Biomedical subjects

D Ganten

Publications and source records attributed to D Ganten.

At least 217 records · Page 12Linked to original sources

PubMed1993

Membrane microviscosity does not correlate with blood pressure: a cosegregation study.

OBJECTIVE: To determine whether elevated microviscosity is associated with elevated arterial pressure in segregating (F2) hybrids produced by crossing stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. METHODS: SHRSP and WKY rats were obtained from the colony at the University of Heidelberg. F2 progeny were obtained by brother-sister mating of the F1 progeny of the cross between SHRSP and WKY rats. Membrane microviscosity (the inverse of fluidity) was measured as a fluorescence anisotropy of trimethylammonium diphenylhexatriene incubated with the erythrocyte membranes. The measurements were made using a luminescence spectrometer with computer-controlled excitation and emission polarizers. RESULTS: Membrane microviscosity was significantly greater (fluidity was lower) in erythrocyte membranes obtained from SHRSP than in those obtained from WKY rats. In the F2 cohort there were no significant correlations between membrane microviscosity and systolic blood pressure, diastolic blood pressure, salt-loaded systolic blood pressure or salt-loaded diastolic blood pressure. A similar lack of relationship between these parameters was shown in a subgroup analysis, in which males or females with a male WKY rat progenitor and males or females with a male SHRSP progenitor were analysed separately. CONCLUSIONS: Erythrocyte membrane microviscosity is elevated in SHRSP compared with WKY rats. In segregating F2 hybrid rats the membrane microviscosity trait does not correlate with blood pressure. These results eliminate the microviscosity trait as being directly related to the cause of genetic differences in blood pressure between WKY rats and SHRSP.

Animals↗

PubMed1993

Polymorphism of the angiotensin I converting enzyme gene is apparently not related to high blood pressure: Dutch Hypertension and Offspring Study.

OBJECTIVE: Studies in genetically hypertensive rats and their normotensive Wistar-Kyoto control rats have revealed a linkage of a chromosomal region containing the angiotensin converting enzyme (ACE) gene with blood pressure. This led to the hypothesis that ACE is a possible candidate gene for primary hypertension in humans. We defined the genotypes and allele frequencies of an insertion-deletion (I/D) polymorphism in parental couples who both had either high or low blood pressure and in their offspring. SUBJECTS: Parents (n = 111) and offspring (n = 75) with defined blood pressure status from the Dutch Hypertension and Offspring Study. METHODS: Genomic DNA was amplified by polymerase chain reaction using primers flanking the polymorphic region in intron 16 of the ACE gene. Alleles were detected on agarose gels stained with ethidium bromide. RESULTS: Allele frequencies for the D-allele were similar in parents with high (0.66) and low blood pressure (0.59) and in their offspring (0.67 and 0.69, respectively). A similar lack of difference was found with respect to the complementary I-allele. CONCLUSIONS: In the present rather large sample we failed to find a significant association between I/D polymorphism of the ACE gene and blood pressure status in subjects with high or low blood pressure and in their offspring.

Adult↗

PubMed1993

Dietary salt excess unmasks blunted aldosterone suppression and sodium retention in the stroke-prone phenotype of the spontaneously hypertensive rat.

OBJECTIVE: The mechanisms underlying the accelerating effect of high salt intake on the development of vascular injury in the stroke-prone phenotype of spontaneously hypertensive rats (SHRSP) are still not clear. The aim of the present study was to determine whether young SHRSP can excrete a dietary excess of sodium and to characterize the associated hormonal responses. METHODS: Sodium balance and hormonal parameters were studied during a 1-week high-salt diet (4% NaCl) in 6-week-old SHRSP (n = 84), in age-matched spontaneously hypertensive rats (SHR; n = 73) and in normotensive Wistar-Kyoto (WKY) rats (n = 52). RESULTS: Baseline systolic blood pressure (SBP) was similar in SHR and SHRSP and did not change significantly during the high-salt diet. SBP also remained unchanged in WKY rats during the high-salt diet. Despite similar daily sodium intakes in the three groups during the diet, the response of urinary sodium excretion to sodium loading was reduced significantly in SHRSP compared with SHR or WKY rats (F = 4.09, P < 0.001). Plasma renin activity was suppressed significantly by high salt intake in each group to a comparable extent. Plasma aldosterone concentrations were also reduced significantly by sodium loading in all strains. However, a lesser degree of aldosterone suppression was observed in the SHRSP than in both SHR and WKY rats (F = 3.01, P < 0.01). CONCLUSIONS: Young SHRSP show a blunted suppression of plasma aldosterone and a defective sodium excretion during high salt intake.

Administration, Oral↗

PubMed1993

Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP. DESIGN: We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies. METHODS: Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively. RESULTS: The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY. CONCLUSIONS: Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.

Aging↗

PubMed1993

Immobilization stress induces vasodepressor and altered neuroendocrine responses in the adult stroke-prone spontaneously hypertensive male rat.

The effects of acute (1 h) and daily repeated immobilization stress (14 days, twice-daily, 1 h) were studied on arterial blood pressure and heart rate and on the blood levels of several hormones in the adult (5 months old) stroke-prone spontaneously hypertensive rat (SHRSP) and in the age-matched normotensive Wistar-Kyoto (WKY) rat. The major result was the development of a long-lasting vasodepressor response in the SHRSP, while the same acute or repeated immobilization stress in the WKY rat led to the development of a prolonged vasopressor response. Differential changes to stress were also observed in practically all neuroendocrine axes with the exception of the pituitary-adrenal axis. The vasodepressor response to immobilization stress in SHRSP may be related to an exaggerated defence-like reaction causing an enhanced vasodilation in the skeletal muscle beds associated with a tachycardia similar to that in the normotensive control rats.

Angiotensin II↗

PubMed1993

Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27.

TGR(mREN2)27 is a new monogenetic rat model with fulminant hypertension, low kidney renin, and high extrarenal renin gene expression. This study characterizes and compares expression of the Ren-2 gene in TGR(mREN2)27 with that in DBA/2 mice and with renin gene expression in rats. Except in the submandibular gland, the tissue-specific expression of Ren-2 is similar in TGR(mREN2)27 and DBA/2. This demonstrates maintenance of tissue specificity. Organs that are involved in cardiovascular regulation, such as the adrenal gland, kidney, and brain, express the Ren-2 gene before hypertension has developed, consistent with the possibility of a causal relationship between transgene expression in these tissues and hypertension. Because these tissues express the renin gene in nontransgenic rats as well, we suggest that this model can be used to study the regulation of renin gene expression and its role in hypertension at these sites. In addition, as an indication that interactions may exist between blood pressure and renin gene expression, we describe reciprocal changes in blood pressure and Ren-2 mRNA levels in the kidney and brain.

Adrenal Glands↗

PubMed1993

High blood pressure maintenance in transgenic mRen-2 vs. Lyon genetically hypertensive rats.

The present work was aimed to assess the factors involved in the maintenance of hypertension in adult transgenic mRen-2 (TG) rats. Special attention was paid to the renal handling of sodium, the sympathetic, and the renin-angiotensin system (RAS) activity. TG rats were compared with age-matched Lyon genetically hypertensive rats (LH), as both are of Sprague-Dawley origin. Blood pressure (BP), heart rate, and renal sympathetic nerve activity (RSNA) were recorded in conscious freely moving animals. Kidneys were isolated and single-pass perfused at different pressure levels. It was observed that the peripheral sympathetic drive was identical in TG and LH rats as indicated by their similar 24-h urinary excretion of catecholamines and methoxylated metabolites, baseline RSNA and its control by the baroreflex, and hypotensive response to ganglion-blockade. On the contrary, TG rats differed from LH rats by a more rapid excretion of an oral isotonic sodium load, a greater hypotensive and natriuretic response to furosemide, and a more marked BP response to acute RAS blockade. The TG kidney responses to stepwise changes in renal perfusion pressure (RPP) differed from those of LH rats by significantly higher perfusate flow and glomerular filtration rate. However, the pressure natriuresis curve of TG kidneys did not differ from that of LH rats because of an elevated tubular sodium reabsorption rate. These results suggest that adult TG rats, compared with LH rats, exhibit a tendency toward sodium and water retention, which may explain that despite low renal and circulating renin levels, the RAS remains involved in the maintenance of high BP in that model.

Animals↗

PubMed1993

Angiotensinogen is cleaved to angiotensin in isolated rat blood vessels.

The cleavage of synthetic tetradecapeptide renin substrate has been used to infer the presence of renin in the walls of isolated blood vessels; however, the conversion of natural angiotensinogen to angiotensin in isolated blood vessels has not been reported. We studied the release of angiotensinogen and the formation of angiotensins in a bloodless, perfused, isolated hind limb preparation of the rat. Perfusion with a modified Tyrode's solution resulted in spontaneous release of 4.7 +/- 1.5 pmol per 30 minutes of angiotensinogen as measured directly by radioimmunoassay. Western blot further identified the released material as angiotensinogen. Spontaneous release of angiotensins I and II was demonstrated by high performance liquid chromatography and radioimmunoassay. When highly purified rat angiotensinogen was added to the perfusate, release of angiotensin II was increased 14-fold compared with saline infusion. Captopril (10 mumol/L) inhibited angiotensinogen-induced angiotensin II release by 67% and led to an increase in angiotensin I release by 301%. Bilateral nephrectomy 24 hours before the experiments reduced basal angiotensin release below the detection limit and blunted angiotensinogen-induced angiotensin II formation by 95%. We conclude that active renin is present in the vessel wall and interacts with its natural substrate to form angiotensin peptides. Our data support the notion that the bulk of vascular renin is taken up from the circulation.

Angiotensin I↗

PubMed1993

Circadian blood pressure variation in transgenic hypertensive rats.

Automatic, around-the-clock blood pressure measurements have increased our understanding of hypertension in humans. Patients with essential hypertension display patterns similar to those observed in normotensive subjects, whereas those with secondary hypertension frequently show abnormal circadian rhythms characterized by a failure to reduce blood pressure at night. We have modeled this situation in rats. Normotensive Wistar-Kyoto and Sprague-Dawley rats, spontaneously hypertensive rats, and rats made hypertensive by transgenic implantation of the mouse salivary gland renin gene (TGR[mRen-2]27) underwent chronic implantation of a device that telemetrically monitored their blood pressures, heart rates, and motor activities. In either normotensive or hypertensive rats, motor activity peaked during the dark phase, indicating that animals from all strains were nocturnal. In both normotensive and spontaneously hypertensive rats, the 24-hour blood pressure and heart rate profiles showed peak values during the rats' active phase at night, ie, between midnight and 3 AM. In the transgenic rats, on the other hand, blood pressure values were at maximum during the day around noon, when the rats were in their resting phase. The heart rate of the transgenic rats nevertheless still peaked around midnight. These data suggest that normotensive rats and those with primary and secondary hypertension display circadian rhythms of blood pressure and heart rate analogous to those observed in normotensive and primary or secondary hypertensive humans, respectively. The TGR(mRen-2)27 strain may be a useful model with which to investigate the mechanisms responsible for alterations in circadian rhythms of blood pressure and heart rate in forms of secondary hypertension.

Analysis of Variance↗

PubMed1993

Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions.

Gap junction channels consisting of connexin protein mediate electrical coupling between cardiac cells. Expression of two connexins, connexin40 (Cx40) and connexin43 (Cx43), has been studied in ventricular myocytes from normal and hypertensive rats. Polyclonal affinity-purified rabbit antibodies to Cx43 and Cx40 have been used for immunohistochemical analysis on frozen sections from rat heart. These studies revealed coexpression of Cx43 and Cx40 in ventricular myocytes. In addition, Cx40 is preferentially expressed in three distinct regions: first, in the endothelial layer of the heart blood vessels but not in the smooth muscle layer of the arteries; second, in the ventricular conductive myocardium, particularly in the atrioventricular bundle and bundle branches, where Cx43 is not observed; and third, in the myocyte layers close to the ventricular cavities. These results suggest that Cx40 is preferentially expressed in the fast conducting areas of myocardial tissue. Expression of both Cx40 and Cx43 was also found in immunoblots from normal and hypertensive rat myocardiocytes. Under hypertensive conditions (ie, in spontaneous hypertensive rats and in transgenic rats that exhibit hypertension due to expression of an exogenous renin gene), we found a 3.1-fold increase in Cx40 expression, compared with normal myocardium. Furthermore, we detected a 3.3-fold decrease in Cx43 protein level in transgenic hypertensive rats. The coexpression of Cx40 and Cx43 proteins in rat myocytes, their spatial distribution, and the increased amount of Cx40 protein during cardiac hypertrophy suggest that Cx40 may be involved in mediating fast conduction under normal and pathological conditions. The increased expression of Cx40 in hypertrophic heart may be a compensatory mechanism to increase conduction velocity.

Animals↗

PubMed1993

Increased adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium.

The newly established rat strain TGR(mREN2)27 is a monogenetic model in hypertension research. Microinjecting the mouse Ren-2d renin gene caused it to become a stable part of the genome. The rats are characterized by fulminant hypertension, low plasma active renin, suppressed kidney renin, high plasma inactive renin, and high extrarenal transgene expression, most prominently in the adrenal cortex. Additionally, they exhibit significantly enhanced excretion of corticosteroids. Here we demonstrate that part of the plasma renin and most of the adrenal renin are transgene determined and that the adrenal renin is strongly activated. TGR(mREN2)27 adrenal cells may serve as a new tool to investigate the regulation and processing of Ren-2d-derived renin and its significance in hypertension and steroid metabolism. Adrenal renin in TGR(mREN2)27 is stimulated by 8-bromo-cAMP (8-Br-cAMP), angiotensin II (ANGII), and calcium. 8-Br-cAMP significantly stimulates active renin and prorenin release, as well as Ren-2d mRNA. Interestingly, within 60 min 8-Br-cAMP, ANGII, and calcimycin stimulate active renin, but not prorenin release. This indicates different intracellular pathways. An activated adrenal renin-angiotensin system in TGR (mREN2)27 as well as the lack of negative feedback on renin secretion by ANGII may be of pathophysiological significance in this hypertensive model.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1993

Modulation of tissue angiotensinogen gene expression by glucocorticoids, estrogens, and androgens in SHR and WKY rats.

Local or tissue renin angiotensin systems are thought to participate in cardiovascular regulation. However, little information is available on the mechanisms by which renin and angiotensinogen synthesis and secretion are regulated in these tissues. In view of the importance of steroid hormones in the regulation of hepatic angiotensinogen, we have examined the effects of dexamethasone, ethinyl estradiol, or dihydrotestosterone on angiotensinogen gene expression in peripheral or cerebral tissues of Wistar Kyoto (WKY) or spontaneously hypertensive rats (SHR). Following a single injection of dexamethasone (7 mg/kg) the concentrations of angiotensinogen mRNA increased in nearly all organs examined. The differences to controls were higher in SHR than in WKY. Dexamethasone in low doses (10 micrograms/kg/day) given for 10 days did not alter angiotensinogen mRNA or blood pressure in control animals, but increased both parameters in the hypertensive strain. The response to a single dose of ethinyl estradiol (3 mg/kg) was not as uniform as that to dexamethasone, and a tendency for a higher sensitivity was found in SHR. High stimulation rates were found in liver and kidneys of both strains. A single dose of dihydrotestosterone (10 mg/kg) did not significantly affect angiotensinogen mRNA in any organ. Only when a high dose of 50 mg/kg was given daily for 20 days, was angiotensinogen mRNA increased in some tissues. These data indicate that glucocorticoids and estrogens participate in the regulation of angiotensinogen gene expression in several extrahepatic tissues. The higher sensitivity to glucocorticoids in SHR may be relevant for the development of hypertension in this strain.

Angiotensinogen↗

PubMed1993

Angiotensinogen mRNA and pressor reactions to angiotensin in brain stem areas of spontaneously hypertensive rats.

The role of angiotensin (ANG II) at the tissue level, particularly in the brain, remains imperfectly defined. We measured angiotensinogen (A degrees) mRNA in the brain stems, sensory and sympathetic ganglia, and blood vessels of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHR-SP) by quantitative, liquid hybridization. We micro-injected ANG II and glutamate into the brain stems of these rats to gain insight into the functional significance of our findings. A. mRNA was found in the dorsolateral, dorsomedial, and ventrolateral pons, as well as in the dorsolateral, dorsomedial, and ventrolateral medulla of both strains. A degrees mRNA was 8-10 pg/micrograms total mRNA higher (p < 0.05) in the dorsomedial medulla (nucleus tractus solitarii) in WKY and SHR-SP (28.27 +/- 1.26 and 33.50 +/- 1.42 pg/micrograms RNA respectively) than in the other areas. SHR-SP had higher values (27.22 +/- 1.77 vs. 21.53 +/- 0.57 pg/micrograms mRNA) than WKY (p < 0.05) in the dorsolateral pons (locus coeruleus). A. mRNA was also identified in the optic nerves and chiasm, trigeminal and coeliac ganglia, arteries and veins. Injections of glutamate and ANG II into the dorsomedial, dorsolateral, and ventrolateral medulla increased blood pressure, while ANG II in the dorsal medial pons did not. We conclude that A degrees mRNA is produced to different degrees in brain stem areas which participate in blood pressure regulation. Medullary structures show more response to local ANG II than pontine structures. A degrees mRNA is located in sensory neural tissues as well as sympathetic ganglia. A degrees mRNA is present in both arteries and veins. These findings underscore the scope and complexity of ANG production in tissues.

Angiotensin II↗

PubMed1993

The transition from experimental to clinical pharmacology: the renin-angiotensin paradigm.

Modern molecular medicine is increasingly bridging the gap between basic research and experimental pharmacology and clinical therapeutics and practical medicine. The challenge in hypertension research is to elucidate the primary, genetic causes of elevated blood pressure. The problems with understanding primary (genetic) hypertension in humans are that (a) several genes are involved in the cardiovascular control mechanisms, (b) the genetics are complex, and (c) environmental factors that act over long spans of time confound the genotype/phenotype relationship individually, within a family, and regionally. Polygenetic diseases such as primary hypertension remain puzzles, which necessitates well-defined experimental models and new strategies in the genetics of human primary hypertension. This article will focus on the advances in molecular genetics of hypertension. Using gene technology it is possible to introduce new, additional genes in normotensive and hypertensive animals. In the mouse, it is possible to delete or mutate specific genes; similar technology is being developed for use in the rat.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1993