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Biomedical subjects

T Unger

Publications and source records attributed to T Unger.

At least 235 records · Page 13Linked to original sources
PubMed1990

Determining the origins and the structural aberrations of small marker chromosomes in two cases of 45,X/46,X, + mar by use of chromosome-specific DNA probes.

A 17-year-old girl (S.M.) and a 13-year-old girl (C.L.) both with Ullrich-Turner syndrome (UTS) were found to have 45,X/46,X, + mar mosaicism. The marker chromosomes in both patients were very small in size. In S.M. the marker chromosome was present in 80% of phytohemagglutinin-stimulated lymphocytes, 28% of skin fibroblasts, and 11-20% of gonadal fibroblasts. In C.L., the small marker chromosome was found in 50% of stimulated lymphocytes. S.M. is of normal height, but C.L. is short. Molecular hybridization with a number of Y-specific DNA probes demonstrated their presence in S.M. but absence in C.L. In situ hybridization with Y-specific and X-centromere-specific DNA probes confirmed the Y origin of the marker chromosome in S.M. and the X origin of the minute chromosome in C.L. Biotinylated centromere and telomere probes were also used for in situ hybridization to show the presence of centromeric and telomeric sequences in the Y-marker chromosome, suggesting that the deletion of this marker chromosome is interstitial.

Adolescent↗
PubMed1990

The X protein of the hepatitis B virus acts as a transcription factor when targeted to its responsive element.

The X protein of hepatitis B virus (HBV) stimulates transcription of a large number of viral enhancers. This protein augments the activity of the HBV enhancer through a specific cis element, termed X responsive element (XRE). Multimers of XRE exhibit enhancer activity which is further stimulated by X. XRE binds multiple cellular transcription factors one of which is the C/EBP. We have constructed the DB gene containing the DNA-binding domain of the C/EBP. This gene efficiently represses the enhancer activity of the XRE by competitive displacement of the XRE-binding factors. Under these conditions, X was found to have only a partially stimulatory effect on transcription, suggesting that the XRE-binding proteins are required for the activity of X. In contrast, an X-DB hybrid protein that binds to the XRE is a strong transcription factor and acts without additional XRE-binding proteins. Furthermore, studies of X mutants revealed that the carboxy-terminus of the protein is required for this activation. These data show that X directly stimulates the cellular transcription machinery, possibly by protein-protein interaction with the XRE-binding factors.

Amino Acid Sequence↗
PubMed1990

Improved methods for baroreceptor investigations in chronically instrumented rats.

We developed a novel approach using inflatable cuffs in order to test the baroreceptor reflex in conscious rats. The cuffs we employed differ from previous approaches in which cuffs are implanted in the thorax. Instead, we placed cuffs around the abdominal aorta and vena cava immediately below the diaphragm. We assessed the utility of this approach in several ways. First, we found that implantation could be accomplished without the stress associated with opening the thoracic cavity. Functioning preparations were far easier to obtain compared to the thoracic approach. The thoracic approach using two-vessel constriction resulted in inordinant mortality and failed preparations. We found that blood pressure changes could be easily exerted over a considerable range in conscious animals with the abdominal cuffs. For instance, blood pressure could be easily manipulated over a range of 100 mmHg (increased or decreased by 50 mmHg from baseline). This simpler and more reliable approach will facilitate baroreceptor investigations in conscious rats.

Animals↗
PubMed1990

Atrial natriuretic peptide (ANP) as a neuropeptide: interaction with angiotensin II on volume control and renal sodium handling.

1. Angiotensin II (ANG II) and atrial natriuretic peptide (ANP) are functionally antagonistic circulating hormones involved in blood pressure and body fluid regulation. An inappropriate atrial secretion of ANP has been implicated in the pathogenesis of hypertension, but clinical and experimental results on the role of ANP in hypertension are still conflicting. 2. In the brain both peptides have been localized in close proximity, preferentially in areas involved in central cardiovascular, electrolyte and volume control. ANP was shown to inhibit ANG II-induced drinking, release of pituitary hormones and natriuresis, and to induce sodium retention when given alone. 3. These findings suggest that also in the brain ANG II and ANP exert functionally antagonistic effects. However, in contrast to their peripheral effects, ANG II induces natriuresis while ANP appears to cause antinatriuresis in the brain.

Angiotensin II↗
PubMed1990

Hemodynamic actions of intravenous endothelin in rats: comparison with sodium nitroprusside and methoxamine.

We investigated hemodynamic actions of endothelin (ET) in conscious rats. Intravenous injections of ET produced dose-dependent biphasic blood pressure (MAP) responses: initial decreases of up to 84 +/- 11 s were followed by increases of up to 1-h duration. Corresponding responses in cardiac output (CO), heart rate, and efferent splanchnic nerve activity were reciprocal to changes in MAP. Mesenteric blood flow showed an immediate and sustained decrease. Compared with equidepressor doses of sodium nitroprusside (NNP), ET produced a markedly different regional hemodynamic response pattern during the initial depressor phase. Compared with equipressor doses of the alpha-adrenoceptor agonist methoxamine, ET produced significantly greater vasoconstriction in hindlimb and renal vascular bed during pressor phase. ET-induced changes in CO were significantly greater than the respective CO responses to NNP and methoxamine in intact animals and following cardiac autonomic blockade with atenolol and methscopolamine. ET has vasodilator and vasoconstrictor properties that induce a unique hemodynamic response pattern on intravenous injection. Persistence of ET-induced changes in CO following cardiac autonomic blockade suggests direct cardiostimulatory actions of the peptide during depressor phase as well as direct cardiodepressant actions during pressor phase.

Animals↗
PubMed1990

Role of the kidney in primary hypertension: a renal transplantation study in rats.

We have previously shown that transplantation of kidneys from genetically hypertensive to normotensive rats result in hypertension in renal graft recipients. To investigate whether this posttransplantation hypertension may have been the result of damage to the renal graft by high perfusion pressure before transplantation, we normalized blood pressure throughout life in spontaneously hypertensive rat (SHR) kidney donors by continuous antihypertensive treatment with the angiotensin-converting enzyme inhibitor ramipril (1 mg.kg-1.day-1 in drinking fluid). When kidneys from these rats were transplanted at age 20 wk to age-matched bilaterally nephrectomized F1 hybrids bred from SHR and Wistar-Kyoto (WKY) parents, posttransplantation hypertension still developed. In contrast, blood pressure did not change significantly in recipients of kidneys from ramipril-treated WKY rats. In the initial phase, recipients of SHR kidneys had a lower body weight and higher plasma urea concentrations than recipients of WKY kidneys. However, in the chronic phase, there were no significant differences between the two groups with respect to daily water intake, plasma urea concentration, glomerular filtration rate, renal blood flow, and weight of transplanted kidneys; no histological differences were observed between renal grafts from WKY and SHR donors, except for structural vascular hypertrophy in the latter group. We conclude that posttransplantation hypertension in recipients of SHR kidney grafts also develops, when the grafts have not been subjected to high renal perfusion pressure before transplantation. Our data support the hypothesis that SHR kidneys carry a primary defect, which can induce hypertension in renal graft recipients.

Animals↗
PubMed1990

Hypertension in rats induced by renal grafts from renovascular hypertensive donors.

Renal transplantations were performed, using microsurgical techniques, with adult male two-kidney, one clip hypertensive rats (n = 9) and sham-operated normotensive Wistar-Kyoto rats (n = 8) as kidney donors and with F1 hybrids, bred from Wistar-Kyoto and stroke-prone spontaneously hypertensive rat parents, as recipients. Systolic blood pressure before surgery was 200 +/- 2.7 mm Hg in hypertensive and 115 +/- 1.7 mm Hg in normotensive donors and 144 +/- 7.1 and 138 +/- 3.5 mm Hg in the two groups of recipients. Renal hypertension in donors was maintained for 14 weeks before surgery was performed and the nonischemic kidneys were transplanted. Bilaterally nephrectomized recipients of renal grafts from hypertensive donors developed sustained hypertension (185 +/- 3.9 mm Hg). In contrast, in recipients of renal grafts from normotensive donors, blood pressure decreased significantly to the level of the donors (111 +/- 3.7 mm Hg). Posttransplantation hypertension in recipients of renal grafts from hypertensive donors was associated with intrarenal vascular hypertrophy, smaller kidneys, a decreased glomerular filtration rate, an increased plasma urea concentration, and polydipsia as compared with normotensive transplanted controls. Renal pyelograms revealed no gross anatomic alterations of transplanted kidneys. Our data indicate that secondary damage to the renal grafts caused by high perfusion pressure before transplantation can induce hypertension in recipients of these kidneys. Furthermore, our data suggest that renal mechanisms may be necessary to maintain borderline hypertension in F1 hybrids.

Animals↗
PubMed1990

Converting enzyme inhibition in kinin-deficient brown Norway rats.

The contribution of endogenous kinins to the acute antihypertensive actions of the converting enzyme inhibitor ramipril was investigated in kinin-deficient Brown Norway rats and in Brown Norway-Hannover rats and Wistar rats as controls. In Brown Norway rats, urinary kinin excretion was measurable but extremely low when compared with control strains. The depressor responses to intra-arterial bradykinin injections 1) were not different between Brown Norway and Brown Norway-Hannover rats, 2) were potentiated by intravenous ramipril (60 micrograms), and 3) were attenuated by intra-arterial infusion of the bradykinin antagonist B4146 (40 micrograms/kg/min) to a similar extent in both strains. In renal hypertensive (two-kidney, one clip) Brown Norway rats, the blood pressure reductions to intravenous bolus injections of ramipril (100 micrograms) were significantly reduced both in extent and duration when compared with hypertensive Brown Norway-Hannover and Wistar rats. Intra-arterial infusion of B4146 (40 micrograms/kg/min) attenuated the depressor response to ramipril in Wistar and Brown Norway-Hannover rats but had no effect in Brown Norway rats. In contrast, all three groups showed similar depressor responses to intravenous infusions of the angiotensin II receptor antagonist saralasin. These responses were not influenced by the bradykinin antagonist. Our data support the hypothesis that kinins are important for the acute antihypertensive actions of converting enzyme inhibitors.

Angiotensin II↗
PubMed1990

Role of the kidney in the pathogenesis of primary hypertension.

Primary hypertension in animals and humans probably represents several different pathophysiological states rather than being a uniform nosological entity. Among other factors, renal mechanisms may be primarily and secondarily involved. The availability of genetically homologous animal models for hypertension has greatly promoted studies on the etiology and pathogenesis of high blood pressure disease. In particular, renal transplantation studies between genetically hypertensive and normotensive rats from three different models have provided strong evidence for a primary role of the kidney in genetic hypertension. Other factors, such as vascular, neural, and humoral mechanisms have also been shown to be involved and may be particularly effective in increasing blood pressure, when they act through the kidney. Several functional and biochemical differences have been identified between kidneys from genetically hypertensive and normotensive animals. However, the relative contribution of each of these factors to the development of primary hypertension remains to be determined. Evidence from studies on human renal graft recipients also indicates that, among other factors, the kidney plays an important role in the development of primary hypertension in humans.

Animals↗
PubMed1989

Sensitization to pressor effects by repeated central injections of vasopressin in conscious rats.

Arginine vasopressin (AVP) injected intracerebroventricularly (i.c.v.) in the nanogram range elicits increases in mean arterial blood pressure (MAP), heart rate (HR) and efferent sympathetic nerve activity (SpNA) via central V1 AVP receptor stimulation. In this study in conscious rats we investigated, whether the cardiovascular and sympathetic responses can be augmented by repeated central applications of AVP, as has been previously shown for the convulsive responses to higher i.c.v. doses of the peptide. The AVP-induced pressor (0.1 and 1.0 ng) and the SpNA (0.1 ng) responses were significantly enhanced by a second AVP challenge 24 h after the first injection. With higher doses of the peptide (3 ng), the blood pressure responses were not different between two subsequent injections, but barrel rotation occurred in 21% of the animals upon the second challenge. The pressor responses to a threshold i.c.v. dose of 1 ng angiotensin II (ANG II) were not enhanced upon a second ANG II challenge. Our results demonstrate that AVP, unlike ANG II, can sensitize central mechanisms leading to increased MAP and SpNA responses.

Adrenergic Fibers↗
PubMed1989

Centrally administered atrial natriuretic factor inhibits central angiotensin-induced natriuresis.

Atrial natriuretic factor (ANF) and angiotensin II (ANG II) have been demonstrated in close vicinity in forebrain areas involved in the central fluid and electrolyte regulation. Previous reports suggested an inhibitory effect of ANF on some of the central actions of ANG II, such as water intake and vasopressin release. In the present study in conscious, unrestrained, sodium-repleted rats we investigated the effects of intracerebroventricularly (i.c.v.) administered ANF (alpha r-APIII) on the central natriuretic action of ANG II. Urine was collected through a novel chronically implanted ureteral catheter. I.c.v. injections of ANG II (100 pg) produced a marked natriuresis of rapid onset without altering urinary volume or blood pressure. Pretreatment with ANF (100 pg, 1 ng, 100 ng i.c.v.) 5 min before ANG II dose-dependently antagonized the ANG II-induced natriuretic effect. The lowest dose caused approximately 50% reduction, the intermediate dose a complete abolition and the highest dose even a reversal of the ANG II-induced natriuretic effect to salt retention. Urinary volume and blood pressure were not altered by the combined treatment with ANG II and ANF. Our results support the idea of a functional antagonism between ANG II and ANF in the central fluid and electrolyte control.

Angiotensin II↗
PubMed1989

Natriuretic action of central angiotensin II in conscious rats.

The effects of intracerebroventricular (i.c.v.) injections of angiotensin II (ANG II, 10 pg, 100 pg and 10 ng) on renal sodium excretion were investigated in conscious rats instrumented with a chronic urethral catheter. ANG II increased renal sodium excretion dose-dependently with a threshold i.c.v. dose of 10 pg. Only after the highest dose was a concomitant increase in arterial blood pressure and urinary flow observed. The ANG II-induced natriuresis began within 5 min of the i.c.v. injection and lasted for more than 1 h. The angiotensin receptor antagonist saralasin (1 ng, i.c.v.) largely prevented the natriuretic effect of i.c.v. injected ANG II (100 pg). Our results lend further support to the hypothesis that brain ANG II by its potent natriuretic actions may be instrumental in central osmotic control.

Angiotensin II↗
PubMed1989

Selective local action of angiotensin II on dopaminergic neurons in the rat hypothalamus in vivo.

Microdialysis was used to investigate whether angiotensin II modulates the basal and K+-induced release of endogenous noradrenaline, dopamine and their metabolites 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the anterior hypothalamus of the anaesthetized rat. The release of the amines was stimulated twice (ST1 and ST2) with either 50 mmol/l or 100 mmol/l K+. The release of each amine induced by K+ was reproducible and concentration-dependent. Angiotensin II when present in the perfusion fluid after ST1 at a concentration of 0.1 and 10 mumol/l (chosen after in vitro experiments had shown that the recovery of the peptide across the dialysis membrane was only 3.6%), had no significant effect on amine release. However, 10 mumol/l angiotensin II induced an immediate, significant increase in basal DOPAC outflow which reached a maximum of 89% in the 100 mmol/l K+ and 53% in the 50 mmol/l K+ experiments. No such effect was observed with DOPEG outflow. In a separate experimental series, addition of angiotensin II without a preceding K+ stimulation period did not significantly affect the outflow of the amines and metabolites. The results suggest that angiotensin II can selectively influence dopamine metabolism in the anterior hypothalamus in vivo but does not act locally to acutely facilitate the release of endogenous catecholamines from this brain area.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Angiotensin II and atrial natriuretic peptide in the brain: effects on volume and Na+ balance.

Atrial natriuretic peptide (ANP) and angiotensin II (ANG II), although originally isolated from peripheral sources, are now known to be present in the central nervous system. The distribution of the peptides and their binding sites are found in areas involved in cardiovascular and volume/electrolyte regulation. Since ANP administered centrally can antagonize the actions of ANG II, the two peptides may function as opposing mechanisms involved in maintaining fluid and electrolyte homeostasis.

Angiotensin II↗
PubMed1989

Converting enzyme inhibitors and their effects on the renin-angiotensin system of the blood vessel wall.

A local vascular tissue renin-angiotensin system (RAS) may contribute to blood pressure control and the maintenance of high blood pressure in some forms of hypertension, independently of the plasma RAS. Vascular converting enzyme (CE), present mainly in the endothelial layer of arteries and veins, can be altered in hypertension. Locally generated vascular angiotensin II (ANG II) may exert a number of actions on vascular tone and function, including directly and sympathetically mediated vasoconstriction, changes in vascular compliance in larger vessels, influence on vascular reactions to inflammation and injury, and alterations in vascular texture. Orally administered CE inhibitors have been shown to block not only the plasma RAS but also CE in the vasculature, leading to decreased vascular ANG II concentrations and possibly to an accumulation of locally generated vasodilator peptides and prostaglandins in the vascular wall. In spontaneously hypertensive rats, the slow recovery of CE activity in the vasculature on drug withdrawal was more closely associated with the slow return of blood pressure to hypertensive levels than the fast recovery of the plasma RAS. These and other experimental data discussed in this article favor the hypothesis that local CE inhibition in the vascular wall of resistance vessels, large arteries and veins contributes to the beneficial therapeutic effects of CE inhibitors in cardiovascular disorders such as hypertension and congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗