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T Unger

Publications and source records attributed to T Unger.

At least 109 records · Page 6Linked to original sources
PubMed1998

Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27.

BACKGROUND: Activation of the renin-angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin- -) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. OBJECTIVE: Tissue renin-angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. METHOD: Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 microg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. RESULTS: Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. CONCLUSIONS: Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' agent in malignant hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

The Mdm2 oncoprotein interacts with the cell fate regulator Numb.

The Mdm2 oncoprotein is a well-known inhibitor of the p53 tumor suppressor, but it may also possess p53-independent activities. In search of such p53-independent activities, the yeast two-hybrid screen was employed to identify Mdm2-binding proteins. We report that in vitro and in transfected cells, Mdm2 can associate with Numb, a protein involved in the determination of cell fate. This association causes translocation of overexpressed Numb into the nucleus and leads to a reduction in overall cellular Numb levels. Through its interaction with Numb, Mdm2 may influence processes such as differentiation and survival. This could potentially contribute to the altered properties of tumor cells which overexpress Mdm2.

Amino Acid Sequence↗
PubMed1998

Central angiotensin AT1 and muscarinic receptors in ITF expression on intracerebroventricular NaCl.

In the present study, we investigated the expression pattern of the inducible transcription factors (ITF) c-Fos, c-Jun, JunB, JunD, and Krox-24 following intracerebroventricular injections of hyperosmolar saline (0.2, 0.3, and 0.6 M NaCl) and its mediation via angiotensin and/or muscarinic receptors. c-Fos, c-Jun, and Krox-24 were differentially expressed in organum vasculosum laminae terminalis, median preoptic area, subfornical organ (SFO), and paraventricular and supraoptic nuclei. Expression of c-Fos and c-Jun was inhibited by pretreatment with the angiotensin AT1 receptor antagonist losartan (10 and 20 nmol icv) following 0.20 and 0.30 M saline. Pretreatment with atropine (15 nmol icv) inhibited the 0.30 and 0.60 M NaCl-induced expression of c-Fos, c-Jun, and Krox-24 in all areas except the SFO. Coexpression of the ITF with vasopressin and oxytocin, the major effector peptides in osmoregulation, was demonstrated, implying the corresponding genes as putative target genes of the ITF. The results show a highly differentiated ITF expression pattern in the brain mediated by angiotensinergic and muscarinergic pathways, suggesting a finely tuned regulation of target genes.

Animals↗
PubMed1998

AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism.

In the present study we tested the hypothesis whether an angiotensin AT2 receptor-mediated stimulation of the bradykinin (BK)/nitric oxide (NO) system can account for the effects of AT1 receptor antagonism on aortic cGMP described previously in SHRSP. Adult SHRSP were treated for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or vehicle (0.9% NaCl I.V.). Animals were pretreated with vehicle, losartan (100 mg/kg P.O.), PD 123319 (30 mg/kg I.V.), losartan plus PD 123319, icatibant (500 microg/kg I.V.), N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg I.V.), or minoxidil (3 mg/kg I.V.). Mean arterial blood pressure (MAP) was continuously monitored over the 4-hour experimental period, and plasma ANG II and aortic cGMP were measured by RIA at the end of the study. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II as well as minoxidil plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated animals, respectively. Plasma levels of ANG II were increased 2-fold by ANG II infusion alone or by ANG II in combination with icatibant, L-NAME, or minoxidil. The increase in plasma ANG II levels was even more pronounced after losartan treatment. Aortic cGMP content was significantly increased by ANG II, losartan, losartan plus ANG II, and minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05). The effects of ANG II and of losartan plus ANG II on aortic cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319. Icatibant and L-NAME abolished the effects of ANG II on aortic cGMP. Our results demonstrate the following: (1) ANG II increases aortic cGMP by an AT2 receptor-mediated action because the effect could be prevented by an AT2 receptor antagonist; (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with minoxidil; (3) losartan increased aortic cGMP most likely by increasing plasma ANG II levels with a subsequent stimulation of AT2 receptors; and (4) the effects of AT2 receptor stimulation are mediated by BK and, subsequently, NO because they were abolished by B2 receptor blockade as well as by NO synthase inhibition.

Angiotensin II↗
PubMed1998

Oxytocin pathways mediate the cardiovascular and behavioral responses to substance P in the rat brain.

Stimulation of brain periventricular and hypothalamic substance P receptors induces a pressor response and tachycardia associated with mesenteric and renal vasoconstriction and hindlimb vasodilation resembling thus the classical defense reaction. This cardiovascular response is brought about by the activation of the sympathoadrenal system and is accompanied by grooming behavior. To address the role of oxytocinergic pathways in the brain in the mediation of these responses, we investigated the effects of central pretreatment of rats with oxytocin antisense, mixed base, and sense oligodeoxynucleotides on mean arterial pressure, heart rate, and grooming behavior induced by intracerebroventricular injections of substance P (50 pmol). Central pretreatment of conscious rats with the oxytocin antisense oligodeoxynucleotide (intracerebroventricular injections, 8 and 4 hours before administration of substance P) attenuated the mean arterial pressure (by 55%) and heart rate responses (by 58%) as well as grooming behavior induced by the peptide. A complete recovery of all substance P-induced responses was observed 28 hours after antisense oligodeoxynucleotide pretreatment. Intracerebroventricular pretreatment of rats with mixed base and sense oligodeoxynucleotides did not affect the cardiovascular and behavioral responses to substance P. The signal for oxytocin mRNA in the paraventricular nucleus was reduced only in rats pretreated with the antisense oligodeoxynucleotide. These results demonstrate that oxytocin neurons in the paraventricular nucleus, which innervate the cardiovascular centers in the hindbrain and the spinal cord, mediate the increases in blood pressure and heart rate induced by stimulation of substance P receptors in the forebrain. These neurons may also transmit signals, which are generated by substance P in the hypothalamus and are responsible for the sympathoadrenal activation in response to stress.

Animals↗
PubMed1998

Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin.

The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after STZ injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.

Animals↗
PubMed1998

Differential contribution of angiotensinergic and cholinergic receptors in the hypothalamic paraventricular nucleus to osmotically induced AVP release.

We studied the involvement of periventricular and hypothalamic angiotensinergic and cholinergic pathways in osmotically induced arginine vasopressin (AVP) release into the blood. In conscious Wistar rats, i.c.v. injections of 0.2, 0.3 and 0.6 M hyperosmolar saline (5 microl) resulted in concentration-dependent increases in AVP release (5.2 +/- 1.5, 10.6 +/- 2.2 and 18.0 +/- 2.2 pg/ml, respectively, vs. 2.0 +/- 0.1 in controls). The two lower saline concentrations did not affect arterial blood pressure (non-pressure-associated AVP release), whereas 0.6 M saline induced increase in blood pressure (pressure-associated AVP release). In the first set of experiments, periventricular angiotensin AT1, muscarinic or nicotinic receptors were blocked by i.c.v. administration of losartan (10 nmol), atropine (100 nmol) or hexamethonium (100 nmol), respectively, before i.c.v. hyperosmolar saline injections. Losartan significantly reduced the 0.2 M and 0.3 M, but not the 0.6 M, saline-induced increase in AVP release. The 0. 3 M saline-induced AVP release was blocked by atropine and hexamethonium, whereas the 0.6 M saline-induced AVP release was blocked by atropine only. In the second set of experiments, losartan (4 nmol), atropine (200 nmol) or hexamethonium (200 nmol) was injected bilaterally into the paraventricular nucleus before i.c.v. hyperosmolar saline injections. Losartan reduced 0.3 M and potentiated 0.6 M saline-induced AVP release. On the other hand, atropine and hexamethonium significantly reduced both 0.3 and 0.6 M saline-induced AVP release. We conclude that afferents arising from periventricular osmosensitive neurons to the hypothalamic paraventricular nucleus, which are involved in non-pressure-associated osmotically induced AVP release, are both angiotensinergic and cholinergic, whereas those mediating pressure-associated AVP release are cholinergic in nature.

Angiotensin Receptor Antagonists↗
PubMed1998

Sensitivity of hypothalamic paraventricular nucleus to C- and N-terminal angiotensin fragments: vasopressin release and drinking.

We studied the effect of angiotensin (ANG) peptides and their C- and N-terminal fragments, microinjected bilaterally into the hypothalamic paraventricular nucleus (PVN) of male Wistar rats, on arginine vasopressin (AVP) release into the blood and drinking. ANG II (1-8) and the C-terminal ANG III (2-8) at 0.1-100 pmol/200 nl induced a dose-dependent increase in AVP release with a maximum of 26.45+/-6.0 and 31.86+/-7.0 pg/ml, respectively, vs 1.6+/-2.0 pg/ml in vehicle treated controls (P<0.001). The highest dose of ANG II and ANG III also induced drinking responses of 4.3+/-0.78 and 2.91+/-0.54 ml water/15 min, respectively. Bilateral pretreatment of the PVN with the AT1 receptor antagonist losartan (4 nmol/200 nl) inhibited ANG II- and ANG III-induced AVP release and drinking. Different doses of the C-terminal ANG IV (3-8), ANG (4-8) or ANG (5-8) peptides did not induce AVP release or drinking. The N-terminal ANG (1-7) peptide induced a dose-dependent increase in AVP release (maximum 8.5+/-3.5 pg/ml after 100 pmol) but the effect was much less potent than that induced by the same dose of ANG II or ANG III. ANG (1-7) failed to induce a drinking response. Pretreatment of the PVN with losartan or the AT2 receptor antagonist, PD 123177 (4 nmol/200 nl), inhibited the 100 pmol ANG (1-7)-induced AVP release. The N-terminal ANG (1-4) peptide did not affect AVP release or drinking at any dose tested. Our data demonstrate that the C-terminal ANG II (1-8) and ANG III (2-8), but not shorter fragments, can induce AVP release and drinking response via AT1 receptors in the PVN. The N-terminal ANG (1-7) was less potent in stimulating AVP release than ANG II or ANG III and had no influence on drinking. Thus, the presence of both arginine2 and phenylalanine8 in the angiotensin peptide sequence appears to be important to elicit AVP release and drinking from the PVN in vivo.

Angiotensin II↗
PubMed1998

Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence.

BACKGROUND: The renin-angiotensin system is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is the production of the active peptide angiotensin II. Because angiotensin II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the renin-angiotensin system. Angiotensin II also may be involved in end-organ damage in hypertension, heart failure, and vascular disease. ANGIOTENSIN II RECEPTORS: At least two subtypes of angiotensin II receptors have been identified, angiotensin type 1 (AT)1 and type 2 (AT2). The AT1 receptor mediates all the known actions of angiotensin II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known about the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses the AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects. ANGIOTENSIN RECEPTOR ANTAGONISTS: This newly introduced class of drugs is able to inhibit the renin-angiotensin system at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of angiotensin II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1 receptor antagonists may provide end-organ protection by blocking angiotensin II effects via the AT1 receptor, leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction and other conditions resulting from structural alterations in the heart, kidney, and vasculature.

Angiotensin Receptor Antagonists↗
PubMed1997

Effects of angiotensin-converting enzyme inhibition and angiotensin II AT1 receptor antagonism on cardiac parameters in left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is considered to be an independent risk factor giving rise to ischemia, arrhythmia, and left ventricular dysfunction. In this article, we summarize recent studies performed in our laboratory to investigate (1) the contribution of the renin-angiotensin system to the cardiac remodeling process, which is triggered by myocardial infarction (MI) or hypertension-induced cardiac hypertrophy; (2) the effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism on cardiac parameters, such as myocardial infarct size, cardiac hypertrophy, heart function, and myocardial metabolism; (3) the mechanism of an ACE inhibitor-induced increase in cardiac capillary density in spontaneously hypertensive rats (SHR) and stroke prone SHR (SHR-SP). We observed that AT1 receptor gene expression in rat vascular smooth muscle cells (but not in rat coronary endothelial cells) was markedly enhanced after an ischemic insult in vitro. In a rat model in which MI was induced by coronary artery ligation, the AT1 receptor mRNA levels were transiently increased after MI and reached a peak level 24 hours post-MI. The AT2 receptor gene expression increased in a pattern similar to that of the AT1 receptor. ACE expression at the protein level in the repairing scar, which was demonstrated by monoclonal antibody staining, started to increase 2 weeks after MI and reached a peak level 3 weeks post-MI. Furthermore, long-term treatment with an ACE inhibitor limited infarct size, prevented cardiac hypertrophy, and improved heart function in the rat MI model. In SHR-SP, long-term treatment with either an ACE inhibitor or an AT1 receptor antagonist improved cardiac function and metabolism. Cardiac metabolism was even improved after low-dose ACE inhibitor treatment, which did not prevent hypertension and cardiac hypertrophy. In both SHR and SHR-SP, we found that the ACE inhibitor ramipril significantly increased capillary length density independently of its antihypertensive and antihypertrophic actions. Most of the cardiac effects of the ACE inhibitor could be abolished by a bradykinin B2 receptor antagonist. Thus, these cardiac effects of ACE inhibitors can be ascribed, at least under our experimental conditions, to ACE inhibitor-induced bradykinin potentiation.

Angiotensin Receptor Antagonists↗
PubMed1997

The angiotensin AT2 receptor down-regulates neurofilament M in PC12W cells.

The angiotensin (ANG II) AT2 receptor mediates antiproliferative effects and induces neurite outgrowth in PC12W cells. To further investigate the molecular events following AT2 receptor stimulation in these cells, we determined the expression pattern of the middle-sized neurofilament subunit (NF-M) using Western and Northern blot analysis and reverse-transcription polymerase chain reaction. On both, the protein and the mRNA level, ANG II via AT2 receptors not only counteracted nerve growth factor (NGF)-mediated NF-M up-regulation but also reduced NF-M levels in the absence of NGF by maximally 72%. The ANG II-induced effects were completely abolished by pretreatment with the AT2 receptor antagonist, PD123177. In view of previous findings of decreased NF levels in regenerating neurons and in neuronal cultures undergoing apoptosis, our observation suggests a new role of AT2 receptors in either of these processes.

Angiotensin Receptor Antagonists↗