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Biomedical subjects

M Böhm

Publications and source records attributed to M Böhm.

At least 19 recordsLinked to original sources
PubMed1999

Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen.

Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.

Angiotensin II↗
PubMed1999

Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite.

OBJECTIVES: This study examined the effects of endotoxin on cardiac contractility in human myocardium. BACKGROUND: In animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown. METHODS: Left ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N(G)-mono-methyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 micromol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay. RESULTS: Isoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin. CONCLUSIONS: Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction.

Adult↗
PubMed1999

Three-dimensional quantitative structure-activity relationship analyses using comparative molecular field analysis and comparative molecular similarity indices analysis to elucidate selectivity differences of inhibitors binding to trypsin, thrombin, and factor Xa.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities (Ki values) toward thrombin, trypsin, and factor Xa to yield statistically reliable models of good predictive power. Two methods were compared: the widely used comparative molecular field analysis (CoMFA) and the recently reported CoMSIA approach (comparative molecular similarity indices analysis). CoMSIA produced significantly better results for all correlations. Furthermore, in contrast to CoMFA, CoMSIA is not sensitive to changes in orientation of the superimposed molecules in the lattice. The correlation results obtained by CoMSIA were graphically interpreted in terms of field contribution maps allowing physicochemical properties relevant for binding to be easily mapped back onto molecular structures. The advantage of this feature is demonstrated using the maps to design new molecules. Finally, the CoMSIA method was applied to elucidate structural features among ligands which are responsible for affinity differences toward thrombin and trypsin. These selectivity-determining features were interpreted graphically in terms of spatial regions responsible for affinity discrimination. Such indicators are highly informative for the lead optimization process with respect to selectivity enhancement.

Binding Sites↗
PubMed1999

Disseminated superficial actinic porokeratosis: treatment with topical tacalcitol.

Disseminated superficial actinic porokeratosis is characterized by multiple, brown, annular, keratotic lesions that develop predominantly on the extensor surfaces of the legs and arms during the third and fourth decades of life. No ideal treatment of disseminated superficial actinic porokeratosis has been found. We describe a patient with this condition whose skin lesions responded to topical tacalcitol.

Administration, Topical↗
PubMed1998

Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms.

BACKGROUND: An interaction of insulin with angiotensin II effects could be pathophysiologically important for the pathogenesis of atherosclerosis and hypertension. METHODS AND RESULTS: We examined the effect of insulin on AT1 receptor gene expression in cultured vascular smooth muscle cells (VSMCs). A 24-hour incubation with insulin (100 nmol/L) produced a 2-fold increase in AT1 receptor density on VSMCs, as assessed by radioligand binding assays. This enhanced AT1 receptor expression was caused by a time- and concentration-dependent upregulation of the AT1 receptor mRNA levels, as assessed by Northern analysis. The maximal effect was detected after a 24-hour incubation of cells with 100 nmol/L insulin (270+/-20%). AT1 receptor upregulation was caused by a stabilization of the AT1 receptor mRNA, because the AT1 receptor mRNA half-life was prolonged from 5 hours under basal conditions to 10 hours after insulin stimulation. In contrast, insulin had no influence on AT1 receptor gene transcription, as assessed by nuclear run-on assays. The insulin-induced AT1 receptor upregulation was followed by an increased functional response, because angiotensin II evoked a significantly elevated intracellular release of calcium in cells that were preincubated with 100 nmol/L insulin for 24 hours. The insulin-induced AT1 receptor upregulation was dependent on tyrosine kinases, as assessed by experiments with the tyrosine kinase inhibitor genistein. Furthermore, experiments using the intracellular calcium chelator bis(2-amino-5-methylphenoxy)ethane-N, N,N',N'-tetraacetic acid tetraacetoxymethyl ester suggest that intracellular calcium release may be involved in AT1 receptor regulation. CONCLUSIONS: Insulin-induced upregulation of the AT1 receptor by posttranscriptional mechanisms may explain the association of hyperinsulinemia with hypertension and arteriosclerosis, because activation of the AT1 receptor plays a key role in the regulation of blood pressure and fluid homeostasis.

Angiotensin II↗
PubMed1998

Overexpression of the Na(+)-Ca2+ exchanger leads to enhanced inotropic responsiveness to Na(+)-channel agonist without sarcoplasmic reticulum protein changes in transgenic mice.

The present study investigated the influence of over-expression of the cardiac Na(+)-Ca2+ exchanger on myocardial force of contraction and alterations in sarcoplasmic reticulum (SR) Ca(2+)-handling proteins in a transgenic mouse model. Inotropic effects of Na+ channel agonist BDF 9148 and isoprenaline were determined in isolated electrically driven atria. Protein levels of key SR Ca(2+)-handling proteins were determined by Western blot analysis. Transgenic animals had no myocardial hypertrophy or failure. The positive inotropic effect of BDF 9148 was significantly more pronounced in myocardium for transgenic animals, whereas the inotropic response to isoprenaline was similar in both groups. Strong immunoreactivity of the transgene Na(+)-Ca2+ exchanger was detected in myocardium of transgenic animals. Protein levels of SR Ca(2+)-ATPase, phospholamban, and calsequestrin were unchanged. In conclusion, transgenic overexpression of the Na(+)-Ca2+ exchanger is accompanied by increased force development following Na+ channel agonist administration, even though Ca2+ proteins of the SR are unchanged.

Animals↗
PubMed1998

Functional coupling of overexpressed beta 1-adrenoceptors in the myocardium of transgenic mice.

To assess functional and cellular effects of myocardial beta 1-adrenoceptor overexpression, alterations of the beta-adrenergic signal transduction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Radioligand binding experiments confirmed a 5- to 6-fold increase in beta-adrenoceptor density and a 2.7-fold increase in high-affinity binding sites in atria of transgenic mice. Dose-response curves for isoprenaline-induced force of contraction showed unchanged maximum effects but significantly increased pD2 values. Basal, MnCl2- and isoprenaline-stimulated adenylyl cyclase activities did not significantly differ, whereas the Gpp(NH)p and forskolin effect tends to be reduced in transgenic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosylation) was unchanged, whereas the bioactivity of Gs alpha (reconstitution experiments into S49 cyc- cell membranes) was reduced by about 19% in the transgenic group. These results suggest that overexpressed beta 1-adrenoceptors act as functional spare receptors. In addition, increased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity.

Adenosine Diphosphate Ribose↗
PubMed1998

Estrogen modulates AT1 receptor gene expression in vitro and in vivo.

BACKGROUND: The AT1 receptor has been implicated in the pathogenesis of hypertension and atherosclerosis. Estrogen deficiency is also associated with cardiovascular diseases. Therefore, we examined the AT1 receptor gene expression in ovariectomized rats with and without estrogen replacement therapy and the influence of estrogen on AT1 receptor expression in cultured vascular smooth muscle cells. METHODS AND RESULTS: Rat aortic tissue was examined 5 weeks after ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered during the 5-week period. Functional experiments assessed angiotensin II-induced contraction of aortic rings. AT1 receptor mRNA levels were measured by quantitative polymerase chain reaction and Northern blotting. AT1 receptor density was assessed by radioligand binding assays. These techniques were also applied in cultured vascular smooth muscle cells. The efficacy of angiotensin II on vasoconstriction was significantly increased in aortas from ovariectomized rats. As assessed by radioligand binding assays, AT1 receptor density was increased to 160% without changes in receptor affinity during estrogen deficiency. AT1 receptor mRNA levels were consistently increased to 187% in ovariectomized rats compared with sham-operated animals. Estrogen substitution therapy in ovariectomized rats reversed this AT1 receptor overexpression. To explore the underlying mechanisms, the direct influence of estradiol on AT1 receptor expression was investigated in VSMCs. Estradiol (1 micromol/L) led to a time-dependent downregulation of AT1 receptor mRNA, with a maximum of 33.3% at 12 hours. There was a correlative decrease in AT1 receptor density. CONCLUSIONS: This novel observation of estrogen-induced downregulation of AT1 receptor expression could explain the association of estrogen deficiency with hypertension and atherosclerosis, because activation of the AT1 receptor plays a key role in the regulation of blood pressure, fluid homeostasis, and vascular cell growth.

Angiotensin II↗
PubMed1998

[Mycotic aneurysm in endocarditis lenta as the etiology of intraparenchymatous cerebral hemorrhage].

CASE REPORT: A 49-year-old male was admitted for left-side headache and mild speech defect. Clinical examination showed a pansystolic murmur of mitral regurgitation and mild Wernicke aphasia. In laboratory studies ESR and CRP were increased. Computed tomography of brain revealed a left temporoparietal hematoma. Echocardiographic examination demonstrated vegetations and mitral valve perforation. In blood cultures grew alpha-streptococci. Cerebral angiography was performed and a fusiform aneurysm on a distal branch of the left middle cerebral artery was identified. Follow-up angiography showed a total resolution of the aneurysm after 6 weeks of intravenous antibiotics. CONCLUSION: This case demonstrate that patients with intracerebral hematomas associated with infectious endocarditis should be investigated for mycotic intracranial aneurysm.

Aneurysm, Infected↗
PubMed1998

Pharmacological intervention in age-associated brain disorders by Flupirtine: Alzheimer's and prion diseases.

Alzheimer's disease, a major form of dementia in the elderly has become an increasingly important health problem in developed countries. In vitro studies on primary neurons demonstrate that Flupirtine (Katadolon) at a concentration of 1 microg/ml, significantly reduces the neurotoxic (apoptotic) effect displayed by A beta25-35, a segment of the amyloid beta-protein precursor the etiologic agent of Alzheimer's disease. Flupirtine, which has been in clinical use since 10 years ago, prevents the toxic effect of PrP, the presumed etiologic agent of the Creutzfeldt-Jakob disease as well as the excitatory amino acid glutamate on cortical neurons. Flupirtine displays a bimodal activity. Its strongest cytoprotective effect against glutamate-induced neurotoxicity was measured if administered at least 120 min prior to the addition of the glutamate. A likewise potent anti-apoptotic activity was measured if cells were simultaneously incubated with Flupirtine and the apoptotic inducers. Administration of Flupirtine during postincubation time in the experiments with glutamate did not result in neuroprotection. In parallel with the determination of the effect of Flupirtine on the toxin (A beta, PrP or glutamate)-induced neuronal death the effect of the drug on the intracellular Ca2+ level [Ca2+]i, was measured. It is well established that incubation of neurons with glutamate causes an increase in [Ca2+]i. It was found that a simultaneous administration of Flupirtine and glutamate did not reduce the glutamate-induced high Ca2+ level. Only if the cells had been preincubated for approximately 30 min with the drug the intracellular Ca2+ level was significantly lower. Experimental evidence given here shows that the molecular basis for the antiapoptotic effect of Flupirtine against glutamate, triggered during pre-incubation, is an increased expression of the protooncogene bcl-2. The neuroprotective effect determined during coincubation with the inducer is attributed to a normalization of the glutathione level which dropped in the presence of the inducers. It is concluded that Flupirtine is a promising drug to treat neurodegenerative disorders occurring with age, e.g. Alzheimer's disease and prion based diseases, like Creutzfeldt-Jakob disease. This conclusion is corroborated by the favourable pharmacokinetic profile of Flupirtine.

Aging↗
PubMed1998

Endothelin receptors in the failing and nonfailing human heart.

BACKGROUND: In patients with chronic heart failure (CHF), plasma endothelin-1 (ET-1) levels are increased. We studied whether the cardiac ET-receptor system is altered in CHF patients. METHODS AND RESULTS: We assessed ET-evoked inositol phosphate (IP) formation in slices from right atria and left ventricles from 6 potential heart transplant donors (NFH) and 15 patients with end-stage CHF; in membranes from the same tissues, we studied ET-induced inhibition of isoprenaline- and forskolin-stimulated adenylyl cyclase and ET-receptor density. ET (10[-9] to 10[-6] mol/L, ET-1 >>> ET-3) increased IP formation in right atria and left ventricles through ET(A)-receptor stimulation in a concentration-dependent manner; no difference in potency or efficacy between NFH and CHF hearts was observed. ET-1 (10[-10] to 10[-6] mol/L), via ET(A)-receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase in right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase in both tissues; again, the potency and efficacy of ET- or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts. [125I]ET-1 binding revealed the coexistence of ET(A) and ET(B) receptors in both tissues; however, the density of ET(A) receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricular Gq/11 protein did not differ between NFH and CHF hearts. CONCLUSIONS: In the human heart, ET(A) and ET(B) receptors coexist; however, only ET(A) receptors are of functional importance. In right atria, ET(A) receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET(A)-receptor system is not altered.

Adenylyl Cyclases↗
PubMed1998

Analysis of gene expression patterns in small amounts of human ventricular myocardium by a multiplex RNase protection assay.

End-stage human heart failure is associated with changes in expression of steady-state messenger RNA (mRNA) levels. These changes correspond to alterations in protein levels and myocardial function and may have clinical implications regarding etiology, clinical state, or prognosis. However, analysis of mRNA levels in endomyocardial biopsies can be accomplished only by the quantitative polymerase chain reaction, which is difficult to standardize. The aim of the study was to evaluate whether the RNase protection assay is applicable to measure mRNAs of multiple genes simultaneously in small amounts of ventricular myocardium comparable to myocardial biopsies. Total RNA was prepared from left ventricular myocardium from terminally failing hearts with idiopathic (n=9) or ischemic cardiomyopathy (n=7) and from nonfailing control hearts (n=10). mRNA was measured by an optimized RNase protection assay for the beta1-adrenoceptor, the stimulatory G protein alpha-subunit (Gsalpha), phospholamban, the calcium ATPase of the sarcoplasmic reticulum (SERCA), beta-myosin heavy chain (beta-MHC), and the atrial natriuretic peptide (ANP). We extracted 10.7+/-2.1 microg total RNA from three myocardial biopsies taken in vitro. All of the six genes were measurable in duplicate in a total of 7 microg RNA. mRNAs of beta1-adrenoceptor, phospholamban, and SERCA were lower in failing than in nonfailing myocardium by 50%, 33%, and 42% respectively, whereas beta-MHC and Gsalpha mRNAs were unchanged. mRNA of ANP was expressed at high levels only in the failing myocardium, providing a highly specific and sensitive marker for discriminating nonfailing and failing hearts. A direct comparison with ANP and Gsalpha levels obtained by Northern blot analysis with 7.5 microg total RNA showed a good correlation between the two methods. The RNase protection assay is thus a suitable method for simultaneous measurements of multiple mRNA levels in human myocardial biopsies. Changes in mRNA levels closely reflected those identified by other methods using larger amounts of RNA. Increased myocardial ANP mRNA levels determined by the RNase protection assay may serve as a molecular marker of heart failure.

Adolescent↗
PubMed1998

Molecular aspects of adrenergic signal transduction in cardiac failure.

Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.

Animals↗
PubMed1998

Interaction between insulin and AT1 receptor. Relevance for hypertension and arteriosclerosis.

The AT1 receptor mediates many biological effects of the renin angiotensin system such as vasoconstriction and cell proliferation. The expression level of the AT1 receptor is subjected to various pathophysiological influences. Insulin, which is elevated in the metabolic syndrome, induces a overexpression of vascular AT1 receptors leading to an enhanced biological efficacy of angiotensin II. This heterologous regulation of the AT1 receptor by insulin may explain the fact that the metabolic syndrome is frequently associated with hypertension and atherosclerosis.

Animals↗