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M Böhm

Publications and source records attributed to M Böhm.

At least 235 records · Page 13Linked to original sources
PubMed1997

Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats.

The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to produce a positive inotropic effect in some species, and differences in atrial and ventricular myocardium have been described. So far, the molecular events which govern angiotensin II-mediated changes in cardiac contractility are not completely understood. In order to study the dependency of the angiotensin II-induced positive inotropic effect on receptor density, we examined the effect of angiotensin II on cardiac function in atria, papillary muscles and isolated ventricular cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1997

Deletion analysis at the DEL-27, APC and MTS1 loci in bladder cancer: LOH at the DEL-27 locus on 5p13-12 is a prognostic marker of tumor progression.

Inactivation of relevant tumor-suppressor genes by allelic or homozygous deletion is a characteristic event in tumor cells. Here, the prognostic value of allelic deletions on 5p13-12 at the putative del-27 tumor-suppressor locus and in the APC tumor-suppressor gene on 5q21, as well as homozygous deletions of the MTS1 (p16INK4, CDKN 2) tumor-suppressor gene on 9p21 was assessed in 87 bladder cancers using microdissection and PCR-based assays. Tumor-specific LOH was detected in 10 of 38 (26%, del-27), and 15 of 30 (50%, APC) informative specimens. Homozygous deletion of the MTS1 gene was detected in 33% of 84 tumors investigated. These deletion frequencies implicate the 3 tumor-suppressor regions in the genesis of transitional-cell carcinoma. In contrast to deletions of the APC or MTS1 genes, LOH at the del-27 locus correlated with tumor progression. This suggests that loss of the putative tumor-suppressor gene DEL-27 is involved in an aggressive behavior of the tumor cells and appears to be a prognostic marker for the clinical outcome of patients with transitional-cell carcinoma.

Carcinoma, Transitional Cell↗
PubMed1997

[Carvedilol].

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Adrenergic beta-Antagonists↗
PubMed1997

Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.

BACKGROUND: Because LDL and the angiotensin II type 1 (AT1) receptor are thought to be involved in the pathogenesis of chronic vascular disease, we studied possible interactions between these two biological systems in cultured rat vascular smooth muscle cells. METHODS AND RESULTS: Incubation of vascular smooth muscle cells with 100 micrograms/mL LDL profoundly increased AT1 receptor mRNA to approximately 250% of control levels as assessed by Northern hybridization analysis. This effect is maximal 12 hours after addition of LDL to the culture medium and is sustained for up to 24 hours. The LDL-induced upregulation is dose dependent, with a maximal effect obtained with 100 micrograms/mL LDL. There is a correlative increase of cell surface-associated AT1 receptors as assessed by saturation radioligand binding assays. The half-life of AT1 receptor mRNA is increased substantially by LDL compared with that of cells treated only with 5,6-dichlorobenzimidazole to block transcription. Angiotensin II-induced elevation of cytosolic calcium concentration is significantly increased in vascular smooth muscle cells pretreated with LDL to 368 +/- 41 nmol/L compared with control cells pretreated with vehicle (248 +/- 33 nmol/L). Moreover, angiotensin II-induced DNA synthesis is markedly enhanced when cells are coincubated with 100 micrograms/mL LDL. CONCLUSIONS: These data reveal a significant upregulation of AT1 receptor gene expression by LDL in vascular smooth muscle cells through mechanisms that involve posttranscriptional mRNA stabilization. Ultimately, this AT1 receptor upregulation leads to an elevated functional response of vascular smooth muscle cells on angiotensin II stimulation.

Animals↗
PubMed1997

Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart.

We investigated the effects of the expression of myosin light chain (MLC) isoforms on the Ca2+ sensitivity of isometric force production of demembranated (skinned) fibers of papillary muscle from the left ventricle of three groups: patients with ischemic cardiomyopathy, patients with dilated cardiomyopathy (NYHA IV) and normal human hearts. Expression and phosphorylation of the phosphorylatable MLC isoforms (MLC-2) was equal within all three groups. However, 72% of the patients investigated in this study expressed the atrial essential MLC (ALC-1) in addition to the essential ventricular MLC (VLC-1) ranging between 2.4% and 10.3%. Using fibers from failing hearts, we observed a significant positive correlation between ALC-1 and Ca2+ sensitivity in that the higher the ALC-1 expression the higher the Ca2(+)-sensitivity: pCa50 (Ca2+ required for half-maximal force production) was 5.87 without ALC-1 and 6.08 with 10.3% ALC-1. Fibers from a normal heart (no ALC-1) revealed a pCa50 of 5.85. Isoform and phosphorylation patterns of tropomyosin and troponin I remained unchanged in the patients and normal hearts. Our results suggest that Ca2+ responsiveness and force development of the human heart is regulated by the expression of different MLC-1 isoforms.

Calcium↗
PubMed1997

The role of Gi-proteins and beta-adrenoceptors in the age-related decline of contraction in guinea-pig ventricular myocytes.

A decline in contractility in myocytes from ageing guinea-pig hearts was demonstrated, which is more pronounced for maximum beta-adrenoceptor-stimulated activity than contraction in high Ca2+. In this study the role of the inhibitory G-proteins (Gi) in this process was investigated. Comparisons were made between young (Y, < 400 g, < 4 weeks), adult (A. > 600 g, > 8 weeks) and senescent guinea pigs (S, 58-65 weeks, 1136 +/- 30 g). Gi alpha activity, detected by pertussis toxin-catalysed ADP ribosylation, was significantly increased in senescent compared to young animals, but immunodetectable levels of Gi alpha were unchanged, beta-adrenoceptor number was decreased by 27% in senescent compared with young animals (P < 0.002). Pertussis toxin treatment increased the maximum response to isoproterenol in contacting myocytes so that there was no longer any significant decline with age. Maximum contraction amplitudes (sarcomere length change, micron) with isoproterenol before pertussis toxin were 0.144 +/- 0.011 (Y, n = 22 animals), 0.104 +/- 0.009 (A. 18) and 0.098 +/- 0.009 (S. 14), P < 0.01 by analysis of variance (ANOVA). Following toxin treatment amplitudes were 0.140 +/- 0.012 (Y. 12), 0.117 +/- 0.010 (A. 10) and 0.117 +/- 0.018 (S. 8), P = N.S. Pertussis toxin treatment also reversed the effects of ageing on contraction and relaxation velocity in isoproterenol. In contrast, the effect of age on contraction amplitude or velocity in maximum Ca2+ was more pronounced after toxin treatment. The EC50 value for isoproterenol increased with age: pertussis treatment decreased the EC50 in each group, but the effect was especially pronounced for senescent animals. There was no significant difference in the concentration-response curves for the negative inotropic effect of adenosine (in the presence of isoprotenerol) between the three age groups before toxin treatment. All effects of adenosine were abolished after pertussis exposure. We conclude that increased Gi alpha activity is likely to contribute to the decreased response to isoproterenol, but not to high Ca2+, in myocytes from ageing guinea-pigs.

Adenosine Diphosphate↗
PubMed1997

Detection of loss of heterozygosity in the APC tumor suppressor gene in nonpapillary renal cell carcinoma by microdissection and polymerase chain reaction.

The role of the APC (adenomatous polyposis coli) tumor suppressor gene in the genesis of nonpapillary renal cell carcinoma is addressed. The frequency of allelic deletion in the APC gene was analyzed using microdissection of the tumor specimens and a PCR (polymerase chain reaction)-based assay for the detection of intragenic loss of heterozygosity (LOH). Twelve of 29 carcinomas investigated were informative (41%). In five of these (42%) LOH was detected in the APC gene, LOH did not correlate with tumor grade or stage. This high frequency of intragenic LOH suggests an implication of the APC gene or a closely linked gene in the genesis of a subset of nonpapillary renal cell carcinoma. The use of a microdissection technique allows the reliable detection of tumor-specific LOH when using a PCR-based assay.

Aged↗
PubMed1997

[Preoperative cardiac risk assessment and diagnosis. The view of the cardiologist].

Perioperative morbidity and mortality in noncardiac surgery are mainly due to cardiovascular complications. Therefore, perioperative risk assessment is crucial to avoid these adverse events. In patients above the age of 40 years, the ECG is a basic investigation, often providing hints for cardiovascular diseases. Stress testing and, in special cases, stress echocardiography or scintigraphy (the latter only in those patients, in which exercise is impossible) can detect significant coronary artery disease. The vascularization reduced the perioperative risk in particular in those patients with unstable angina or severe coronary artery disease. However, prophylactic revascularization the stable patient does not improve overall outcome, because the risk of the revascularizing procedure must be added to the risk of noncardiac surgery. Other diagnostic procedures like echocardiography, chest roentgenogram, routine scintigraphy, halter ECG or halter blood pressure measurement do not add information to the perioperative risk assessment, although these techniques might be very relevant in evaluating other coexisting diseases (heart failure; valve lesions, in particular aortic stenoses etc.) and can be useful to improve medical treatment preoperatively (e.g. normalization of blood pressure).

Heart Diseases↗
PubMed1997

[Hypomelanosis guttata idiopathica].

A 37-year-old white female with dark complexion presented with progressive hypopigmented macules on the face and upper trunk. She was in good health and her family history was unremarkable. Histologic examination of the hypopigmented patches revealed reduced melanin within the basal layers of the epidermis. Using immunohistochemical and ultrastructural studies, the number of melanocytes appeared normal but signs of degeneration were evident and dendrites were shortened. The diagnosis of idiopathic guttate hypomelanosis was established. The clinical picture, etiology and treatment of this relatively common but often unrecognized skin disease is discussed.

Adult↗
PubMed1997

Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure.

OBJECTIVES: This study tested the hypothesis that metoprolol restores the reduction of the inotropic effect of the cyclic adenosine monophosphate (cAMP)-phosphodiesterase inhibitor milrinone, which is cAMP dependent but beta-adrenoceptor independent. BACKGROUND: Treatment with beta-adrenergic blocking agents has been shown to lessen symptoms and improve submaximal exercise performance and left ventricular ejection fraction in patients with heart failure. Restoration of the number of down-regulated beta-adrenoceptors has been suggested to be one mechanism of beta-blocker effectiveness. However, the reversal of postreceptor events, namely, an increase in inhibitory G-protein alpha-subunit concentrations, could also play a role. METHODS: Fifteen patients with heart failure due to dilated cardiomyopathy (left ventricular ejection fraction 24.6 +/- 1.5% [mean +/- SD], New York Heart Association functional class II or III) were treated with metoprolol (maximal dose 50 mg three times daily) for 6 months. Before and after metoprolol treatment, inotropic responses to milrinone (5 to 10 micrograms/kg body weight per min) were measured echocardiographically. For comparison, responses to milrinone were determined under control conditions and after accelerated application of 150 mg of metoprolol to inactivate beta-adrenoceptors in subjects with normal left ventricular function. RESULTS: In subjects with normal left ventricular function, treatment with metoprolol did not alter the increase in fractional shortening or pressure/dimension ratio of circumferential fiber shortening after application of milrinone. In patients with heart failure, treatment with metoprolol significantly increased left ventricular ejection fraction, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations and functional class. After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blocker treatment. CONCLUSIONS: Milrinone increases inotropic performance independently of beta-adrenoceptors in vivo. Metoprolol treatment restores the blunted inotropic response to milrinone in patients with heart failure, indicating that postreceptor events (e.g., increase in inhibitory G-protein) are favorably influenced. This mechanism could contribute to the beneficial effects observed in the study patients and represents an important mechanism of how beta-blocker treatment influences the performance of the failing heart.

Adrenergic beta-Antagonists↗
PubMed1997

Cut out or poke in--the key to the world of single genes: laser micromanipulation as a valuable tool on the look-out for the origin of disease.

The optical micromanipulation systems UV(ultraviolet)-Laser Microbeam and Optical Tweezers Trap, already proven to be powerful tools for 'non-contact' micro-manipulation of gametes, cells and organelles, have now made their way into the nanocosmos of genes and molecules. Force measurements of DNA transcription have been performed and selective DNA molecule micromanipulation gives insight into single molecule behaviour. Retrievement of selected single cells without contamination is an import prerequisite for further processing with modern methods of molecular biology. Laser micro-dissection allows to precisely eliminate any unwanted material or to isolate pieces of chromosomes or single cells of interest with high accuracy and efficiency. This enables the cell or chromosome specific molecular analysis of genes and genetic defects underlying disease, such as cancer or infection. This review article gives an overview of current topics of laser microbeam application in biological or medical research and advanced molecular diagnosis.

Animals↗
PubMed1997

Effects of beta 2-agonist- and dexamethasone-treatment on relaxation and regulation of beta-adrenoceptors in human bronchi and lung tissue.

1. Long-term treatment with beta 2-adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to beta-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with beta 2-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2. The effect of beta 2-agonist incubation alone and after coincubation with dexamethasone on density and affinity of beta-adrenoceptors was investigated by radioligand binding experiments. 3. In human isolated bronchi, isoprenaline induces a time- and concentration-dependent beta-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73 +/- 4% in efficacy of isoprenaline to relax human bronchial smooth muscle. 4. After an incubation period of 60 min with 100 mumol l-1 terbutaline, a significant decline in its relaxing efficacy (81 +/- 8%) and potency (by a factor 5.5) occurred. 5. Incubation with 30 mumol l-1 isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6. Coincubation of dexamethasone with isoprenaline (120 min; 30 mumol l-1) preserved the effect of isoprenaline on relaxation (129 +/- 15%). 7. In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 mumol l-1) resulted in a decrease in beta-adrenoceptor binding sites (Bmax) to 64 +/- 1.6% (P < 0.05), while the antagonist affinity (KD) for [3H]-CGP-12177 remained unchanged. 8. In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 mumol l-1) or isoprenaline (30 mumol l-1) plus dexamethasone (30 mumol l-1) for 120 min did not lead to a significant change of Bmax (160 +/- 22.1% vs 142.3 +/- 28.7%) or KD (5.0 nmol l-1 vs 3.5 nmol l-1) compared to the controls. 9. In conclusion, pretreatment of human bronchi with beta-adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down-regulation of beta-adrenoceptors. This effect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identification of mechanisms of beta-adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable effects of long-term beta-adrenoceptor stimulation.

Adrenergic beta-2 Receptor Agonists↗
PubMed1997

G protein-independent stimulation of human myocardial phospholipase C by mastoparan.

1 Phosphoinositide-specific phospholipase C (PLC) is involved in the regulation of many cellular functions. In the myocardium, PLC-generated second messengers play a role in the regulation of contractile function and in the pathophysiology of myocardial hypertrophy. 2 In the present study, the effect of mastoparan, a tetradecapeptide which is capable of activating heterotrimeric G proteins by mimicking the action of an activated receptor, on membrane-bound human myocardial PLC, was investigated in a cell-free assay with exogenous phospholipids as a substrate. 3 Mastoparan stimulated human myocardial PLC approximately two fold with a half-maximal effect at approximately 2 microM and a maximal effect at 10 microM. The peptide did not alter the dependence of PLC on free calcium ions. In order to exclude non-specific effects of mastoparan due to its amphiphilic properties, different mastoparan derivatives were used as positive and negative controls. Mas17, an inactive mastoparan analogue with physical properties very similar to mastoparan, did not induce substantial PLC stimulation in human myocardial membranes. In contrast, Mas7, the most active mastoparan derivative known, caused a more pronounced PLC activation compared with the mother compound indicating that the effect was sequence-specific. Human myocardial PLC stimulation was pertussis toxin-insensitive and could not be abolished by addition of excess alpha-subunits from purified retinal transducin or by excess GDP or GDP/beta S. In order to investigate whether mastoparan stimulate PLC via pertussis toxin-insensitive alpha q, a deletion mutant of PLC beta 2 deficient of the site of interaction with alpha q-subunits was expressed in COS-1 cells. Both wild-type and mutant PLC beta 2 were similarly sensitive to stimulation by mastoparan. It is concluded that mastoparan stimulates human myocardial PLC by a mechanism distinct from heterotrimeric G proteins.

Animals↗
PubMed1997

Influence of oxidized low-density lipoprotein on vascular angiotensin II receptor expression.

OBJECTIVES: To investigate the effect of oxidized low-density lipoprotein (LDL) on angiotensin type 1 (AT1) receptor expression and on angiotensin-induced mitogenesis in vascular smooth muscle cells. DESIGN: Since both LDL and the AT1 receptor are thought to be involved in the pathogenesis of chronic vascular disease, we studied possible interactions between these two biological systems in cultured rat vascular smooth muscle cells. Recent studies have demonstrated that native LDL profoundly increases the AT1 receptor gene expression in vascular smooth muscle cells. The present study was designed to show whether an oxidative modification of LDL, which has been implicated as a major participant in atherogenesis, has similar effects on vascular smooth muscle cells. MATERIALS AND METHODS: Vascular smooth muscle cells isolated from rat thoracic aorta were cultured with oxidized LDL and assessed for their ability to synthesize DNA, and messenger (m)RNA expression, using Northern blot technology. RESULTS: Oxidized LDL had no significant effect on AT1 receptor mRNA steady-state levels when incubated for 0-24 h. Moreover, oxidized LDL itself had no stimulatory effect on DNA synthesis in vascular smooth muscle cells, nor was the angiotensin II-induced increase in DNA synthesis influenced by oxidized LDL. CONCLUSIONS: These data show that in contrast to native LDL, oxidized LDL has no effect on AT1 receptor mRNA expression and no effect on angiotensin II-induced mitogenesis in vascular smooth muscle cells.

Angiotensin II↗
PubMed1997

Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy.

BACKGROUND: Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure. OBJECTIVE: To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation. METHODS AND RESULTS: Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap. CONCLUSIONS: In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

Angiotensin I↗
PubMed1997

Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil.

Mibefradil (Ro 40-5967) is a novel nondihydropyridine calcium antagonist. The aim of our study was to compare the negative inotropic effects of the well-known 1,4-dihydropyridine nifedipine and the phenylalkylamine verapamil with those of mibefradil. Isometric force of contraction in response to these substances was determined in isolated, electrically driven left ventricular papillary muscle strips from failing human hearts (1 Hz, 37 degrees C). The hearts were obtained during cardiac transplantation (n = 9) and mitral valve-replacement operations (n = 9). The calcium antagonists studied significantly (p < 0.05) depressed basal force of contraction in a concentration-dependent manner. The effect started at concentrations > 0.001 microM for nifedipine and > 0.01 microM for verapamil, but only at concentrations > 10 microM for mibefradil. Only in the presence of nifedipine and verapamil was a significant rightward shift of the inotropic concentration--response curves to calcium and a depression of the maximal effects of calcium observed. With respect of the relation between the therapeutic active plasma concentration in vivo and the negative intropic potency in vitro, it became evident that the difference between therapeutically beneficial concentrations and potentially hazardous cardiodepressant activity increases from nifedipine to mibefradil. We conclude that this new generation of calcium antagonists, almost lacking cardiodepressant effects, could lead to a greater therapeutic index and greater safety in the treatment of cardiovascular diseases.

Benzimidazoles↗