. However, it has been difficult to determine if in fact c-fos can participate in control of behaviour. Here we can report that direct unilateral infusion into the rat neostriatum of an antisense phosphothioate oligodeoxynucleotide to c-fos mRNA leads to the rapid induction of ipsilateral rotational behaviour after d-amphetamine administration. This is associated with an elimination of the in vivo expression of Fos-like immunoreactivity within the infused region of neostriatum. Following infusion of these oligodeoxynucleotides labelled with fluorescein isothiocyanate they appear with a nuclear and cytoplasmic location in a large number of nerve cells, many of which are immunoreactive for dopamine and cyclic AMP regulated phosphoprotein. The present findings suggest that the immediate-early gene c-fos has a role also in control of behavioural activity, as illustrated in D1 receptor containing striatal neurones.

Animals↗
PubMed1993

Photochemically induced focal cerebral ischemia in rat: time dependent and global increase in expression of basic fibroblast growth factor mRNA.

Induction of basic fibroblast growth factor (bFGF) mRNA expression was studied in a Rose bengal induced focal cerebral ischemia during a time course of 2, 4, 24, 72 h and 7 days. Focal cerebral ischemia induced by Rose bengal resulted in a global upregulation in bFGF gene expression at the 24 h time-interval. This upregulation in bFGF gene expression was due to an upregulation in glial bFGF expression in most of the areas studied as seen by means of non-radioactive in situ hybridization in combination with immunocytochemistry for glial fibrillary acidic protein. However, in the piriform cortex a putative neuronal upregulation of bFGF could be detected by combination of non-radioactive in situ hybridization, immunohistochemistry for glial fibrillary acidic protein and nuclear staining with Neutral red. Semiquantitative data concerning bFGF mRNA expression were obtained by use of computer-assisted microdensitometry and revealed substantial increases in bFGF mRNA expression in the cingulate cortex, the neostriatum, a 1 mm marginal zone close to the external capsule and the olfactory tubercle at bregma levels 1 to 2 mm rostral to the lesion. No changes in bFGF gene expression were seen in field CA1 of Ammon's horn on the lesioned side and in dentate gyrus at bregma levels between -2.12 to -3.30 mm. We observed significant changes in bFGF upregulation in the caudate putamen, the piriform cortex and the amygdaloid region and the frontoparietal cortex at bregma levels -2.12 to -3.30 mm. These data indicate that photochemically induced focal cerebral ischemia leads to an early and global response in bFGF gene expression, which is due to an upregulation mainly in astrocytes. The observed widespread upregulation of the bFGF gene transcription rostral and caudal to the lesion is suggested to be due in part to neuronal glutaminergic connections between the areas investigated and in part due to increases in extracellular fluid signals (volume transmission).

Animals↗
PubMed1993

[Primary hyperreninemia. An unusual cause of secondary arterial hypertension].

In 1975, scintigraphy revealed a 6.5 x 5 cm tumour in the region of the left adrenal in a 36-year-old man with known hypertension for 5 years (systolic pressure up to 250 mm Hg, diastolic up to 130 mm Hg). A laparotomy was performed for a suspected phaeochromocytoma. A tumour was located in the upper pole of the kidney and removed together with the kidney. The blood pressure quickly returned to normal after the operation: it remained stable for the following 17 years (between 130/80 to 150/90 mm Hg). Originally the tumour could not be clearly classified either clinically or histologically. But recently the paraffin-imbedded tumour specimen was re-examined by immunohistochemistry and in-situ hybridization. This identified a renin-producing tumour so that primary reninism was the cause of the arterial hypertension.

Adult↗
PubMed1993

The renin-angiotensin system in the brain: an update 1993.

The renin-angiotensin system is considered to be one of the most important hormonal systems in the regulation of blood pressure and body fluid homeostasis. Ever since this system has been demonstrated to be present also in the brain, vast efforts have been made in investigating its central impact and function. The last few years, and especially the development of non-peptidic angiotensin II receptor subtype specific antagonists and the subsequent pharmacological characterization of these subtypes, brought this field of research a large step forward. This progress also might have opened up new avenues of developing highly specific anti-hypertensive drugs and thereby new ways of treating hypertension. This paper intends to provide a summary of the knowledge about the brain renin-angiotensin system accumulated during recent years; an update 1993.

Angiotensin II↗
PubMed1993

Regional expression of angiotensinogen mRNA in the brain of one-week-old, adult and old male rats.

The purpose of this study was to investigate possible regional differences in the distribution of angiotensinogen-mRNA in the postnatal versus the aging animal using in situ hybridization and computer-assisted microdensitometry. An essentially identical regional distribution pattern of angiotensinogen-mRNA in the brains of postnatal, adult and old rats was demonstrated. Substantial differences in angiotensinogen expression were observed in brain areas of postnatal versus adult and old animals. Also large differences were seen in the ratios of angiotensinogen-mRNA levels in different brain areas within one age. The medulla of young animals contained the largest amounts of angiotensinogen-mRNA compared to hypothalamus and midbrain. In contrast, adult and old animals showed approximately the same expression levels in midbrain and medulla, whereas the largest amounts of angiotensinogen-mRNA were expressed in the hypothalamus.

Aging↗
PubMed1993

Cellular localization of angiotensin type 1 receptor and angiotensinogen mRNAs in the subfornical organ of the rat brain.

The cellular localization of angiotensin type 1 receptor (AT 1) and angiotensinogen mRNA expression in the subfornical organ (SFO) of the rat brain has been studied by means of non-radioactive in situ hybridization combined with immunocytochemistry for glial fibrillary acidic protein (GFAP) and Neutral red staining. The AT 1 receptor mRNA expression is shown to be within putative nerve cells without any association with the glial fibrillary acidic protein (GFAP)-immunoreactive (IR) cells. In contrast the angiotensinogen cRNA expression is associated predominantly with GFAP-IR cells. The results demonstrate that a neuronal AT 1 receptor mediates the actions of circulating angiotensin II on the SFO and that the angiotensinogen mRNA is predominantly expressed in the SFO astroglial cells.

Angiotensin I↗
PubMed1993

Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat.

Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.

Angiotensinogen↗
PubMed1993

Expression of the mouse ren-2 gene in the small intestine is regulated by food intake.

The existence of a local renin/angiotensin system in the intestine of mammals is speculative despite the known importance of angiotensin II for water and electrolyte homeostasis. We demonstrate the presence of ren-2 transcripts in the small intestine of DBA/2 mice. The marked expression of the ren-2 gene is blunted tissue-specifically by starvation, corroborating a local renin/angiotensin system in this organ.

Animals↗
PubMed1993

Tissue distribution of angiotensinogen mRNA during experimental inflammation.

It has been proposed that angiotensinogen is an acute phase protein, because its plasma concentrations increase during some forms of acute inflammation. However, this is not a consistent finding. Furthermore, no specific function of circulating angiotensinogen in the inflammatory reaction is known. This may be different for extrahepatic synthesis of angiotensinogen, as the local generation of angiotensin II has been implicated in inflammation-related processes in some organs. We have therefore examined the expression of the angiotensinogen gene in liver and extrahepatic tissues under the influence of experimental inflammatory stimuli in comparison to the effects of dexamethasone. Dexamethasone (7 mg/kg intraperitoneally) induced a several-fold increase in angiotensinogen mRNA in liver, aorta, heart, adrenal, and a moderate increase in kidney, testis, and brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, whereas albumin concentrations decreased. Lipopolysaccharide (500 micrograms/kg subcutaneously) stimulated angiotensinogen mRNA in hepatic, cardiac, renal, adrenal, and testicular tissues, but not in the brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, those of albumin decreased. In turpentine-treated rats (5 ml/kg subcutaneously), angiotensinogen mRNA was reduced in liver and kidney; stimulated in adrenals, testis, and heart; and not influenced in the brain. Plasma concentrations of the acute phase proteins increased, whereas angiotensinogen and albumin decreased. It is concluded that hepatic and extrahepatic angiotensinogen gene expression seem to be regulated similarly by dexamethasone and lipopolysaccharide. The different response to turpentine may reflect differences in the pattern of cytokines induced by turpentine or be associated with additional pharmacological effects of turpentine or its metabolites.

Angiotensinogen↗
PubMed1993

Fast and widespread increase of basic fibroblast growth factor messenger RNA and protein in the forebrain after kainate-induced seizures.

Basic fibroblast growth factor promotes the survival and outgrowth of neurons and protects neurons from glutamate mediated excitotoxicity. The present study investigates the effects of kainate-induced epileptic seizures on the cellular expression of basic fibroblast growth factor messenger RNA and protein. Seizures were induced by injection of 12 mg/kg kainic acid. Rats were killed 3 h, 6 h, and 24 h after injection of the drug and analysed by radioactive and non-radioactive in situ hybridization as well as immunohistochemistry for glial fibrillary acidic protein and basic fibroblast growth factor. Radioactive in situ hybridization revealed a fast (6 h), strong (300-400% of control) and widespread increase of basic fibroblast growth factor messenger RNA after kainate-induced seizures. Non-radioactive in situ hybridization using digoxigenin-labeled riboprobes combined with glial fibrillary acidic protein immunohistochemistry showed that basic fibroblast growth factor messenger RNA was markedly increased in astroglial cells throughout the brain. Immunohistochemistry for basic fibroblast growth factor revealed labeling of nuclei in astrocytes in many forebrain areas and in neurons in area CA2 and fasciola cinereum. Kainate markedly increased basic fibroblast growth factor-like immunoreactivity in nuclei of astrocytes in several forebrain areas. This effect peaked 24 h after injection. It is concluded that basic fibroblast growth factor may play a neuroprotective role in kainate mediated excitotoxicity as seen from a massive and widespread astroglial increase in basic fibroblast growth factor messenger RNA and -like immunoreactivity. These effects may, to a large degree, be mediated through the excessive release of endogenous glutamate, induced by the epileptic seizures, leading to activation of glutamate receptors on astroglial cells through volume transmission, i.e. via diffusion of electrochemical signals in the extracellular fluid pathways.

Animals↗
PubMed1993

Cellular expression of angiotensin type-1 receptor mRNA in the kidney.

Angiotensin II has multiple renal effects that are important in the regulation of renal hemodynamics and electrolyte secretion, and binding sites for angiotensin II have been demonstrated in different cells of the kidney. In the present study the cellular localization of mRNA for the angiotensin type 1 (AT1) subtype of the angiotensin II receptor was studied in adult rat kidney using a cRNA probe and in situ hybridization. Strong labeling was demonstrated in tubule cells of the inner and outer stripe of the outer medulla. In emulsion-dipped sections, counter-stained with hematoxylin-eosin, labeling was identified in segment S3 of proximal tubules and in the thick ascending limb of loop of Henle (mTAL). The results suggest expression of AT1-receptor mRNA with a distinct compartmentalization within the nephron.

Animals↗
PubMed1993

Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1.

OBJECTIVES: The SA-gene shows markedly higher levels of expression in the kidneys of spontaneously hypertensive rats (SHR) than in their non-hypertensive reference strain, the Wistar-Kyoto (WKY) rat. Based on the important role of the kidney in blood pressure regulation, the possibility has been raised that this gene, the translational product of which remains unknown, may participate in the pathogenesis of primary hypertension. The present study was conducted to test this hypothesis and to ascertain the chromosomal localization of the SA-gene. DESIGN: A cosegregation study was performed using an F2 intercross between stroke-prone SHR (SHRSP) and WKY rats, and a previously described restriction fragment length polymorphism of the SA-gene for characterization of genotype. Mapping of the SA-gene was accomplished by screening a somatic cell-hybrid panel and by linkage group analysis. RESULTS: A statistically significant difference in systolic blood pressure was found after sodium loading, but not under basal conditions between groups of rats defined by zygosity at the SA locus, consistent with a hypertensive effect of the SHRSP allele. No effect of SA genotype on diastolic blood pressure was observed. The SA-gene was localized on rat chromosome 1. CONCLUSIONS: This study establishes the SA locus on chromosome 1 as a region in which a gene or genes contributing to blood pressure regulation in this model are localized, and provides further evidence for a possible role of the SA-gene in the pathogenesis of hypertension.

Animals↗