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D Ganten

Publications and source records attributed to D Ganten.

At least 145 records · Page 8Linked to original sources
PubMed1995

Evidence for a differential modulation of the alpha-2 adrenoceptors by angiotensin II in the nucleus tractus solitarii of the spontaneously hypertensive and the Wistar-Kyoto normotensive rats.

An interaction between angiotensin II (Ang II) receptors and alpha 2-adrenoceptors was evaluated in the nucleus tractus solitarii (NTS) of the normotensive Wistar-Kyoto rat (WKY) and of the spontaneously hypertensive rat (SHR) using quantitative receptor autoradiography and cardiovascular analysis. In the WKY rat, Ang II promoted a dose-dependent increase in the IC50 value of l-noradrenaline when competing for ([3H]p-aminoclonidine ([3H]PAC) binding sites, which reached a maximum of 400% with 10 nM of Ang II and was associated with a small decrease in the B0 value (20%). In the SHR Ang II (0.1 nM) had an opposite effect leading to a decrease in the IC50 value of about 57%, and no change was observed in the B0 value. Saturation analysis also showed that Ang II (0.1 nM) increased the KD value of [3H]PAC in the WKY strain but in contrast decreased the KD value of [3H]PAC in the SHR. The Bmax value was not significantly changed neither in the WKY rat nor in the SHR. The cardiovascular analysis showed that a threshold dose of Ang II (0.05 pmol) counteracted the vasodepressor effect produced by l-noradrenaline coinjected in the NTS of the WKY rat. No effect was observed in heart rate. In the SHR no counteraction of the l-noradrenaline-induced vasodepressor effect was found, and in contrast a slight increase of the vasodepressor effect associated with a significant increase in the bradycardiac response was observed. The results give evidence for an antagonistic Ang II/alpha 2 receptor interaction in the cardiovascular part of the NTS of the WKY rat as previously observed in the Sprague-Dawley rat. However, this interaction is altered in the SHR, so that in this strain the Ang II/alpha 2 receptor interaction enhances alpha 2 affinity and possibly alpha 2 receptor function. This opposite effect observed in the SHR may represent one compensatory mechanism to counteract the development of high blood pressure in the SHR.

Angiotensin II↗
PubMed1995

Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues.

We isolated the mas proto-oncogene from a mouse genomic library. Sequence analysis showed that it contains an open reading frame without intervening sequences. The amino acid sequence deduced confirms the seven-transmembrane-domain structure and exhibits 97% and 91% amino acid homology with the rat and the human Mas, respectively. In mice and rats, mas mRNA was detected in the testis, kidney, heart, and in the brain regions: hippocampus, forebrain, piriform cortex, and olfactory bulb. Testicular mas mRNA from rats increases markedly during development, while cerebellar mRNA is high postnatally but completely disappears at later stages. We conclude that the product of the mouse mas gene may be involved in the development of the brain and testis.

Amino Acid Sequence↗
PubMed1995

Transcriptional silencer in intron I of the rat renin gene.

In the present study we investigated the influence of intron I of the rat renin gene on the transcriptional activity of its promoter in cell culture. The presence of intron I abolished the transcription of reporter genes (luciferase and lacZ) in the non-renin-expressing human embryonic kidney cell line 293, while it did not significantly affect the activity of the rat renin promoter in rat sceletal myoblast line L8 expressing renin. We conclude from these results that intron I of the rat renin gene contains a tissue-specific silencer element probably also responsible for the transcriptional repression of the endogeneous renin gene in 293 cells.

Animals↗
PubMed1995

Induction of cardiac angiotensin I-converting enzyme with dietary NaCl-loading in genetically hypertensive and normotensive rats.

We have recently shown that the angiotensin I converting enzyme (ACE) gene is linked to NaCl-loaded blood pressure in the stroke-prone spontaneously hypertensive rat (SHRSP), and that high-NaCl loading selectively stimulates ACE in the aorta of SHRSP but not in normotensive Wistar-Kyoto (WKY) rats. We therefore investigated the relationship between cardiac ACE and the development of hypertension and left ventricular hypertrophy in response to normal- and high-NaCl diet in these rats. ACE mRNA and ACE activity were measured in left ventricular tissue after completion of hemodynamic characterization of the animals. While SHRSP rats increased blood pressure (P < 0.0001) and heart rate (P < 0.005) in response to high NaCl, blood pressure remained unchanged in WKY. Similarly, relative left ventricular weight increased only in SHRSP after high NaCl (P < 0.002). A significant two- to threefold increase of cardiac ACE mRNA and fourfold stimulation of ACE enzyme activity in response to high NaCl was found in both WKY and SHRSP rats (P < 0.005). The induction of ACE gene expression was significantly more pronounced in SHRSP compared to WKY (P < 0.02), whereas no significant strain differences in left ventricular ACE activity were found after either normal- or high-NaCl diet. Thus, arterial blood pressure and left ventricular weight remained unchanged in the WKY rats despite the activation of left ventricular ACE activity after high-NaCl exposure. These results demonstrate that left ventricular ACE activity is equally upregulated in response to high-NaCl in the normotensive and hypertensive strain, independently from the development of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1995

Decreased renal haemodynamic response to inhibition of nitric oxide synthase in subtotally nephrectomized rats.

To assess the renal haemodynamic response to manipulations of the nitric oxide (NO) system, we examined subtotally nephrectomized (SNX) rats and control rats (CON) 28 days after their operation. Bolus infusions of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) were given intravenously at doses of 2 mg/kg and 10 mg/kg. Blood pressure was measured intra-arterially, glomerular filtration rate was measured by inulin clearance and fractional changes in renal blood flow (RBF) were determined by a Doppler flow probe. Both doses of L-NA caused a similar and dose-dependent increase in mean blood pressure in both SNX and CON rats. In contrast, the decrease in RBF and the increase in the renovascular resistance index (RVRI) was less in SNX rats as compared to CON rats (RBF = -70.1 +/- 2.2% of baseline vs -52.7 +/- 5.2%, P < 0.01; RVRI = +177 +/- 9% of baseline vs +243 +/- 24%, P < 0.05). These changes were not affected by autonomic blockade (hexamethonium), or by blockade of the angiotensin II receptor (Losartan). The exogenous NO donor sodium nitroprusside (0.5 and 1.5 micrograms.kg-1.min-1) lowered mean blood pressure to a similar degree in SNX and CON rats; in contrast, RVRI decreased less in SNX rats (86.9 +/- 9.2% of baseline) than in CON rats (68.2 +/- 4.6%, P < 0.05). We conclude that the reaction of the renal vasculature to manipulations of the NO system is altered in the SNX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Rodent models for studying steroids and hypertension: from fetal development to cells in culture.

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11 beta (11 beta-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1995

Mechanisms of angiotensin II formation in humans.

Various organs, including the heart and blood vessels, apparently contain tissue renin-angiotensin systems. Through autocrine and paracrine activity, locally produced angiotensin II (Ang II) may well play an important role in cardiovascular homeostasis; in pathological conditions. Ang II may also contribute to the remodelling of the heart and vasculature. In addition to angiotensin converting enzyme (ACE), a cardiac Ang II forming serine proteinase (human heart chymase) has been identified in the left ventricle of the human heart. The different cellular and regional distributions of ACE and chymase in the heart as well as in the blood vessels suggest distinct pathophysiological roles for these two Ang II forming enzymes. Several reports indicate that both ACE-dependent and ACE-independent Ang II formation appear to occur in hypoxic or ischaemic hearts or blood vessels in vivo and seem to be involved in the pathological changes seen in these organs. However, chymase-dependent Ang II formation--which is chymostatin sensitive but aprotinin insensitive--does not explain all ACE-independent Ang II formation. Therefore, it is important to elucidate the mechanisms of tissue Ang II formation in humans and their contribution to the pathophysiological changes in cardiovascular disease.

Angiotensin II↗
PubMed1995

Infertility in a transgenic rat due to impairment of cytoplasmic elimination and sperm release from the Sertoli cells.

In line TGR(mRen2)26 transgenic rats (TGR26) bearing a randomly inserted additional renin transgene, the males, but not the females, were found to be infertile. Tissue was obtained from TGR26 males and littermate controls after perfusion fixation, and the morphology of the testes and epididymides was examined. Testis size was normal as was gross morphology, but careful examination revealed that the release of many spermatozoa at stage IX of the spermatogenic cycle was impaired. In addition, the process of cytoplasmic elimination was abnormal, as cytoplasmic fragments of elongate spermatids were present in the epididymis. In TGR26 males, seminiferous tubule lumen size was significantly larger (p < 0.001) than in littermate controls, a difference that was most marked at stages IX-XIV--an effect that could be related to the retention of spermatozoa. In situ hybridization confirmed that expression of renin mRNA could be detected in testes of TGR26 rats but not in normal controls or in a fertile line (TGR27) of rats bearing the same transgene. Immunocytochemistry and in situ and Northern hybridization were used to elucidate the pattern of expression of genes that previous studies have implicated in the process of sperm maturation and/or release. Of the gene products examined (sulphated glycoproteins 1 and 2 [SGP-1, SGP-2], transition proteins 1 and 2 [TP-1, TP-2], urokinase, and cyclic protein 2[CP-2], none showed any major change in the pattern of expression compared with that in controls. We postulate that TGR26 transgenic male rats may be infertile because the expression of a gene (or genes) involved in the process of cytoplasmic elimination and/or sperm release has been disrupted by the presence of the transgene close to or within the gene(s). Future planned studies will involve determination of the insertion site(s) and ultrastructural analysis of the final phases of spermiogenesis.

Animals↗
PubMed1995

Infertility in a transgenic rat due to impairment of cytoplasmic elimination and sperm release from the Sertoli cells.

In line TGR(mRen2)26 transgenic rats (TGR26) bearing a randomly inserted additional renin transgene, the males, but not the females, were found to be infertile. Tissue was obtained from TGR26 males and littermate controls after perfusion fixation, and the morphology of the testes and epididymides was examined. Testis size was normal as was gross morphology, but careful examination revealed that the release of many spermatozoa at stage IX of the spermatogenic cycle was impaired. In addition, the process of cytoplasmic elimination was abnormal, as cytoplasmic fragments of elongate spermatids were present in the epididymis. In TGR26 males, seminiferous tubule lumen size was significantly larger (p < 0.001) than in littermate controls, a difference that was most marked at stages IX-XIV--an effect that could be related to the retention of spermatozoa. In situ hybridization confirmed that expression of renin mRNA could be detected in testes of TGR26 rats but not in normal controls or in a fertile line (TGR27) of rats bearing the same transgene. Immunocytochemistry and in situ and Northern hybridization were used to elucidate the pattern of expression of genes that previous studies have implicated in the process of sperm maturation and/or release. Of the gene products examined (sulphated glycoproteins 1 and 2 [SGP-1, SGP-2], transition proteins 1 and 2 [TP-1, TP-2], urokinase, and cyclic protein 2 [CP-2]), none showed any major change in the pattern of expression compared with that in controls. We postulate that TGR26 transgenic male rats may be infertile because the expression of a gene (or genes) involved in the process of cytoplasmic elimination and/or sperm release has been disrupted by the presence of the transgene close to or within the gene(s). Future planned studies will involve determination of the insertion site(s) and ultrastructural analysis of the final phases of spermiogenesis.

Animals↗
PubMed1995

Chronic dexamethasone treatment suppresses hypertension development in the transgenic rat TGR(mREN2)27.

INTRODUCTION: The transgenic rat TGR(mREN2)27 is a monogenetic rat model in hypertension research. Integration of mouse Ren-2 gene into the rat genome led to fulminant hypertension despite suppressed plasma and kidney renin concentrations. Renin is highly expressed in extrarenal tissues, especially throughout the adrenal cortex. AIMS AND METHODS: Because plasma and urinary corticosteroid concentrations are elevated during the development of hypertension in these rats, we investigated the effect of dexamethasone on blood pressure, adrenal renin and steroid metabolism. RESULTS: A daily injection of 100 micrograms/kg dexamethasone for 8 weeks was capable of suppressing the development of hypertension in the transgenic rats. The same regimen did not alter blood pressure in Sprague-Dawley control rats. Plasma concentrations of adrenocorticotrophic hormone (ACTH)-dependent steroids (corticosterone and 18-hydroxydeoxycorticosterone) decreased markedly in both strains treated with dexamethasone, but more pronouncedly in transgenic rats. Surprisingly, plasma aldosterone concentrations increased exclusively in the transgenic rats, and not in control rats, treated with dexamethasone. The decrease in corticosterone and 18-hydroxydeoxycorticosterone production was accompanied by a decrease in the abundance of the messenger RNA (mRNA) encoding the rate-limiting enzyme in steroidogenesis (P450scc cholesterol side-chain cleavage) and a decrease in the mRNA encoding P450c11 beta (11 beta-hydroxylase). The increase in aldosterone was accompanied by a massive increase in the abundance of the mRNA encoding zona glomerulosa-specific P450c11AS (aldosterone synthase), which was not increased in control rats. CONCLUSION: We conclude that ACTH-dependent steroids other than the mineralocorticoid aldosterone are responsible for the development of hypertension in the transgenic rat.

Adrenal Glands↗
PubMed1995

Local renin-angiotensin systems in cardiovascular tissues: localization and functional role.

In its classical definition, the renin-angiotensin system (RAS) acts predominantly by endocrine mechanisms. This view has been modified since several components of the RAS and their mRNAs were found in peripheral tissues. These findings gave rise to the concept of local tissue renin-angiotensin systems. Although no cells of cardiovascular organs containing a complete RAS have been identified as of this writing, angiotensinogen and angiotensin-converting enzyme (ACE) are most likely synthesized within the vasculature for example. Local synthesis of renin may be limited to very small amounts, but uptake of renin from the circulation is very likely. The function of local RASs is shown by reduction of blood pressure by ACE inhibitors, which correlates better with the inhibition of ACE activity in certain tissues than with its activity in the plasma. Further studies have put forward the notion that the circulating RAS could mainly be important for acute hemodynamic stability, whereas the tissue RAS could be involved in more long term maintenance of hemodynamics. This review will try to summarize the findings leading to the concept of a local tissue renin-angiotensin system, and discuss interactions between the circulating and the local RAS in the light of recent experimental findings.

Angiotensin II↗
PubMed1995

Differential gene expression of renin and angiotensinogen in the TGR(mREN-2)27 transgenic rat.

Transgenic rats carrying the murine Ren-2 gene represent a monogenetic model of hypertension characterized by low plasma renin and high extrarenal expression of the transgene. The hypothesis has been raised that stimulated local reninangiotensin systems may be responsible for the development of hypertension in this model. This study analyzes the effects of the converting enzyme inhibitor lisinopril, which specifically interferes with the renin-angiotensin system, and the direct vasodilator dihydralazine on the renal and extrarenal expression of renin and angiotensinogen. A comparison of gene expression between heterozygous and homozygous transgenic and normal Sprague-Dawley rats was also performed. We demonstrate high sensitivity of blood pressure toward converting enzyme inhibition in transgenic TGR(mREN-2)27 rats. In the kidney, expression of the transgene and the endogenous renin gene increased, suggesting that both are modulated by lisinopril in a similar manner. On the other hand, blood pressure reduction by dihydralazine did not abolish renal renin suppression in transgenic rats, indicating that mechanisms different from direct effects of blood pressure account for renin suppression. Homozygosity for the transgene led to increased Ren-2 expression and higher blood pressure and had opposite effects on angiotensinogen expression compared with heterozygous rats. Cardiac hypertrophy was reduced by lisinopril but not dihydralazine and was positively correlated with cardiac angiotensinogen expression. Increased angiotensin II in the adrenal gland of TGR(mREN-2)27 rats, which overexpresses the transgene, provides evidence that this leads to enhanced generation of tissue angiotensin II. We conclude that expression of the mouse transgene, the endogenous rat renin gene, and the angiotensinogen gene is subject to differential tissue-specific regulation. Reversal of cardiovascular damage with the converting enzyme inhibitor but not dihydralazine suggests that angiotensin II generated locally may be involved in the pathogenesis of hypertension and structural changes in TGR(mREN-2)27 rats.

Angiotensin II↗
PubMed1995

Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat.

The transgenic TGR(mRen-2)27 rat, in which the Ren-2 mouse renin gene is transfected into the genome of the Sprague-Dawley rat, develops severe hypertension at a young age that responds to inhibitors of angiotensin-converting enzyme and to antagonists of the type 1 angiotensin II (Ang II) receptor. Despite this evidence that the hypertension is Ang II dependent, TGR(mRen-2)27 rats have suppressed renal renin and renin mRNA content, and there is controversy concerning the plasma levels of renin and Ang II in these rats. We investigated the effect of the transgene on circulating and tissue levels of angiotensin and bradykinin peptides in 6-week-old male homozygous TGR(mRen-2)27 rats. Systolic blood pressure of TGR(mRen-2)27 rats was 212 +/- 4 mm Hg (mean +/- SEM, n = 25) compared with 108 +/- 2 mm Hg (n = 29) for age- and sex-matched Sprague-Dawley rats. Compared with control rats, TGR(mRen-2)27 rats had increased plasma levels of active renin (4.5-fold), prorenin (300-fold), and Ang II (fourfold) as well as tissue levels of Ang II (twofold to fourfold in kidney, adrenal, heart, aorta, brown adipose tissue, and lung and 18-fold in brain). Plasma angiotensinogen levels were reduced to 73% of control, and plasma aldosterone levels were increased fourfold. Plasma angiotensin-converting enzyme was reduced to 64% of control. Compared with control rats, TGR(mRen-2)27 rats had increased bradykinin levels in brown adipose tissue (1.9-fold) and lung (1.6-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1995

Opposing actions of angiotensin-(1-7) and angiotensin II in the brain of transgenic hypertensive rats.

Lack of specific antagonists to the amino-terminal heptapeptide angiotensin-(1-7) [Ang-(1-7)] prompted us to evaluate the central effects of delivering a specific affinity-purified Ang-(1-7) antibody on the blood pressure and heart rate of 12-week-old conscious homozygous female rats (n = 12) expressing the mouse submandibular Ren-2d gene [(mRen-2d)27] in their genome. Another group of transgenic hypertensive and strain-matched Sprague-Dawley controls were injected with a specific Ang II monoclonal antibody (KAA8). Cerebroventricular administration of the affinity-purified Ang-(1-7) antibody in conscious transgenic hypertensive rats caused significant dose-related elevations in blood pressure associated with tachycardia. The hypertensive response was augmented in transgenic rats studied 7 to 10 days after cessation of lisinopril therapy. Neutralization of Ang II with the Ang II antibody caused a hemodynamic response opposite to that obtained with the Ang-(1-7) antibody. All doses of the Ang II antibody produced hypotension and bradycardia. The magnitude of the depressor response was significantly augmented in transgenic rats weaned off lisinopril therapy. In contrast, central administration of either the Ang-(1-7) or Ang II antibodies had no effect on normotensive rats. Central injections of an affinity-purified IgG fraction were ineffective in both control and transgene-positive rats. These data suggest that in the brain of transgenic hypertensive rats, Ang-(1-7) opposes the action of Ang II on the central mechanism or mechanisms that contribute to the maintenance of this model of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1995

Gene expression of brain nitric oxide synthase and soluble guanylyl cyclase in hypothalamus and medulla of two-kidney, one clip hypertensive rats.

Nitric oxide may act at autonomic sites in the brain to regulate arterial blood pressure. Our goal was to determine whether gene expressions of the brain isoform of nitric oxide synthase and of the beta subunit of soluble guanylyl cyclase, the target of nitric oxide, were altered in discrete autonomic brain regions after induction of hypertension in rats. The two-kidney, one clip model was used to induce hypertension, and measurements were made 3 and 6 weeks after the left renal artery was clipped. Only experimental rats with blood pressures elevated by at least 25 mm Hg were used. Total RNA was purified from microdissected tissue blocks containing hypothalamus, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nitric oxide synthase and guanylyl cyclase mRNA were semiquantified in each region by use of reverse transcription-polymerase chain reactions in which known concentrations of deletion mutants of the two genes were coamplified as internal standards. Compared with controls, significant decreases and increases in nitric oxide synthase mRNA were found in the hypothalamus (x 2.2) and caudal ventrolateral medulla (x 6.4), respectively, of hypertensive rats 3 weeks after clipping. These alterations were reversed in hypertensive rats at 6 weeks; levels increased (x 4.6) in the hypothalamus and decreased (x 5.5) in the caudal ventrolateral medulla. Changes in guanylyl cyclase expression paralleled those for nitric oxide synthase in some but not all areas at both time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Effects of human renin in the vasculature of rats transgenic for human angiotensinogen.

Transgenic rats, which express the human angiotensinogen gene, provide a unique model for studying local vascular effects of human renin. We examined the cleavage of human angiotensinogen to angiotensin I (Ang I) by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from such rats. Perfusion resulted in the sustained release of human angiotensinogen, which decreased from 19.4 to 11.8 pmol/mL over 45 minutes. Active human renin at doses of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I release from undetectable levels (mean +/- SEM) to 31.9 +/- 3.3, 147.1 +/- 26.2, and 206.4 +/- 17.1 fmol/mL, respectively, by 9 minutes. In separate experiments aimed at the quantification of renin-induced vasoconstriction, captopril decreased the perfusion pressure and lowered Ang II concentrations to nondetectable levels, whereas Ang I values increased sharply. When renin (30 ng/mL) was infused for 15 minutes, renin values in the perfusate decreased to barely detectable levels within minutes after termination of the infusion. However, Ang I values remained high for at least 30 minutes thereafter. The addition of a human renin inhibitor during renin infusion caused Ang I values to promptly decrease within minutes to undetectable levels. Hindlimbs from non-transgenic control rats released no detectable amounts of Ang I, with or without human renin. Finally, by in situ hybridization we documented the presence of human angiotensinogen message in the vessels of the hindlimb. We conclude that renin acts on angiotensinogen at a site in the vascular wall. The cleavage depends on renin and not on other lysosomal proteases.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗