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Biomedical subjects

T Unger

Publications and source records attributed to T Unger.

At least 55 records · Page 3Linked to original sources
PubMed2001

Pharmacological properties of angiotensin II antagonists: examining all the therapeutic implications.

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I), or more recently the Ang II AT(1)-receptor blockers (ARBs), has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT(1)-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT(2)-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for the beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT(1)- and AT(2)-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

Angiotensin II↗
PubMed2001

AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats.

The effects of systemic treatment with the AT1 receptor antagonist telmisartan on central effects of angiotensin II (Ang II), namely, increase in blood pressure, vasopressin release into the circulation, and drinking response, were investigated in conscious, normotensive rats. The central responses to i.c.v. Ang II (30 ng/kg) were measured at 0.5, 2, 4, and 24 h following acute i.v. or acute and chronic oral telmisartan application. At a dose of 10 mg/kg i.v., the drinking response to i.c.v. Ang II was completely blocked over 4 h, while the pressor response and the release of vasopressin in response to i.c.v. Ang II were blocked by 60 to 80%. The inhibition of the centrally mediated pressor and drinking response to Ang II was sustained over 24 h. The lower doses of telmisartan (0.3 and 1 mg/kg) significantly inhibited the Ang II-induced actions over 4 h. A consistent 24-h inhibition of the central responses to i.c.v. Ang II was obtained after acute and chronic oral treatment with 30 mg/kg telmisartan. Oral treatment with 1 and 3 mg/kg telmisartan produced a slight but inconsistent inhibition of the central actions of Ang II. Telmisartan concentrations measured in the cerebrospinal fluid following 8 days of consecutive daily oral treatment (1-30 mg/kg) ranged from 0.87 +/- 0.27 ng/ml (1 mg/kg/day) to 46.5 +/- 11.6 ng/ml (30 mg/kg/day). Our results demonstrate that, following peripheral administration, the AT1 receptor antagonist telmisartan can penetrate the blood-brain barrier in a dose- and time-dependent manner to inhibit centrally mediated effects of Ang II.

Angiotensin II↗
PubMed2000

A block of spinal nitric oxide synthesis leads to increased background activity predominantly in nociceptive dorsal horn neurones in the rat.

Previous studies have shown that nitric oxide (NO) has a strong influence on the background (resting) activity of dorsal horn neurones. The background activity of dorsal horn neurones is generally assumed to be responsible for the presence of paraesthesia or spontaneous pain in patients depending on the functional type of neurones that are active. However, nothing is known about a possible selective action of NO - or a lack of NO - on a particular functional class of neurone. In the present study the background activity of lumbar dorsal horn neurones was examined in anaesthetized rats before and during spinal superfusion with L-NAME, an unspecific blocker of NO synthesis. The neurones were divided into five classes: (1) low-threshold mechanosensitive (LTM) cells with deep receptive fields (LTM deep units); (2) LTM cells with cutaneous receptive fields (LTM cutaneous units) (these two classes were considered to be non-nociceptive); (3) high-threshold mechanosensitive (HTM) deep cells; (4) HTM cutaneous cells; and (5) multireceptive (MR) cutaneous cells (the last three classes were assumed to be nociceptive). HTM neurones increased the frequency of their background activity significantly during L-NAME superfusion and 80% of the initially silent neurones became active after administration of the NOS blocker. MR neurones likewise increased their background activity. In contrast, the background activity of non-nociceptive (LTM) neurones was not significantly affected. The results support previous studies showing that NO has a tonic depressing effect on the background activity of dorsal horn neurones and demonstrate for the first time that this effect is largely restricted to nociceptive neurones. Therefore, a reduction in spinal NO synthesis which often occurs during a long-lasting peripheral lesion is likely to cause increased background activity in nociceptive neurones and thus might contribute to spontaneous pain in patients.

Animals↗
PubMed2000

Angiotensin AT(2) receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells.

To investigate the influence of AT(2) receptor stimulation on the ERK pathway and elucidate potential mechanisms of angiotensin II (ANG II)-mediated neuronal differentiation, we analysed tyrosine phosphorylation and activity of ERK after ANG II treatment of both quiescent and NGF-treated PC12W cells. Tyrosine phosphorylation of ERK1 and ERK2 corresponded with the activity of ERK. While ANG II induced an initial activation of ERK in quiescent cells, the NGF-mediated plateau of ERK-stimulation was lowered by costimulation with ANG II. All effects of ANG II were sensitive to AT(2) - but not AT(1) receptor blockade. Ang II-mediated neurite outgrowth in PC12W cells was inhibited by co-treatment with the MEK inhibitor PD 098059. These findings demonstrate that the AT(2) receptor modulates ERK activity depending on the overall cellular input. The distinct regulation of ERK by ANG II and NGF further indicates basic differences in AT(2) receptor- and NGF-induced neuronal differentiation.

Angiotensin II↗
PubMed2000

The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats.

Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dt(max)) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dt(max) were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dt(max) were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.

Animals↗
PubMed2000

Expression of angiotensin AT(1) and AT(2) receptors in adult rat cardiomyocytes after myocardial infarction. A single-cell reverse transcriptase-polymerase chain reaction study.

The effector hormone of the renin-angiotensin system, angiotensin II, plays a major role in cardiovascular regulation. In rats, both angiotensin receptor subtypes, AT(1) and AT(2), are up-regulated after myocardial infarction but previous studies failed to identify the cell types which express the AT(2) receptor in the heart. To address this question we established a single-cell reverse transcriptase-polymerase chain reaction for AT(1) and AT(2) receptors to determine whether these receptor subtypes are expressed in adult rat cardiomyocytes before and 1 day after myocardial infarction. By laser-assisted cell picking, section profiles of single cells without genomic DNA contamination were isolated. After dividing samples into two identical aliquots, polymerase chain reaction amplification for AT(1) and AT(2) receptors was carried out and polymerase chain reaction products were subjected to gel electrophoresis. Compared to control (n = 4) and sham-operated animals (n = 4), the number of cardiomyocytes expressing the AT(1) receptor mRNA 1 day after myocardial infarction (n = 4) was not changed (42% and 33% versus 45%, respectively). On the other hand, AT(2) receptor mRNA was expressed in 8% and 13%, respectively, of cardiomyocytes gained from control (n = 4) and sham-operated animals (n = 4) and in 14% isolated after myocardial infarction (n = 4). These results demonstrate for the first time that the AT(2) receptor is expressed in adult cardiomyocytes in vivo. They further suggest that the previously observed up-regulation of cardiac AT(1) and AT(2) receptors after myocardial infarction involves cell types other than cardiomyocytes.

Animals↗
PubMed2000

Cardioprotective effects of the Na(+)/H(+)-exchange inhibitor cariporide in infarct-induced heart failure.

OBJECTIVE: We investigated the effect of chronic treatment with the new Na(+)/H(+)-exchange inhibitor, cariporide, on cardiac function and remodelling 6 weeks after myocardial infarction (MI) in rats. METHODS: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats. RESULTS: Compared to sham animals, untreated MI-controls developed pronounced heart failure after 6 weeks. Basal left ventricular end-diastolic pressure (in mmHg) was reduced in the groups in which cariporide was started 1 week pre (16.0+/-1.7) or 30 min (12.5+/-1.1), 3 h (11.8+/-1.0) and 24 h (13.0+/-2.5) after MI compared to untreated MI-controls (22. 4+/-1.5; P<0.01). Basal myocardial contractility (in 1000 mmHg/s) was only increased when treatment was initiated after 30 min (9. 0+/-0.7), 3 h (8.5+/-0.3) and 24 h (8.0+/-0.7) compared to untreated MI-controls (5.8+/-0.7; P<0.05-0.01). Infarct size (in % of left ventricular circumference) was 40.0+/-2.1 in MI-controls and was decreased when treatment was begun after 30 min (32.6+/-2.7) or 3 h (32.4+/-2.3) (P<0.05). In animals, in which cariporide was started 3 h after induction of MI, heart weight/body weight ratio was significantly decreased, indicating reduced cardiac hypertrophy. When treatment started 7 days after MI, cariporide did not exert any beneficial actions on structural and functional cardiac parameters. CONCLUSION: Our results show for the first time that chronic treatment with the Na(+)/H(+)-exchange inhibitor cariporide engendered marked cardioprotective effects when commenced before and up to 24 h after MI. The optimal time for the start of treatment was between 30 min and 3 h post MI.

Analysis of Variance↗
PubMed2000

Tachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain.

Recent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and SR 48965, was without effect. Our results show that (i) the modified formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both tachykinin receptor antagonists were able to attenuate the behavioural response to pain and to reduce the formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist, RP 67580, was more effective in inhibiting the behavioural response to formalin and the pain-induced activation of c-Fos than the antagonist for neurokinin-2 receptors, SR 48968, indicating that neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain tachykinin receptors, especially of the neurokinin-1 receptor, reduces the behavioural response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to pain, the present data indicate that tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.

Analgesics↗
PubMed2000

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy.

The development of angiotensin-converting enzyme inhibitors and selective angiotensin type 1 (AT1)-receptor antagonists has provided new insights into understanding the mechanism of the renin-angiotensin system (RAS) in the pathophysiology of cardiovascular disease. There is good evidence from meta-analyses that shows that inhibition of the RAS achieves organ protection features that go beyond blood pressure control. Candesartan cilexetil, a new angiotensin II receptor antagonist, is characterised by its tight binding to and slow dissociation from the AT1 receptor, and high antagonistic potency, resulting in long-lasting antagonistic effects. It is anticipated that these pharmacological characteristics may bring additional benefits to patients, not only for the management of essential hypertension but also for the management of end-organ damage.

Angiotensin II↗
PubMed2000

Neurohormonal modulation in cardiovascular disease.

The renin-angiotensin system (RAS) is one of the oldest known hormone systems. Its effector hormone, angiotensin (Ang) II, acts through 2 receptor subtypes, AT(1) and AT(2). Most physiologic effects of Ang II, including vasoconstriction, renal salt and water retention, aldosterone and vasopressin release, and sympathetic facilitation, are mediated by AT(1). Recent data, however, suggest that Ang II also contributes to cell proliferation, left ventricular hypertrophy, vascular media hypertrophy, neointima formation in atherosclerosis, and nephrosclerosis by stimulation of AT(1) receptors. AT(2) receptors are associated with antiproliferation, cell differentiation and development, tissue regeneration, and apoptosis. They also antagonize AT(1) receptor-mediated effects, which suggests that the ratio of angiotensin receptors expressed on a particular cell can determine the net effect of Ang II. Selective AT(1) receptor antagonists ("sartans") have been used to treat several million hypertensive patients worldwide. These agents offer a powerful therapeutic alternative to angiotensin-converting enzyme (ACE) inhibitors, which reduce the generation of Ang II. Conversely, AT(1) receptor antagonists block the RAS by acting on cellular angiotensin receptors and do not interfere with the breakdown of kinins. These medications inhibit the RAS more completely than do the ACE inhibitors because their action is independent of Ang II-generating pathways. At the same time, early, preliminary data suggest that AT(1) receptor antagonists offer target-organ protection similar to that provided by the ACE inhibitors. Because AT(2) receptors are left unopposed and Ang II levels are increased with AT(1) receptor antagonist treatment, it is important to understand the function of AT(2) to fully appreciate the mechanisms of action of AT(1) receptor antagonists, especially their potential for target-organ protection.

Angiotensin II↗
PubMed2000

Concentration profiles and reaction fronts in A+B-->C type processes: effect of background ions

The diffusion and reaction of initially separated ions A- and B+ in the presence of counterions Ainsertion mark(+) and Binsertion mark(-) are studied. The dynamics is described in terms of reaction-diffusion equations obeying local electroneutrality, and the time evolution of ion concentrations is determined. We find that, in the absence of reactions, unequal mobility of ions generates nontrivial features in the macroscopically observable concentration profiles. Switching on the reaction A-+B+-->C leads to the formation of a localized, diffusive reaction front, and one finds that the properties of the front (e.g., the effective diffusion constant) are affected by the background ions. The consequences of this effect on the formation of Liesegang patterns are discussed.

Journal Article↗
PubMed2000

Tissue-specific expression of a rat renin transcript lacking the coding sequence for the prefragment and its stimulation by myocardial infarction.

An alternative transcript of the rat renin gene was recently characterized in the adrenal gland, in addition to the known messenger RNA (mRNA) coding for preprorenin. In the alternative transcript, exon 1 is replaced by exon 1A, a domain originating in intron 1. The reading frame of this mRNA, termed exon 1A-renin transcript, codes for a truncated prorenin that presumably remains intracellular, in contrast to preprorenin, which is targeted to the secretory pathway by its prefragment. We here demonstrate the tissue-specific regulation of expression of both transcripts by RT and PCR. In many tissues both transcripts are present, for example in the adrenal gland, spleen, liver, and hypothalamus. In some organs, however, only one of the renin mRNAs is found. In the kidney only the full-length mRNA coding for preprorenin is detected. In the heart exclusively the exon 1A-mRNA is expressed, but not the preprorenin transcript. After myocardial infarction, which is known to activate the intracardiac renin-angiotensin system, expression of exon 1A-renin mRNA in the left ventricle was stimulated about 4-fold, compared with that in sham-operated animals, whereas no mRNA corresponding to preprorenin was detectable. These findings may have implications for the current concepts of local extrarenal renin-angiotensin systems, as they provide the molecular basis for a possible intracellular function of renin and exclude a role for locally produced secretory renin in the heart.

Alternative Splicing↗
PubMed2000

Identification of regulated genes in rat heart after myocardial infarction by means of differential mRNA display.

In order to testify the hypothesis that unknown mechanisms are involved in the process of cardiac remodeling after myocardial infarction (MI), we employed differential display reverse transcription-polymerase chain reaction (DDRT-PCR) as our primary inspection tool. An animal model of MI was established by ligation of the left anterior descending coronary artery (LAD) in rat. Fifty upregulated candidate cDNA fragments were obtained in the right ventricle (RV) of the heart six weeks after MI. Eight cDNA fragments isolated from DD denaturing gel were extracted and reamplified, cloned into pCR II vector and sequenced. A Genbank search of these clones showed that three of them have a high homology with known genes not previously associated with cardiac remodeling, i.e., mouse interleukin-4 receptor gene, rat ferritin mRNA, and T-cell receptor beta chain V beta 5. The remaining clones have no similarity to known sequences. These data suggest that certain genes which were not previously being associated with cardiac hypertrophy are turned on during the process of cardiac remodeling after MI.

Animals↗
PubMed2000

Effects of losartan on haemodynamic parameters and angiotensin receptor mRNA levels in rat heart after myocardial infarction.

We investigated the haemodynamic parameters and the regulation of cardiac mRNA levels of the angiotensin receptor subtypes, AT1 and AT2, by the AT,-receptor antagonist losartan in rat heart during the acute phase of myocardial infarction. AT1- andAT2-receptor mRNA levels markedly increased at 30 minutes and peaked at 24 hours post myocardial infarction (12.6-fold increase for AT1- and 17.2-fold increase for AT2 compared with controls). Losartan significantly reduced mean blood pressure in sham-operated rats and decreased mean blood pressure and left ventricular end-diastolic pressure in myocardial infarction rats. However, the AT,- andAT2-receptor mRNA levels of losartan-treated rats showed a pattern similar to that of water-treated rats. The time-dependent increase of AT1- and AT2-receptor mRNA levels is associated with the early remodelling process of non-infarcted myocardium post MI and is independent of AT1-receptor blockade.

Angiotensin Receptor Antagonists↗
PubMed2000

Angiotensin receptor blocker selectivity at the AT1- and AT2-receptors: conceptual and clinical effects.

The advent of specific angiotensin II (Ang II) receptor blockers (ARBs) some ten years ago has provided substantial information on the specific actions of the AT1- and AT2-receptors. Most of the early research concentrated on the AT1-receptor, and the actions and biological roles of the AT2-receptor are much less well characterised. The AT2-receptor is involved in the inhibition of cell proliferation, and in cell differentiation and development, regeneration and apoptosis. By raising local Ang II concentrations at the AT2-receptor, selective blocking of the AT1-receptor may therefore have beneficial effects. This concept may be important for antihypertensive therapy and in cardiovascular disease in general.

Angiotensin II Type 1 Receptor Blockers↗