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D Ganten

Publications and source records attributed to D Ganten.

At least 253 records · Page 14Linked to original sources
PubMed1992

Increased vascular angiotensin formation in female rats harboring the mouse Ren-2 gene.

Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin activity. We tested the hypothesis that these rats exhibit an increase in vascular angiotensin formation caused by the presence of the transgene. We measured the release of angiotensins I and II from isolated perfused hindquarters by high-performance liquid chromatography and radioimmunoassay. Female rats heterozygous for the transgene had significantly elevated mean arterial pressure compared with control rats (189.3 +/- 9.5 versus 110.0 +/- 5.4 mm Hg, p less than 0.05). Plasma angiotensin II was significantly decreased in transgenic rats. Transgenic rat hindquarters released more angiotensin I (121 +/- 37 versus 39 +/- 12 fmol/30 min, n = 7 each) and more angiotensin II (210 +/- 21 versus 62 +/- 12 fmol/30 min, p less than 0.05, n = 7 each) than control rat hindquarters. Captopril increased angiotensin I release and decreased angiotensin II values in both transgenic and control rat hindquarters. Bilateral nephrectomy 24 hours before hindquarter perfusion greatly reduced angiotensin release from control rat hindquarters but not from transgenic rat hind limbs. We also tested for the presence of Ren-2 messenger RNA in mesenteric and aortic tissue by RNase protection assay and Northern blot analysis. We found that Ren-2 messenger RNA was present in mesenteric and aortic tissue of transgenic but not of control rats. We conclude that the Ren-2 transgene is expressed in vascular tissue of transgenic rats and may be responsible for substantial increases in vascular angiotensin formation.

Angiotensin II↗
PubMed1992

Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones.

The regulation of angiotensinogen gene expression by steroid hormones in the rat liver has been examined. In the intact animal, dexamethasone (7 mg/kg ip) and estradiol (7 mg/kg sc) caused an increase in plasma angiotensinogen, which became first apparent after 5 or 9 h, respectively, and resulted in plasma concentrations 4.6- and 1.9-fold higher than in controls at 24 h. These changes were preceded by comparable increases in hepatic angiotensinogen messenger RNA (mRNA). In contrast, dihydrotestosterone (10 mg/kg sc) failed to alter plasma angiotensinogen, although hepatic angiotensinogen mRNA and total RNA were slightly elevated. In isolated hepatocytes exposed to either dexamethasone or estradiol (10 microM each) angiotensinogen mRNA started to increase within less than 1 or 3 h, respectively, followed, with a further time lag of about 2 h, by an increase in secretion rate of angiotensinogen. Dihydrotestosterone (10 and 100 microM) induced a rapid increase in total hepatocyte RNA (1.3-fold) and angiotensinogen mRNA (2-fold) with a peak at 2 h. Surprisingly, angiotensinogen secretion remained either unaltered (10 microM dihydrotestosterone) or even decreased (100 microM dihydrotestosterone). In a hepatoma cell line (FT02B) and a subclone (Fe 33) stably transfected with the human estrogen receptor, dexamethasone and estradiol induced an increase in angiotensinogen mRNA and secretion with the same characteristics as in hepatocytes. In conclusion, in this study a direct effect of estradiol on angiotensinogen mRNA and secretion in hepatocytes could be established, which differs from that of dexamethasone by a delayed onset of action. The observation, both in vivo and in vitro, that dihydrotestosterone induced an increase in total RNA and angiotensinogen mRNA, which is not accompanied by an increased angiotensinogen secretion, cannot be explained at present. This study also demonstrates the usefulness of a hepatoma cell line stably transfected with the estrogen receptor gene for the investigation of estrogen-dependent effects in vitro.

Analysis of Variance↗
PubMed1992

The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27.

The TGR(mREN2)27 is a new monogenetic rat model in hypertension research. As the mouse Ren-2d renin gene is integrated into their genome, they develop fulminant hypertension between 5 and 15 weeks of age, with blood pressure maxima of 300 mm Hg. Their plasma renin-angiotensin system (RAS) is suppressed, but the transgene is highly expressed in the adrenal gland, so we investigated its possible role in steroid metabolism and the pathogenesis of hypertension. During the phase of hypertension development (between 6-18 weeks), the urinary excretion of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone, and aldosterone is 1.5- to 2.5-fold elevated compared with that in Sprague-Dawley (SD) rats (P less than 0.0005) despite the suppressed plasma RAS. Moreover, the adrenal gland in TGR(mREN2)27 shows an increased maximal response to ACTH stimulation in regard to urinary excretion of DOC (after ACTH, 244 +/- 42 ng/24 h in TGR; 62 +/- 10 ng/24 h in SD; P less than 0.0005) and B (after ACTH, 5144 +/- 346 ng/24 h in TGR; 2607 +/- 324 ng/24 h in SD; P less than 0.0005). Additionally, plasma prorenin in TGR was stimulated more than 10-fold, indicating transgene regulation by ACTH. Since spironolactone treatment did not lower the blood pressure in TGR, hypertension solely due to hypermineralocorticoism is unlikely. Our results indicate that the adrenal steroid metabolism is markedly stimulated in young TGR, and the absolute increase in urinary DOC and B after ACTH injections is enhanced, possibly due to a stimulated local intraadrenal RAS.

18-Hydroxycorticosterone↗
PubMed1992

Zonal distribution and regulation of adrenal renin in a transgenic model of hypertension in the rat.

The hypertensive transgenic rat [TGR (mRen-2)27] is a genetic model of hypertension in which transfection of the Ren-2 mouse renin gene into rats results in severe hypertension. These transgenic rats express a high level of renin in the adrenal gland, and the hypertension is ameliorated by treatment with angiotensin-converting enzyme inhibitors. In this study we investigated the distribution of adrenal renin in the TGR rat and examined the regulation of adrenal renin in a monolayer culture of adrenal cells. High concentrations of active renin and prorenin were found in the adrenal capsular (glomerulosa) and decapsular (fasciculata-medullary) portions of the TGR adrenal. This is in contrast with the Sprague-Dawley (S-D) rat, in which adrenal renin is found mostly in the active form and located primarily in the glomerulosa cells. The zonal distribution of aldosterone was also different in the TGR, with substantial amounts of aldosterone in the zona fasciculata as well as in the glomerulosa, while in the S-D rat, aldosterone is limited to the zona glomerulosa. In the primary monolayer culture of glomerulosa cells, TGR cells had significantly higher levels of active renin and prorenin and showed an increased response to ACTH and high potassium in the medium. Renin activity in the medium was predominantly in the form of prorenin and significantly higher than that in the S-D rat. Cultured fasciculata cells from TGR also produce renin that is stimulated by ACTH, but not by a high potassium concentration. Renin activity in the adrenal homogenate, medium, and plasma from TGR rats was completely inhibited by the renin inhibitor (CP 71362; 1 microM), but only slightly inhibited (12.3 +/- 3%) by a monoclonal antibody that inhibits renin activity from S-D rat tissues by 79.2 +/- 2.5%, suggesting that renin in the plasma and adrenal glands from TGR appears to derive primarily from mouse renin. In conclusion, the TGR (mRen-2)27 rats have higher than normal levels of adrenal renin, and the cultured cells show an exaggerated renin response to ACTH and potassium. The distribution of the renin enzyme in the adrenal zones of the TGR is similar to the distribution of mouse adrenal renin.

Adrenal Glands↗
PubMed1992

Molecular genetics of hypertension.

During the last decades the evidence that a genetic component contributes to the development of primary hypertension has been accumulating. The identification of the genes involved in blood pressure regulation, however, is only starting to emerge. The recent advances in recombinant DNA technology provide new molecular genetic strategies in cardiovascular research. In this review we will discuss the testing of candidate genes in vivo by transgenic techniques. Furthermore, we will describe the possibilities to identify the genes implicated in primary hypertension by genetic linkage analysis using polymorphic DNA markers.

Animals↗
PubMed1992

Left ventricular remodeling after myocardial infarction: does the cardiac renin-angiotensin system play a role?

Possible cardioprotective effects are one of the most intriguing aspects of the expanding spectrum of clinical indications for the use of converting-enzyme inhibitors. Among them, the prevention of postinfarction ventricular remodeling--a deleterious process leading to eccentric cardiac hypertrophy and, eventually, to congestive heart failure--has attracted particular interest and attention. This communication examines the possible role of the endogenous cardiac renin-angiotensin system in the pathophysiology of ventricular remodeling. Although much of the evidence is indirect, there are several lines of investigation that strongly support the causative participation of the cardiac renin-angiotensin system in ventricular remodeling.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

The molecular basis of cardiovascular hypertrophy: the role of the renin-angiotensin system.

Factors that can influence cardiovascular growth are becoming increasingly important for our understanding of such complex diseases as cardiac hypertrophy, coronary artery disease, atherosclerosis, and hypertension. Several proto-oncogenes were found to be involved in the regulation of abnormal cell growth in cardiovascular disease. It is also evident that some peptide hormones, which are well known to be involved in blood pressure control, may play a role as growth modulators. Angiotensin II is one such peptide. It elevates blood pressure through its direct vasoconstrictor, sympathomimetic, and (through release of aldosterone) sodium-retaining activity but also appears to have mitogenic actions. Interestingly, all components of the renin-angiotensin system were found locally in cardiovascular tissues. The question remains whether angiotensin can act directly as a growth factor or whether it does so indirectly by influencing or modulating cell growth factors. A better understanding of the renin-angiotensin system as a direct or indirect mediator for cardiovascular hypertrophy would offer new and interesting insights into the pathophysiology of hypertension and possibly novel options for the treatment of cardiovascular disease.

Angiotensin II↗
PubMed1991

Characterization of rat intestinal angiotensin II receptors.

In rat ileum and duodenum 125I-sarcosine1,isoleucine8-angiotensin II labels a single population of binding sites with comparable receptor densities of 98 and 94 fmol/mg protein, respectively. Radioligand binding was dose dependently antagonized by angiotensin II (AII) and related peptides. DuP 753, a selective antagonist for the angiotensin AT1 receptor subtype, potently inhibited radioligand binding in both tissues (Ki: 12.7 and 11.8 nM), while AT2-selective ligands like PD 123.177 or p-amino-phenylalanine6-AII were inactive in concentrations lower than 1 microM. The contractile response to AII (1 microM) in ileal longitudinal and circular smooth muscle preparations amounted to 96 and 16%, respectively, of the response to 100 microM methacholine. The contractile response to AII was inhibited by DuP 753 (pA2 7.53) but unaffected by PD 123.177 (pA2 less than 5). The AII effect in longitudinal duodenal preparations amounted to only 24% of the methacholine response and was totally abolished in the presence of 1 microM DuP 753. No contraction due to AII was observed in duodenal circular smooth muscle preparations. The results obtained demonstrate the existence of functional AT1 receptors in the rat ileum and duodenum. In the ileum these receptors are mainly located on the longitudinal smooth muscle and coupled to contraction. In duodenal smooth muscle AII receptors may be either less effectively coupled to contractile elements or involved in another, additional function.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1991

Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a well-characterized model for primary hypertension in humans. High blood pressure in SHRSP shows polygenic inheritance, but none of the loci responsible have previously been identified. To locate genes controlling this quantitative trait, we mapped a large collection of DNA polymorphisms in a cross between SHRSP and the normotensive WKY strain. Here we report strong genetic evidence that a gene, Bp1, having a major effect on blood pressure maps to rat chromosome 10 with a LOD score of 5.10 and is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE), an enzyme that plays a major role in blood pressure homeostasis and is an important target of anti-hypertensive drugs. We also find significant, albeit weaker, linkage to a locus, Bp2, on chromosome 18. We discuss the implications of genetic dissection of quantitative disease-related phenotypes in mammals.

Animals↗
PubMed1991

The role of neuropeptides in cardiovascular regulation.

During the past few years more than 30 novel, biologically active peptides have been discovered. Some are produced in endocrine glands and circulate as hormones in the blood; others are contained in the enterochromaffin cells of the gut and may be involved in the regulation of intestinal functions. The vast majority of new peptides, however, have been detected in the central and peripheral nervous systems, where they are synthesized in distinct neurons and stored in neurovesicles. Many of these neuropeptides may be involved in circulatory regulation. There is evidence supporting such a role, especially for centrally located angiotensin, opioid peptides, substance P, neuropeptide Y (NPY), vasopressin, atrial natriuretic peptide (ANP), kinins, corticotropin releasing factor, bombesin, and somatostatin. In this review we discuss the cardiovascular actions of angiotensin, neuropeptide Y, and calcitonin gene related peptide.

Angiotensin II↗
PubMed1991

Sexual dimorphism of blood pressure: possible role of the renin-angiotensin system.

The prevalence of hypertension in men is higher than in women and the onset of this disease is earlier in male than in female subjects. In spontaneously hypertensive rats, males also have higher blood pressures than females. Evidence from epidemiological, physiological, molecular biological and morphological studies concerning this sexual dimorphism is reviewed. We demonstrate that the gonadal steroids testosterone and estrogen have important effects on the gene regulation of the renin-angiotensin system. This may in part contribute to the sexual dimorphism in blood pressure control. The direct effect of steroid hormones on genes related to hypertension provides a suitable paradigm to improve our understanding of molecular and cellular mechanisms of cardiovascular control.

Angiotensin II↗
PubMed1991

Changes in the central ANF-system of renovascular hypertensive rats.

The central atrial natriuretic peptides (ANF)-system was investigated in volume-dependent, one-kidney, one-clip (1K1C) and renin-dependent two-kidney, one-clip (2K1C) renovascular hypertensive rats by radioimmunological measurement of ANF concentration in 18 selected brain areas. Significant changes were found in nine brain areas of 1K1C and in eight brain areas of 2K1C hypertensive rats. Except undirectional changes in the organum vasculosum laminae terminalis and the supraoptic nucleus, ANF concentration was changed in the opposite direction in all other brain areas, with an activation of the central ANF system in 1K1C and an inhibition in 2K1C hypertension. The localization of the alterations (circumventricular organs, anteroventral third ventricle region, hypothalamo hypophyseal system, brain stem) implies major differences in the central regulation of blood pressure and electrolyte and fluid homeostasis between these two models. The activation of the central ANF system in 1K1C hypertension may be a compensatory mechanism to prevent further increments in blood pressure and plasma volume. In contrast, the depression of the central ANF system in 2K1C hypertension may promote the elevation of the blood pressure.

Animals↗
PubMed1991

Glucocorticoid- and estrogen-responsive elements in the 5'-flanking region of the rat angiotensinogen gene.

We investigated the 5'-flanking region of the rat angiotensinogen gene to define the DNA elements conferring inducibility by glucocorticoids and estrogens. Two putative glucocorticoid-responsive elements (GREs) based on sequence comparison were identified. Here we report the functional importance of these sequences. We constructed several deletion mutants of the 5'-region in front of the bacterial reporter gene for chloramphenicol acetyltransferase (CAT). The angiotensinogen-CAT-reporter plasmids (pRagCAT) were transiently transfected into the rat hepatoma cells FTO 2B and Fe 33. All pRagCAT constructs in which the 5'-region contained at least one of the two GRE consensus sequences were stimulated by dexamethasone. On the other hand, deletion mutants containing no GRE sequences were not inducible with dexamethasone. In additional experiments, the transcriptional functions of the two putative GREs were assessed by cloning synthetic oligonucleotides encompassing the GRE sequences directly in front of the heterologous herpes simplex virus thymidine-kinase promoter. Our results showed that each synthetic GRE was capable of stimulating the heterologous TK promoter after administration of dexamethasone and that both GREs together act synergistically. We also investigated the transcriptional control of angiotensinogen by estrogen. Although no estrogen-responsive element consensus sequences were detectable by sequence comparison, we did identify sequences between -60 to -92 which conferred estrogen inducibility to the rat angiotensinogen gene. In this region, a so-called half-palindromic estrogen-responsive element is localized at nucleotides -87 to -91.

Amino Acid Sequence↗
PubMed1991

Vascular production and regulation of angiotensin.

To test the hypothesis that angiotensin (Ang) I and II are produced by blood vessels, we investigated the formation of both Ang I and Ang II in isolated, perfused rat hindquarters. To characterize the nature of this production further, we modulated plasma renin by total or subtotal nephrectomy and tested the effects of exogenous renin and renin substrate on vascular Ang formation. Assays of the perfusate by high-performance liquid chromatography and radioimmunoassay demonstrated the spontaneous release of Ang I and Ang II from the hindlimb vasculature. Conversion of Ang I to Ang II in hindquarter vasculature was approximately 75% and was totally suppressed by captopril. The spontaneous formation of Ang peptides was abolished by bilateral nephrectomy but was not affected by subtotal 5/6 nephrectomy. The addition of purified rat angiotensinogen to the preparation increased Ang II levels. The infusion of renin into the hindlimb vasculature led to substantial increases in local Ang formation and also raised the perfusion pressure. Both effects were sensitive to captopril and to the renin inhibitor H-142. The data indicate that Ang I and Ang II are produced locally within blood vessels. However, the origin of vascular renin remains controversial. Our results suggest that part of the enzyme is taken up from plasma.

Angiotensin I↗
PubMed1991

Tissue renin-angiotensin systems and their modulation: the heart as a paradigm for new aspects of converting enzyme inhibition.

Local tissue-resident renin-angiotensin systems are increasingly recognized as important elements of neurohumoral mediation which may act in concert with, but also independently of, the circulating system. The presence of such a system within the heart is of particular interest; current evidence supporting its existence, functional integration, and physiopathological importance as well as the role which its pharmacological modulation may play are reviewed. The elements of the catalytic cascade, renin, angiotensinogen, and angiotensin-converting enzyme, have all been demonstrated in cardiac tissues; both at the protein level and (with the exception of converting enzyme) with regard to local expression of the respective genes. Modulation of gene expression in response to various perturbations has been demonstrated and may occur independently of the plasma or other tissue renin-angiotensin systems. In isolated hearts the generation of biologically active peptides, angiotensins I and II, has been documented, establishing the capability of this system to act as an independently regulated, functionally integrated catalytic pathway for the production of angiotensin II. Activation of either angiotensinogen to angiotensin I or of angiotensin I to angiotensin II is dose dependently inhibited by the administration of renin inhibitors and converting enzyme inhibitors, respectively. Through specific receptors, present in the heart as in other tissues, angiotensin mediates profound effects on cardiomyocyte function and, as we are beginning to learn, on structure and growth. We now have strong evidence that converting enzyme inhibition at a tissue level may profoundly influence and modulate these actions of the cardiac renin-angiotensin system, particularly in the setting of myocardial ischaemia. This may, in the future, open up new vistas for the application of converting enzyme inhibitors and their indications in a widening spectrum of cardiovascular disorders.

Angiotensin-Converting Enzyme Inhibitors↗