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Thomas Unger

Publications and source records attributed to Thomas Unger.

At least 37 records · Page 2Linked to original sources
PubMed2005

Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury.

Several lines of clinical and experimental evidence suggest an important role of the renin-angiotensin system in ischemic brain injury although the cellular regulation of the angiotensin AT1 and AT2 receptors and their potential relevance in this condition have not yet been clearly defined. We first assessed the regulation of brain AT1 and AT2 receptors in response to transient unilateral medial cerebral artery occlusion in rats by real-time RT-PCR, Western blot, and immunofluorescence labeling. AT2 receptors in the peri-infarct zone were significantly upregulated 2 days after transient focal cerebral ischemia. Increased AT2 receptors, which were abundantly distributed in a large number of brain regions adjacent to the infarct area including cerebral frontal cortex, piriform cortex, striatum, and hippocampus, were exclusively expressed in neurons. By contrast, AT1 receptors, which remained unaltered, were mainly expressed in astrocytes. In neurons of ischemic striatum, increased AT2 receptors were associated with intense neurite outgrowth. Blockade of central AT2 receptors with PD123177 abolished the neuroprotective effects of central AT1 receptor blockade with irbesartan on infarct size and neurological outcome. In primary cortical neurons, stimulation of AT2 receptors supported neuronal survival and neurite outgrowth. Our data indicate that cerebral AT2 receptors exert neuroprotective actions in response to ischemia-induced neuronal injury, possibly by supporting neuronal survival and neurite outgrowth in peri-ischemic brain areas.

Angiotensin II↗
PubMed2005

Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat.

In inflamed tissue--including skeletal muscle--the concentrations of cytokines and neurotrophins are known to increase. However, nothing is known about a possible contribution of these agents to muscle pain and hyperalgesia. The present study investigated acute effects of cytokines and neurotrophins on response properties of slowly conducting muscle afferents. In anaesthetised rats, the impulse activity of single mechanosensitive group IV fibres innervating the gastrocnemius-soleus muscle was recorded and tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF) were injected into the muscle. Changes in the mechanosensibility of the endings following administration of the agents were tested with repeated pressure stimuli of defined forces. A low mechanical threshold in the innocuous range was found in 44.4% of the units tested, 55.6% required strong, potentially tissue-damaging pressure stimuli for activation. NGF excited only units that had a high mechanical threshold, while IL-6 was a stimulant for low-threshold mechanosensitive units only. TNF-alpha and BDNF did not excite group IV units but had a desensitising action: after TNF-alpha or BDNF, the response magnitudes to pressure stimuli decreased significantly. The data indicate that cytokines and neurotrophins influence the impulse activity and mechanosensitivity of group IV muscle afferent units. These effects could be of functional significance when the agents are released from muscle cells under pathophysiological circumstances.

Action Potentials↗
PubMed2005

The possible role of the NO-cGMP pathway in nociception: different spinal and supraspinal action of enzyme blockers on rat dorsal horn neurones.

In the literature, the pro- or antinociceptive effects of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are discussed controversially. Our laboratory and others have reported that in the spinal cord a local lack of NO has an excitatory action on the ongoing (background) activity of dorsal horn neurones. Here, we tested the hypothesis that this effect of NO is mediated by cGMP and that part of the controversy is due to differences in the spinal and supraspinal actions of both compounds. In anaesthetised rats, impulse activity of lumbar dorsal horn neurones was recorded, and blockers of NO- and cGMP-synthesis, as well as the phosphodiesterase 5 (PDE5) inhibitor sildenafil (which increases the cGMP level), or 8-Bromo-cGMP (a membrane permeable cGMP analogue) were administered spinally or supraspinally. Topical superfusion of the spinal cord with a blocker of the guanylyl cyclase (ODQ) to reduce the cGMP level led to an increase in background activity of nociceptive lumbar dorsal horn neurones similar to that caused by l-NAME, a blocker of the NO synthase. Spinal superfusion with sildenafil or 8-Bromo-cGMP had no excitatory effect. In contrast, injections of sildenafil or 8-Bromo-cGMP into the third cerebral ventricle caused an increased background activity in lumbar dorsal horn neurones, while l-NAME and ODQ were ineffective. The results show that at the spinal level, a lack of cGMP and NO has an excitatory action on dorsal horn neurones, whereas supraspinally an elevated level of cGMP is excitatory.

Action Potentials↗
PubMed2005

Angiotensin receptor blockers: therapeutic targets and cardiovascular protection.

In the prevention and treatment of cardiovascular disease, pharmacological treatment strategies should have several aims: (i) in individuals without overt cardiovascular disease, but with risk factors such as hypertension and/or diabetes, pharmacotherapy should prevent or delay disease development; (ii) in patients who have already progressed to cardiovascular disease, pharmacotherapy should help either to prevent or regress target organ damage (TOD); and (iii) in patients with TOD, pharmacotherapy should prevent events. Any medication intended for long-term therapy also should be well tolerated. Inhibiting the renin-angiotensin system has proven a successful therapeutic strategy in cardiovascular and renal medicine. Angiotensin-converting enzyme (ACE) inhibitors have demonstrated important advantages over conventional agents such as beta-blockers and thiazide diuretics, and have become a relevant part of treatment for heart failure post-myocardial infarction, left ventricular dysfunction and renal disease. Tolerability concerns may prevent their use in some patients, however. Angiotensin AT1 receptor blockers (ARBs) provide a different form of blockade of the renin-angiotensin system and a growing body of evidence suggests that this alternative approach may confer additional cardiovascular protection for some patient subgroups. In addition, ARBs generally are better tolerated than ACE inhibitors, enhancing patient compliance and persistence with long-term therapy. Furthermore, evidence in favour of combining an ACE inhibitor and an ARB in certain circumstances is continuously growing.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Low-dose lithium combined with captopril prevents stroke and improves survival in salt-loaded, stroke-prone spontaneously hypertensive rats.

OBJECTIVE: A number of potential interactions between angiotensin-converting enzyme inhibitors and lithium have been described in the literature. In the present study, we investigated the effects of a low-dose combination treatment with lithium and captopril on survival and stroke prevention in salt-loaded, stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: Eight-week-old saline-drinking SHRSP (n = 21 per group) were treated with vehicle, LiCl (1 mmol/kg per day), captopril (25 mg/kg per day) and captopril plus LiCl for up to 37 weeks. Body weight, salt water intake blood pressure and mortality were recorded throughout the experimental period. Plasma renin activity, plasma lithium concentration and urinary excretion of albumin, sodium and potassium were measured at different time points. RESULTS: Captopril treatment doubled the life expectancy when compared with vehicle-treated rats. Lithium alone had minor effects on survival but led to a dramatic increase in survival when added to captopril (mean survival time > 237 versus 147 days, P < 0.001). Systolic blood pressure increased with age in all treatment groups but was comparable in the captopril-treated and the captopril-plus-lithium-treated groups. Plasma renin activity as well as urinary sodium and potassium excretion did not differ between both groups. In the captopril group a striking fivefold increase of albuminuria occurred between 14 and 26 weeks of age, while this progression was completely abolished by the addition of lithium. CONCLUSIONS: Our results demonstrate that the addition of lithium to captopril dramatically prolong the effects of the angiotensin-converting enzyme inhibitor on survival in salt-loaded SHRSP. This effect was independent of a reduction in blood pressure.

Albuminuria↗
PubMed2005

Neuroprotection with angiotensin receptor antagonists: a review of the evidence and potential mechanisms.

The peptide hormone angiotensin (A)-II, the major effector peptide of the renin-angiotensin system (RAS), is well established to play a pivotal role in the systemic regulation of blood pressure, fluid, and electrolyte homeostasis. Recent biochemical and neurophysiologic studies have documented local intrinsic angiotensin-generating systems in organs and tissues such as the brain, retina, bone marrow, liver, and pancreas. The locally generated angiotensin peptides have multiple and novel actions including stimulating cell growth and anti-proliferative and/or antiapoptotic actions. In the mammalian brain, all components of the RAS are present including angiotensin receptor subtypes 1 (AT(1)) and 2 (AT(2)). A-II exerts most of its well defined physiologic and pathophysiologic actions, including those on the central and peripheral nervous system, through its AT(1) receptor subtype. While the AT(1) receptor is responsible for the classical effects of A-II, it has been found that the AT(2) receptor is linked to totally different signalling mechanisms and this has revealed hitherto unknown functions of A-II. AT(2) receptors are expressed at low density in many healthy adult tissues, but are upregulated in a variety of human diseases. This receptor not only contributes to stroke-related pathologic mechanisms (e.g. hypertension, atherothrombosis, and cardiac hypertrophy) but may also be involved in post-ischemic damage to the brain. It has been reported that the AT(2) receptor regulates several functions of nerve cells, e.g. ionic fluxes, cell differentiation, and neuronal tissue regeneration, and also modulates programmed cell death. In this article, we review the experimental evidence supporting the notion that blockade of brain AT(1) receptors can be beneficial with respect to stroke incidence and outcome. We further delineate how AT(2) receptors could be involved in neuronal regeneration following brain injury such as stroke or CNS trauma. The current review is focussed on some of the new functions arising from the locally formed A-II with particular attention to its emerging neuroprotective role in the brain.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity.

Selective peroxisome proliferator-activated receptor (PPAR) gamma modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPARgamma-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARgamma protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identifies two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPARgamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade. This may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases and may initiate the development of new classes of drugs combining potent antihypertensive and antidiabetic actions.

3T3 Cells↗
PubMed2004

Regulation of transport of the angiotensin AT2 receptor by a novel membrane-associated Golgi protein.

OBJECTIVE: Synthesis and maturation of G protein-coupled receptors are complex events that require an intricate combination of processes including protein folding, posttranslational modifications, and transport through distinct cellular compartments. Little is known concerning the regulation of G protein-coupled receptor transport from the endoplasmic reticulum to the cell surface. METHODS AND RESULTS: Here we show that the cytoplasmatic carboxy-terminal of the angiotensin AT2 receptor (AT2R) acts independently as an endoplasmic reticulum-export signal. Using a yeast two-hybrid system, we identified a Golgi membrane-associated protein termed ATBP50 (for AT2R binding protein of 50 kDa) that binds to this motif. We also cloned ATBP60 and ATBP135 encoded by the same gene as ATBP50 that mapped to chromosomes 8p21.3. Downregulation of ATBP50 using siRNA leads to retention of AT2R in inner compartments, reduced cell surface expression, and decreased antiproliferative effects of the receptor. CONCLUSIONS: Our results indicate that ATBP50 regulates the transport of the AT2R to cell membrane by binding to a specific motif within its cytoplasmic carboxy-terminal and thereby enabling the antiproliferative effects of the receptor.

Amino Acid Sequence↗
PubMed2004

Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis.

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.

Abdomen↗
PubMed2004

Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats.

Increased cardiac angiotensin converting enzyme-1 (ACE1) is found in individuals who carry a deletion in intron 16 of ACE1 gene or in individuals who suffer from cardiac disorders, such as hypertrophy. However, whether a single increase in ACE1 expression leads to spontaneous cardiac defects remains unknown. To determine if the increased cardiac ACE1 actively plays a role or is merely the consequence of pathological changes in the process of cardiac hypertrophy, we generated a transgenic rat model with selective over-expression of human ACE1 in the cardiac ventricles. The left ventricular ACE1 activity is elevated about 50-fold in transgenic rats. Angiotensin-1 perfusion of isolated hearts demonstrated a significant decrease in coronary artery flow compared with non-transgenic littermates, suggesting that the transgenic ACE1 is functional. Neither cardiac hypertrophy nor other morphological abnormalities were observed in transgenic rats under standard living conditions. It was found, however, after induction of hypertension by suprarenal aortic banding, that the degree of cardiac hypertrophy in transgenic rats was significantly higher than that of banded control rats. The expressions of both ANF and collagen III, molecular markers of cardiac hypertrophy, were also increased in banded transgenic rats compared with banded control. Our results suggest that increased cardiac ACE1 does not trigger but augments cardiac hypertrophy.

Angiotensin I↗
PubMed2004

Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity.

BACKGROUND: Angiotensin type 1 receptor (AT(1)R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARgamma function by ARBs. METHODS AND RESULTS: The ARBs irbesartan and telmisartan (10 micromol/L) potently enhanced PPARgamma-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3+/-0.1-fold induction; telmisartan: 3.1+/-0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 micromol/L: 3.6+/-0.3-fold induction; P<0.01), whereas eprosartan up to 100 micromol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 micromol/L) markedly induced transcriptional activity of PPARgamma by 3.4+/-0.9-fold and 2.6+/-0.6-fold (P<0.05), respectively, compared with 5.2+/-1.1-fold stimulation by the PPARgamma ligand pioglitazone (10 micromol/L). Irbesartan and telmisartan also induced PPARgamma activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARgamma activity independent of their AT(1)R blocking actions. CONCLUSIONS: The present study demonstrates that a specific subset of ARBs induces PPARgamma activity, thereby promoting PPARgamma-dependent differentiation in adipocytes. The activation of PPARgamma demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.

3T3 Cells↗
PubMed2004

Are angiotensin receptor blockers neuroprotective?

Stroke is one of the leading causes of invalidism and death in the industrialized world. Among others, the renin- angiotensin system (RAS) has been implicated in the pathogenesis and outcome of ischemic events, including stroke. Angiotensin II (Ang II), the major effector peptide of the RAS, exerts most of its well-defined physiologic and pathophysiologic actions, including those on the central and peripheral nervous system, through its Ang II type 1 (AT1) receptor subtype. This receptor not only contributes to stroke-related pathologic mechanisms (eg, hypertension, atherothrombosis, and cardiac hypertrophy) but also may be involved in postischemic damage to the brain. However, it has also been demonstrated that Ang II, via its AT2 receptor subtype, accelerates neuronal tissue regeneration after injury. In this article, we review the experimental evidence supporting the notion that blockade of brain AT1 receptors can be beneficial with respect to stroke incidence and outcome. We further delineate how AT2 receptors could be involved in neuronal regeneration following brain injury, such as stroke. In doing so, we also attempt to shed some light on the mechanisms by which AT1 receptor blockers, which leave the AT2 receptor unopposed, might exert protective actions in brain ischemia.

Angiotensin Receptor Antagonists↗
PubMed2004

Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled.

BACKGROUND: Although the relationship between body weight and blood pressure (BP) is well established, there is a lack of data regarding the impact of obesity on the prevalence of hypertension in primary care practice. The objective of this study was to assess the prevalence of hypertension and the diagnosis, treatment status, and control rates of hypertension in obese patients as compared to patients with normal weight. METHODS: A cross-sectional point prevalence study of 45,125 unselected consecutive primary care attendees was conducted in a representative nationwide sample of 1912 primary care physicians in Germany (HYDRA). RESULTS: Blood pressure levels were consistently higher in obese patients. Overall prevalence of hypertension (blood pressure >/=140/90 mm Hg or on antihypertensive medication) in normal weight patients was 34.3%, in overweight participants 60.6%, in grade 1 obesity 72.9%, in grade 2 obesity 77.1%, and in grade 3 obesity 74.1%. The odds ratio (OR) for good BP control (<140/90 mm Hg) in diagnosed and treated patients was 0.8 (95% confidence interval [CI] 0.7-0.9) in overweight patients, 0.6 (95% CI 0.6-0.7) in grade 1, 0.5 (95% CI 0.4-0.6) in grade 2, and 0.7 (95% CI 0.5-0.9) in grade 3 obese patients. CONCLUSIONS: The increasing prevalence of hypertension in obese patients and the low control rates in overweight and obese patients document the challenge that hypertension control in obese patients imposes on the primary care physician. These results highlight the need for specific evidence-based guidelines for the pharmacologic management of obesity-related hypertension in primary practice.

Adolescent↗
PubMed2004

Acidic pH and capsaicin activate mechanosensitive group IV muscle receptors in the rat.

Strenuous exercise of muscle as well as inflammation and ischaemia are associated with tissue acidosis. However, so far, nothing is known about the sensitivity to hydrogen ions of slowly conducting muscle afferent units. The study investigated if acid-sensing ion channels, e.g. the polymodal acid/capsaicin-sensitive vanilloid receptors, were present on unmyelinated (group IV) muscle afferent units of the gastrocnemius-soleus muscle of the rat. Intramuscular injections of acidic phosphate buffer pH 6 excited 56.0% of the group IV units. A similar proportion (54.29%) was activated by capsaicin (655 microM). Tests of the same unit with both adenosine triphosphate at neutral pH (ATP, 7.6 mM; pH 7.4) and acidic phosphate demonstrated that most acid-sensitive units were also excited by ATP at neutral pH. The data show that (1) a high proportion of group IV muscle receptors are responsive to an increased extracellular hydrogen ion concentration, and (2) a subpopulation of these units are sensitive to both acidic pH and ATP.

Action Potentials↗