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D Ganten

Publications and source records attributed to D Ganten.

At least 235 records · Page 13Linked to original sources
PubMed1993

Cardiac angiotensin II formation: the angiotensin-I converting enzyme and human chymase.

Angiotensin-I converting enzyme (ACE) inhibitors have provided a remarkable improvement in the treatment of patients with primary hypertension and congestive heart failure. The cardiac renin-angiotensin system is one of the major targets of ACE inhibitor therapy since recent studies show that the human heart contains high affinity angiotensin II (Ang II) receptors and ACE activity. However, it is not clear why ACE inhibitors are more effective than other vasodilators in the treatment of patients with congestive heart failure. This gap in knowledge led us to study the biochemical mechanism of Ang II formation in the human heart. Such studies have only recently been addressed. So far, two Ang II-forming enzymes (ACE and human chymase) have been identified. Unlike in the rat heart, the minor (10%) component of Ang II-forming activity in the left ventricle is due to ACE, whereas the major (80%) component is due to human chymase. This novel cardiac serine proteinase has been purified from the human left ventricle and characterized, and recently, the cDNA and the gene for this enzyme have been cloned. Biochemical characterization revealed that human chymase is the most efficient and specific Ang II-forming enzyme described thus far, but the cellular and regional distribution of two Ang II-forming enzymes seem to be quite different. ACE is localized mainly in endothelial cells and its expression level is higher in atria than ventricles whereas chymase is localized in the interstitial region of the myocardium and its expression is higher in ventricles than atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Tissue renin-angiotensin systems. Their role in cardiovascular disease.

BACKGROUND: The identification of the components of the renin-angiotensin system (RAS) in various extrarenal tissues suggested the existence of local renin-angiotensin systems with organ-specific functions that may act independently from the plasma RAS. These findings have led to the hypothesis of paracrine-autocrine functions of the RAS, which implies that locally generated angiotensin II mediates effects within one tissue or within one cell. Whereas the circulating endocrine RAS appears to be responsible for acute effects, the tissue RAS seems to participate in more chronic processes such as secondary structural changes and therefore may contribute to the pathogenesis of hypertension as well as other cardiovascular disorders such as cardiac hypertrophy, coronary artery disease, and atherosclerosis. METHODS AND RESULTS: The use of molecular biological techniques has demonstrated that all components of the RAS-renin, angiotensinogen, converting enzyme, and angiotensin receptors-are expressed in several tissues that participate in the regulation of cardiovascular homeostasis. CONCLUSIONS: The therapeutic importance of inhibitors of the RAS, such as converting enzyme inhibitors, is based on their cardioprotective as well as antiproliferative effects and points to a direct involvement of the RAS in the development and preservation of primary hypertension, a pathological condition in which normal or even low plasma renin activity is a common finding. Reversal of cardiovascular structural changes and enhancement of renal sodium excretion by converting enzyme inhibitors are important long-term antihypertensive actions possibly mediated by inhibition of the tissue RAS.

Animals↗
PubMed1993

The renin-angiotensin paradigm. Practical therapeutical consequences of basic research.

The challenge in hypertension research is the elucidation of the primary, genetic causes of elevated blood pressure. The basic information on how a cell, an organ, and the whole body function resides within the chromosomes, the individual genes and their DNA sequence. The problem with understanding primary (genetic) hypertension in man is that several genes are involved in the cardiovascular control mechanisms and that the genetics are complex. In addition, environmental factors which act over long time-spans confound the genotype/phenotype relationship individually, within a family, and regionally. This shows that while monogenetic, dominant traits and diseases such as some lipid disorders may be studied with relative ease, polygenetic diseases like primary hypertension remain puzzles, which make well defined experimental models as well as new strategies in the genetics of human primary hypertension mandatory. The availability of new molecular biological techniques enables us to conduct genetic linkage studies in humans and in animal models on a more extensive basis. Using gene technology it is possible to introduce new, additional genes in normotensive and hypertensive animals. It is also possible, in the mouse, to delete or mutate specific genes, and similar technology is being developed for use in the rat. This marks the important transition from classic breeding, the experiments of nature, to "high tech" genetics with previously impossible and unparalleled opportunities and the use of this in formation and methodology for clinical medicine.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

The renin-angiotensin system in the brain. Localization and functional significance.

Many neuropeptides have been localized in brain areas involved in cardiovascular regulation. In some cases, regulatory systems which have been originally described in other organs have been found in the brain. A prominent member of this group is the renin-angiotensin system. All of its known components have been localized in the central nervous system and angiotensin II has numerous actions in the central regulation of cardiovascular homeostasis. In addition there are actions which go beyond an active role in the control of blood pressure; these include behavioural actions and the regulation of thirst. The brain renin angiotensin system interacts with other neurotransmitters such as the catecholaminergic system and may act as a neuromodulator.

Animals↗
PubMed1992

Effects of angiotensin-converting enzyme inhibitors on tissue renin-angiotensin systems.

The renin-angiotensin system (RAS) plays a major role in the control of blood pressure and cardiovascular homeostasis and is involved in the pathogenesis of a number of cardiovascular disorders. The efficacy of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and congestive heart failure has led to the widespread clinical use of ACE inhibitors in primary or secondary prevention of heart disease. The demonstration of the expression of the components of the RAS in several extrarenal tissues, as well as local generation of angiotensin II, has confirmed the existence of a tissue RAS that may serve organ-specific functions and act independently from the plasma RAS. The concept of paracrine/autocrine functions of the local RAS has changed our understanding of the functions of the RAS and suggests that tissue ACE inhibition may be of greater importance than inhibition of circulating ACE in the treatment of congestive heart failure and other cardiovascular disorders. Whereas the circulating endocrine RAS appears to be responsible for mediation of acute effects, the tissue RAS seems to be involved in more chronic situations, such as secondary structural changes of the cardiovascular system, and therefore could contribute to the pathogenesis of hypertension as well as other cardiovascular disorders, such as cardiac hypertrophy, coronary artery disease, and atherosclerosis. Several experimental and clinical findings suggest that reversal of cardiovascular structural changes secondary to cardiovascular disease and enhancement of renal sodium excretion by ACE inhibitors are important long-term antihypertensive actions possibly mediated by inhibition of the tissue RAS.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

The distribution of angiotensin II AT1 receptor subtype mRNA in the rat brain.

The present study demonstrates the existence and regional distribution of angiotensin II AT1 receptor subtype mRNA expression in the rat brain by the use of in situ hybridization and RNase protection assay. Substantial expression levels in the brain have only been detected in certain distinct areas, such as the subfornical organ, the parvocellular part of the paraventricular hypothalamic nucleus, and the median preoptic nucleus. The results give further evidence for the involvement of the angiotensin II AT1 receptor subtype in the classical functions of central angiotensin II, like blood pressure control, body fluid homeostasis and in corticotropin-releasing factor (CRF) secretion.

Angiotensin II↗
PubMed1992

Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes.

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure. We report here the development of transgenic rats carrying the human angiotensinogen TGR-(hAOGEN) and human renin TGR(hREN) genes. The plasma levels and tissue distribution of the transcription and translation products from both genes are described. A unique species specificity of the enzyme kinetics was observed. The human RAS components in the transgenic rats did not interact with the endogenous rat RAS in vivo. Instead, infusions of exogenous human RAS components specifically interacted with human transgene translation products. Thus, infusion of human renin in TGR(hAOGEN) led to an increase of angiotensin II and an elevation of blood pressure, which could not be antagonized by the human-specific renin enzyme inhibitor Ro 42-5892. Rat renin also elevated blood pressure and angiotensin II in TGR(hAOGEN); however, this effect was not antagonized by the human renin inhibitor. Compared to mice, rats offer the advantage of chronic instrumentation and repetitive, sophisticated, hemodynamic, and endocrinological investigations. Thus, transgenic rat models with human-specific enzyme kinetics permit primate-specific analyses in non-primate in vivo and in vitro experimental systems.

Angiotensin II↗
PubMed1992

High blood pressure in transgenic mice carrying the rat angiotensinogen gene.

Transgenic mice were generated by injecting the entire rat angiotensinogen gene into the germline of NMRI mice. The resulting transgenic animals were characterized with respect to hemodynamics, parameters of the renin angiotension system, and expression of the transgene. The transgenic line TGM(rAOGEN)123 developed hypertension with a mean arterial blood pressure of 158 mmHg in males and 132 mmHg in females. In contrast, the transgenic line TGM(rAOGEN)92 was not hypertensive. Rat angiotensinogen was detectable only in plasma of animals of line 123. Total plasma angiotensinogen and plasma angiotensin II concentrations were about three times as high as those of negative control mice. In TGM(rAOGEN)123 the transgene was highly expressed in liver and brain. Transcripts were also detected in heart, kidney and testis. In TGM(rAOGEN)92 the brain was the main expressing organ. In situ hybridization revealed an mRNA distribution in the brain of TGM(rAOGEN)123 similar to the one in rat. In TGM(rAOGEN)92 the expression pattern in the brain was aberrant. These data indicate that overexpression of the angiotensinogen gene in liver and brain leads to the development of hypertension in transgenic mice. The TGM(rAOGEN)123 constitutes a high angiotensin II type of hypertension and may provide a new experimental animal model to study the kinetics and function of the renin angiotensin system.

Angiotensinogen↗
PubMed1992

Mechanisms of cardiac growth. The role of the renin-angiotensin system.

Hypertension is associated with cardiac hypertrophy, which is a structural adaptation of the heart in order to attenuate the systolic stress on the left ventricle. As cardiac myocytes cannot divide, they increase in mass and volume, probably by activating second messengers and proto-oncogenes involved in cellular differentiation and proliferation. Various mechanisms, such as pressure overload and angiotensin II (Ang II), have been proposed to trigger cardiocyte growth and left-ventricular hypertrophy (LVH). In both cases, activation of second messenger routes which increase the intracellular calcium concentration, protooncogene expression, and protein synthesis have been demonstrated. Ang II also facilitates the action of another trophic agent for cardiocytes, which is noradrenaline (NA). In addition, the prevention and reversal of LVH by inhibitors of angiotensin-converting enzyme (ACE) suggests a key role for Ang II. However, no conclusive evidence has demonstrated the role of a single pathophysiologic factor in LVH. Therefore, it is more attractive to suggest a link between high blood pressure, renin-angiotensin and other vasoactive systems, such as the adrenergic system, which might together lead in a synergistic way to cardiac hypertrophy.

Angiotensin II↗
PubMed1992

Transgenic rats carrying the mouse renin gene--morphological characterization of a low-renin hypertension model.

Transgenic rats [TGR; strain name TGR(mRen2)27] harboring the mouse Ren-2 renin gene have been recently generated as a model for the study of primary hypertension that offers the advantage of a clearly-defined genetic alteration. Expression of the mouse Ren-2 gene causes severe hypertension (200 to 260 mm Hg) which is responsive to converting enzyme inhibitors. Compared to control transgene-negative littermates, plasma renin and angiotensin II values are lowered in TGR, whereas plasma prorenin values are strongly elevated. The adrenal gland in TGR shows marked overexpression of mouse renin messenger RNA; in situ hybridization using a 35S-labelled mouse-renin RNA probe reveals that enhanced renin expression is mainly localized to cells of the zona glomerulosa and outer zona fasciculata. Immunohistochemically, renin protein in the TGR adrenal gland is stored in larger quantities than in controls. Adrenal transgene expression probably accounts for most of the elevated plasma prorenin level in TGR, since bilateral adrenalectomy (ADX) causes a significant decrease in prorenin level (318 +/- 79 ng angiotensin I/ml/hr before ADX to 70 +/- 43 ng 4 days after ADX, P less than 0.0005). In the kidney, renin synthesis is almost completely suppressed in TGR. In situ hybridization demonstrates that few juxtaglomerular afferent arterioles express renin. Immunohistochemically, the TGR kidney shows significantly reduced renin and angiotensin II immunoreactivity at the afferent arteriole. Ultrastructural analysis of the afferent arteriolar wall frequently shows the complete absence of renin secretory granules since the granular cells are mostly converted into smooth muscle cells. Beginning at an age of approximately four to six months, TGR develop hypertension-related alterations and pathological lesions in various tissues. In the kidney, the wall thickness of arterioles and arteries is strongly increased, and glomerular lesions including different stages of sclerosis are observed. The thoracic aorta displays a considerable increase in tunica media thickness due to both myocyte hypertrophy and interstitial fibrosis. Coronary arteries and arterioles of the heart are thickened and perivascular fibrosis is observed. The data show that TGR(mRen2)27 transgenic rats display all typical characteristics of hypertensive pathology, making them an interesting model for therapeutic interventions. The fact that these changes occur in animals with a single gene difference to normotensive rats makes them a particularly suitable model for studies on gene-related hypertensive processes.

Adrenal Glands↗
PubMed1992

Rat gene mapping using PCR-analyzed microsatellites.

One hundred and seventy-four rat loci which contain short tandem repeat sequences were extracted from the GenBank or EMBL data bases and used to define primers for amplification by the polymerase chain reaction (PCR) of the microsatellite regions, creating PCR-formatted sequence-tagged microsatellite sites (STMSs). One hundred and thirty-four STMSs for 118 loci, including 6 randomly cloned STMSs, were characterized: (i) PCR-analyzed loci were assigned to specific chromosomes using a panel of rat x mouse somatic cell hybrid clones. (ii) Length variation of the STMSs among 8 inbred rat strains could be visualized at 85 of 107 loci examined (79.4%). (iii) A genetic map, integrating biochemical, coat color, mutant and restriction fragment length polymorphism loci, was constructed based on the segregation of 125 polymorphic markers in seven rat backcrosses and in two F2 crosses. Twenty four linkage groups were identified, all of which were assigned to a defined chromosome. As a reflection of the bias for coding sequences in the public data bases, the STMSs described herein are often associated with genes. Hence, the genetic map we report coincides with a gene map. The corresponding map locations of the homologous mouse and human genes are also listed for comparative mapping purposes.

Animals↗
PubMed1992

Basic methodology in the molecular characterization of genes.

PURPOSE: During the past two decades, molecular biology techniques have had an increasing impact upon hypertension research. This article will thus review the basic methodology in this field. CONTENTS: Protocols are described for the establishment of a genomic library and its use for the cloning of specific genes, as well as methods for the detection and sequencing of DNA. In addition, techniques to detect and quantify specific messenger RNA, such as Northern blotting, ribonuclease protection assay and in situ hybridization, and the reporter gene approach for the analysis of regulatory gene sequences, are included. The polymerase chain reaction which, as a newly established technique to detect and amplify DNA, has exerted a strong influence upon all areas of molecular biology is the subject of the concluding paragraph. CONCLUSIONS: Molecular biology techniques may be of substantial help in revealing the cause of hypertension and developing tools to prevent and treat this disorder.

Animals↗
PubMed1992

The brain renin-angiotensin system: localization and general significance.

This report summarizes the present data about the existence of components of the renin-angiotensin system in the rat brain. Angiotensinogen mRNA, mas proto-oncogene mRNA, angiotensin II (Ang II), and Ang II receptors have been mapped in the brain by using in situ hybridization, immunocytochemistry, and receptor autoradiography. These markers turned out to be widely distributed throughout the brain and to be not only restricted to areas related to cardiovascular control, but also to be present in functionally different areas, suggesting also other functions of angiotensin peptides. The distribution patterns of these components were correlated with data on the distribution of angiotensinogen, renin, angiotensin converting enzyme, and angiotensin fragments that revealed substantial topological mismatches. Using the model of "volume transmission," possible explanations for these mismatches are proposed. In this regard, a possible involvement of angiotensin fragments and the mas proto-oncogene in the functioning of the brain renin-angiotensin system is also discussed, demonstrating the increasing complexity of this central regulatory system.

Angiotensinogen↗
PubMed1992

Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats.

A transgenic rat line, TGR(mREN2)27, was established by introducing the murine Ren-2 gene into the genome of rats by microinjection techniques. These rats exhibit severe hypertension, making them an interesting model in which to study the role of renin in the pathophysiology of hypertension. However, although the additional renin gene is the only genetic difference compared with control rats, the exact mechanism of hypertension in TGR(mREN2)27 rats is still unclear. It cannot be attributed to a stimulation of the endocrine renin-angiotensin system or to an overexpression of renin in the kidney, since plasma and kidney renin and renin gene expression in the kidney are low in these animals. Here we describe recent progress made toward elucidating mechanisms of hypertension in TGR(mREN2)27 rats. 1) TGR(mREN2)27 rats were bred to homozygosity. The development of high blood pressure in homozygous rats is accelerated compared with that of heterozygous rats. This is paralleled by a higher mortality rate in homozygous TGR(mREN2)27 rats. Blood pressure and mortality rate of homozygous transgenic rats were effectively reduced by 10 mg captopril per kilogram body weight. 2) Treatment of 8-week-old heterozygous TGR(mREN2)27 rats with 10 mg/kg body wt per day of the angiotensin II receptor antagonist DuP 753 for 4.5 weeks normalized blood pressure. After withdrawal of the drug, blood pressure increased rapidly, reaching control levels after 3 weeks. In another group of TGR(mREN2)27 rats treated with 0.5 mg/kg per day, there was no change in blood pressure. Plasma renin and plasma angiotensin II were significantly higher in the high-dose group compared with the low-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗