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Biomedical subjects

T Unger

Publications and source records attributed to T Unger.

At least 199 records · Page 11Linked to original sources
PubMed1992

p53: a transdominant regulator of transcription whose function is ablated by mutations occurring in human cancer.

Gal4-p53 fusion constructs demonstrate that wild type p53 is a potent transactivator in human lung cancer cells with the transactivation domain for p53 residing in amino acids 1-42. Strikingly, a variety of lung cancer derived p53 mutations occurring outside this domain disrupt this activity. Temperature sensitive conformational shifts of p53 mutant proteins to the wild type form exist and, with a temperature downshift, several mutants become transcriptionally active. Wild type p53 protein is known to form oligomers with mutant p53 and cotransfection of wild type and mutant genes shows that p53 acts in a transdominant manner that is independent of the DNA binding specificity. Transcription is either increased or decreased depending on whether the wild type is more or less abundant than the mutant form. Finally, lung cancers differ in their ability to support the transactivation related functions, providing evidence of other abnormalities of the p53 system in human cancer.

Amino Acid Sequence↗
PubMed1992

The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein.

The observed interaction between p53 and the oncoproteins encoded by several DNA tumor viruses suggests that these viruses mediate their transforming activities at least in part by altering the normal growth regulatory function of p53. In this study we examined the effect of viral oncoprotein expression on the transcriptional transactivation function of wild-type p53 in human cells. Plasmids expressing human p53 were cotransfected with either SV40 large T-antigen or human papillomavirus (HPV) type 16 E6 expression plasmids and assayed for transactivation function using a reporter gene driven by a p53-responsive promoter containing multiple copies of the consensus p53 DNA binding motif, TGCCT. Both large T-antigen and E6 were able to inhibit transactivation by wild-type p53. Furthermore, SV40 T-antigen mutants that are defective for p53 binding were not able to inhibit transactivation and HPV E6 proteins that were either mutant or derived from non-oncogenic HPV types and unable to bind p53, had no effect on p53 transactivation. These results demonstrate the physiological relevance of the interaction of SV40 T-antigen and HPV E6 oncoproteins with p53 in vivo and suggest that the transforming functions of these viral oncoproteins may be linked to their ability to inhibit p53-mediated transcriptional activation.

Antigens, Polyomavirus Transforming↗
PubMed1992

Angiotensin receptor subtypes in the brain.

Development of specific angiotensin II receptor ligands has recently provided evidence for the existence of two angiotensin II receptor subtypes, termed AT1 and AT2, which differ in their signal transduction mechanisms and in the effects they mediate. In brain, both receptor subtypes are present. Most of the known central actions of angiotensin II, for example the regulation of blood pressure and of electrolyte and water balance, seem to be mediated by the AT1 receptor, while the role of the AT2 receptor is still an enigma. This review by Thomas Unger and colleagues summarizes the current knowledge and latest hypotheses in this rapidly developing field.

Angiotensin I↗
PubMed1992

Role of brain angiotensin in cardiovascular regulation.

The brain is one of the organs where an intrinsic renin-angiotensin system (RAS) has been described. Stimulation of circumventricular or brainstem angiotensin II (Ang II) receptors engenders a distinct pattern of cardiovascular, endocrine, and behavioral responses featuring blood pressure increase, attenuation of the baroreceptor reflex, drinking, release of pituitary hormones such as vasopressin, oxytocin, and ACTH, and natriuresis. In contrast to most of the other central actions of Ang II, the natriuretic effect cannot be elicited by Ang II as a circulating hormone. Recently, we have shown that stimulation of Ang II AT-1 receptors in the circumventricular organs causes a selective release of norepinephrine (NE) in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). As vasopressin is also released from the PVN and SON, it is possible that the Ang II-NE interaction is involved in the release of vasopressin, thereby contributing to central blood pressure regulation and volume control. Finally, a substantial body of results suggests that an overactivity of the brain renin-angiotensin system is one of the contributors to genetic hypertension. However, this idea needs further confirmation.

Angiotensin II↗
PubMed1992

Use of selective antagonists to dissociate the central cardiovascular and behavioural effects of tachykinins on NK1 and NK2 receptors in the rat.

1. The effects of intracerebroventricular (i.c.v.) pretreatment with selective NK1 ((+/-)-CP 96,345), NK2a (MEN 10,207; MEN 10,376) and NK2b (R 396) tachykinin receptor antagonists on the cardiovascular and behavioural responses to i.c.v. substance P (SP) and neurokinin A (NKA) were studied in conscious rats. 2. SP and NKA (25 pmol) induced mean arterial blood pressure and heart rate increases of the same magnitude and duration. The cardiovascular responses to both peptides were accompanied by excessive face washing, sniffing, grooming and wet dog shakes. 3. The cardiovascular responses to SP but not to NKA were attenuated by pretreatment with a NK1 receptor antagonist, (+/-)-CP 96,345. Of the behavioural responses, only face washing was significantly inhibited. 4. The cardiovascular and behavioural effects of NKA but not of SP were significantly attenuated by pretreatment with the selective NK2b receptor antagonist, R 396. 5. The selective NK2a receptor antagonists, MEN 10,207 and MEN 10,376, did not affect the cardiovascular and behavioural responses to either SP or NKA. 6. These results suggest, firstly, that the cardiovascular and behavioural effects of i.c.v. SP are mediated by NK1 receptors; secondly, that NKA injected i.c.v. does not interact with NK1 receptors but with another type of tachykinin receptor which may belong to the NK2b subclass. These findings provide pharmacological evidence for the existence of functionally active NK2 receptors in the rat brain.

Amino Acid Sequence↗
PubMed1992

Spectrum analysis of sympathetic nerve activity and blood pressure in conscious rats.

This study tests whether the power spectrum of blood pressure (BP) provides information toward the sympathovagal balance of BP control by comparing the BP (femoral arterial catheter) spectrum with the spectrum of the efferent sympathetic nerve activity (SNA, bipolar electrode around splanchnic nerve). A remarkable resemblance between both spectra was found. A high-frequency component (HF) linked to respiration and a slower fluctuation type between 0.15 and 0.6 Hz (LF) were identified. There was a large and significant coherence only in the HF range of the BP and SNA power spectrum (P < 0.01). The phase lag of SNA and BP was roughly 200 ms. The recordings were repeated during pharmacological blockade in nine Wistar-Kyoto rats (WKY) and nine spontaneously hypertensive rats (SHR). alpha 1-Adrenoceptor blockade (prazosin) reduced the proportional LF power of BP in both rat strains (WKY P < 0.01, SHR P < 0.05) in favor of HF (WKY P < 0.01, SHR P < 0.01). Parasympathetic blockade (methylscopolamine) had no effect on proportions of power. Similarly, there were no significant differences in the proportional HF and LF power spectra of WKY and SHR. These data provide direct evidence for a relationship between the BP and SNA power spectra; however, only the acute changes in the sympathetic tone changed the LF-HF relationship.

Animals↗
PubMed1992

Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea.

We have described a rat model that responds to repetitive episodic hypoxia (12-s infusions of nitrogen into daytime sleeping chambers every 30 s, 7 h/day for 35 days) with an increase in diurnal systemic blood pressure. We hypothesized that afferent information from the peripheral chemoreceptors may be necessary to produce diurnal blood pressure elevation in this hypoxia model. Carotid body denervation (CBD) was accomplished by severing both carotid sinus nerves in two groups of male Wistar rats (250-375 g). Group 4 CBD rats were subjected to intermittent hypoxia for 35 days (3-5% nadir ambient O2) as described above, whereas group 5 CBD rats remained unhandled in their usual cages. Additional sham-operated controls included group 2 sham-"hypoxia" rats, which were housed in chambers identical to the hypoxia rats but supplied with compressed air instead of nitrogen, group 1 (not denervated) rats, which remained unhandled in their usual cages, and group 3 sham-operated rats, which were subjected to 35 days of intermittent hypoxia identical to group 4 CBD rats. Femoral arterial baseline and end-of-study blood pressures were measured in conscious rats. The group 3 rats exposed to episodic hypoxia displayed a 13-mmHg increase in mean blood pressure, whereas the other groups showed no significant change from baseline. Left ventricular hypertrophy was evident in all rats exposed to episodic hypoxia, but right ventricular hypertrophy was evident only in the group 4 rats. All CBD rats developed increased hematocrit and hemoglobin, while the group 3 rats (non-CBD, episodic hypoxia) did not. The baroreceptor reflex at baseline was not depressed in the CBD rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats.

An association between chronic high blood pressure and obstructive sleep apnea has been described. We hypothesized that repetitive episodic hypoxia patterned after the hypoxia seen in sleep apnea could contribute to diurnal elevation of blood pressure. Using 12-second infusions of nitrogen into daytime sleeping chambers, four groups of male rats (250-375 g) were subjected to intermittent hypoxia (3-5% nadir ambient oxygen) every 30 seconds, 7 hours per day for up to 35 days. In one group, blood pressure was measured weekly by the tail-cuff method in conscious animals during 5 weeks of episodic hypoxia. In the other three groups, blood pressure was measured in conscious animals via femoral artery catheters at baseline and after 20, 30, or 35 days of exposure. Additional groups served as controls: two sham groups housed in identical "hypoxia" chambers received compressed air instead of nitrogen (35 days) while two other groups remained unhandled in their usual cages (35 days). Both groups challenged with 35 days episodic hypoxia showed significant increases in blood pressure compared with controls: the tail-cuff rats showed a 21 mm Hg increase in systolic pressure (p less than 0.05) and the intra-arterially measured rats a 13.7 mm Hg increase in mean arterial pressure (p less than 0.05). The 30-day exposed rats also showed a 5.7 mm Hg increase in mean pressure over baseline (p less than 0.05). Blood pressure did not change significantly from baseline in the control groups. Left ventricle-to-body weight ratio was higher in both 35-day exposed groups than in unhandled or sham controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chronic kinin receptor blockade attenuates the antihypertensive effect of ramipril.

The contribution of endogenous kinins to the chronic antihypertensive effect of angiotensin converting enzyme inhibitors was investigated in two-kidney, one clip hypertensive Wistar rats, using the new bradykinin B2-receptor antagonist HOE 140 (D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]-bradykinin). In a first protocol, rats were pretreated orally with the angiotensin converting enzyme inhibitor ramipril (1 mg/kg per day), for 4 weeks. Acute blockade of bradykinin receptors by intravenous injections of HOE 140 at doses of 8.4 and 100 micrograms/kg, which inhibited the depressor responses to exogenous bradykinin, did not affect the antihypertensive effect of ramipril in these animals. Bradykinin receptors were then blocked chronically by subcutaneous infusion of HOE 140 (500 micrograms/kg per day) via osmotic minipumps for 6 weeks, while ramipril treatment was continued. HOE 140 partially reversed the antihypertensive effect of ramipril from 115.3 +/- 4.6 to 123.8 +/- 3.3 mm Hg (mean arterial blood pressure) after 3 weeks and to 121.3 +/- 2.9 mm Hg after 6 weeks. In contrast, in controls (ramipril plus subcutaneous vehicle infusion) mean arterial blood pressure decreased further from 112.0 +/- 6.0 to 110.3 +/- 4.9 mm Hg after 3 weeks and to 103.7 +/- 5.0 mm Hg after 6 weeks (p less than 0.05 and p less than 0.01, HOE 140 versus controls). Plasma catecholamines were not significantly different between the two groups at the end of the experiment, indicating that the partial reversal of the antihypertensive effect was not due to a bradykinin-like agonistic effect on catecholamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Distribution and metabolism of angiotensin I and II in the blood vessel wall.

The demonstration of all components of the renin-angiotensin system in vascular tissue has raised questions as to the precise location of the local angiotensin II generation within the vascular wall. We investigated the metabolism of angiotensin I to angiotensin II in the vascular wall in the isolated rabbit thoracic aorta. Angiotensin I (3 x 10(-9) M) applied into the aortic lumen was partially converted to angiotensin II (14% after 60 minutes), but most of the luminal angiotensin I was degraded to peptide fragments or diffused as intact angiotensin I, peptide fragments, or both, into the vessel wall. Incubation studies with [3H]angiotensin I revealed that angiotensin I or angiotensin I fragments mainly diffused into the medial layer of the aorta and to a lesser degree into the adventitia and the endothelium. After removal of the endothelium, angiotensin II generation could no longer be detected. Addition of the angiotensin converting enzyme inhibitor ramiprilat (10(-7) M) to the incubation medium led to a complete blockade of angiotensin II generation by endothelial angiotensin converting enzyme. Our results underline the importance of the endothelium for conversion of angiotensin I to angiotensin II and provide evidence that conversion of angiotensin I to angiotensin II is predominantly achieved by endothelial cells. They also support the concept of an endocrine versus autocrine/paracrine renin-angiotensin system where the endothelium of the vasculature is the critical target site for angiotensin II production by both systems and, thus, the most important site for the actions of angiotensin converting enzyme inhibitors.

Angiotensin I↗
PubMed1992

Effect of early onset angiotensin converting enzyme inhibition on myocardial capillaries.

We investigated the preventive effects of long-term treatment with the angiotensin converting enzyme inhibitor ramipril on myocardial left ventricular hypertrophy and capillary length density in spontaneously hypertensive rats. Rats were treated in utero and subsequently up to 20 weeks of age with a high dose (1 mg/kg per day) or with a low dose (0.01 mg/kg per day) of ramipril. Animals given a high dose of ramipril remained normotensive, whereas those given a low dose developed hypertension in parallel to vehicle-treated controls. At the end of the treatment period, converting enzyme activity in heart tissue was inhibited dose-dependently in the treated groups. Both groups revealed an increase in myocardial capillary length density together with increased myocardial glycogen and reduced citric acid concentrations. Left ventricular mass was reduced only in high dose- but not in low dose-treated animals. Our results demonstrate that early onset treatment with a converting enzyme inhibitor can induce myocardial capillary proliferation, even at doses too low to antagonize the development of hypertension or left ventricular hypertrophy. We hypothesize that potentiation of kinins is responsible for this effect, probably by augmenting myocardial blood flow, which is a well-known trigger mechanism of angiogenesis in the heart.

Administration, Oral↗
PubMed1992

Sympathetic denervation blocks blood pressure elevation in episodic hypoxia.

We have previously described a rat model that responds to repetitive episodic hypoxia (FiO2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia.

Animals↗
PubMed1992

Role of bradykinin in chronic antihypertensive actions of ramipril in different hypertension models.

We investigated the chronic effect of bradykinin B2-receptor blockade on the antihypertensive actions of the angiotensin-converting enzyme (ACE) inhibitor ramipril in three different hypertensive rat models, the two-kidney/one-clip (2K1C) hypertensive Wistar rat, the kinin-deficient 2K1C hypertensive Brown Norway Katholieke (BN-K) rat, and the spontaneously hypertensive rat (SHR). Chronic blockade of bradykinin B2 receptors by subcutaneous infusion of the new bradykinin antagonist HOE 140 (500 micrograms/kg/day) attenuated the antihypertensive effect of ramipril only in 2K1C hypertensive Wistar rats, but not in 2K1C BN-K rats and SHR. Our data demonstrate for the first time that potentiation of endogenous kinins contributes to chronic antihypertensive actions of ACE inhibitors in experimental renal hypertension. Whether this holds also true for other forms of hypertension remains to be answered.

Animals↗
PubMed1992

[Inhibition of the enzyme of conversion and cardioprotection: role of bradykinins].

Ramipril, a converting enzyme inhibitor, was first studied in rats with aortic stenosis, an experimental model of reno-vascular hypertension. In this study, ramipril has an antihypertrophic cardiac effect, independently to its hypotensive effect. The co-administration of Hoe 140, a specific antagonist of bradykinin receptors blocked totally the effect of ramipril on blood pressure, cardiac hypertrophy and on concentration of cGMP. These effects can therefore be explained by an accumulation of bradykinins. Furthermore, we investigated the preventing effects of ramipril on left ventricular hypertrophy, on growth of cardiac capillaries using SHR rats, treated in utero and during the 20 weeks following birth with two doses: a relatively high dose (1 mg/kg/day) and a low dose (0.01 mg/kg/day). Animals treated with a low dose of ramipril presented a high blood pressure similar to that observed in the control group. At the end of the treatment, the converting enzyme activity was inhibited in both groups. An increase in the growth of cardiac capillaries and of the cardiac concentration of glycogen and a decrease in the cardiac concentration of citric acid was observed in both groups. The ventricular weight decreased only in the high dose treatment group. This results demonstrated that early treatment with converting enzyme inhibitor even with a low dose which was unable to prevent the development of hypertension and of left ventricular hypertrophy. We could therefore draw a hypothesis of an accumulation of bradykinin due to the converting enzyme inhibitor which could explain in part this effect through an improvement of cardiac metabolism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Kinin contribution to chronic antihypertensive actions of ACE-inhibitors in hypertensive rats.

The contribution of endogenous bradykinin to the chronic antihypertensive actions of the ACE-inhibitor, ramipril, was investigated in 2-kidney 1 clip (2K1C) hypertensive kinin-deficient Brown Norway Katholieke rats (BN-K) and 2K1C hypertensive Wistar rats (WI) as well as in spontaneously hypertensive rats (SHR). Treatment with ramipril plus the BK B2-receptor antagonist HOE 140 for 6 weeks significantly attenuated the antihypertensive effects of the ACE-inhibitor in 2K1C hypertensive WI rats, but not in 2K1C hypertensive BN-K rats and in SHR. Our data support the hypothesis that potentiation of endogenous kinins contributes to the chronic antihypertensive actions of ACE-inhibitors in experimental renal hypertension. Whether this holds also true for other forms of hypertension remains to be answered.

Animals↗
PubMed1992

ACE inhibition in the tissues.

The discovery of the components of the renin angiotensin system (RAS) in various tissues gave rise to the idea that functional "tissue" renin-angiotensin systems exist that are more or less independent of the hormonal RAS. Further support to this notion came from the recent demonstration of the mRNA for the protein components of the RAS in a number of organs. Last not least, the introduction of the CE inhibitors, generating an enormous scientific interest in the role of the RAS, has contributed to the concept of "tissue" RAS, since some of the effects of these drugs were thought to be reconciled better with "tissue" than with plasma RAS inhibition. However, this model of plasma vs "tissue" RAS still suffers from a number of conceptual problems that have to be dealt with. For instance, with respect to the "tissue" RAS in the vascular wall it is not clear at present whether ACE is at all active inside endothelial cells. In addition, all evidence available speaks against its localisation in the vascular media, while there may be some activity of the enzyme in the adventitial layer. Concerning the heart, there is at present no unequivocal evidence for a local ANG II production through angiotensin converting enzyme (ACE) in cardiac tissue outside the coronary vessels. The localisation of ANG II generation within tissue RAS in the adrenal gland or in the kidney, where ANG II may be generated through CE at the tubular brush border, is far from being elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗