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Biomedical subjects

G Münch

Publications and source records attributed to G Münch.

At least 73 records · Page 4Linked to original sources
PubMed1997

Myocardial technetium-99m-tetrofosmin and technetium-99m-sestamibi kinetics in normal subjects and patients with coronary artery disease.

UNLABELLED: This study was designed to compare the tracer kinetics between 99mTc-sestamibi and 99mTc-tetrofosmin in a heterogeneous group of 24 patients admitted for routine perfusion imaging. METHODS: Twelve patients were studied with 99mTc-tetrofosmin and 12 with 99mTc-sestamibi. In each group, six patients had a low likelihood for coronary artery disease, and six patients had angiographically proven coronary artery stenoses of > 75% or previous myocardial infarction. Analysis of myocardial and liver uptake and clearance as well as target-to-organ contrasts were performed with planar stress images. RESULTS: Myocardial uptake of 99mTc-tetrofosmin was higher from 5 min (0.37 +/- 0.12 counts/pixel x MBq-1, p = 0.008) to 60 min (0.32 +/- 0.10 counts/pixel x MBq-1, p = 0.04) compared to 99mTc-sestamibi. Biological half-life for 99mTc-tetrofosmin (278 +/- 32 min) in normal myocardium was significantly shorter (p = 0.008) than for 99mTc-sestamibi (680 +/- 45 min). Biological liver half-life for 99mTc-tetrofosmin (67 +/- 16 min) was also significantly shorter (p = 0.02) than for 99mTc-sestamibi (136 +/- 18 min). Heart-to-lung ratios for 99mTc-tetrofosmin (2.49 +/- 0.43 at 5 min to 2.66 +/- 0.55 at 60 min) and 99mTc-sestamibi (2.52 +/- 0.37 at 5 min to 2.95 +/- 0.50 at 60 min) were similar. Whereas heart-to-liver ratios for 99mTc-tetrofosmin (1.04 +/- 0.24 at 5 min, increasing to 1.51 +/- 0.44 at 60 min) were significantly higher from 30-60 min postinjection (p = 0.05 at 30 min to p = 0.02 at 60 min) compared to the 99mTc-sestamibi (0.83 + 0.16 at 5 min to 1.08 +/- 0.27 at 60 min). CONCLUSION: Technetium-99m-tetrofosmin displays a shorter myocardial half-life compared to 99mTc-sestamibi. The rapid liver clearance of 99mTc-tetrofosmin, combined with comparable myocardial retention, resulted in higher heart-to-liver ratios but similar heart-to-lung contrasts compared to 99mTc-sestamibi from 30-60 min.

Coronary Disease↗
PubMed1996

[New hypothesis on etiopathogenesis of Alzheimer syndrome. Advanced glycation end products (AGEs)].

Despite intense efforts, it has not yet been possible to clarify the etiopathogenesis of Alzheimer's dementia. There are, however, hypotheses which focus on certain aspects of this type of dementia, characterized by particular neuropathological alterations and clinical correlates. Recently, evidence has accumulated that advanced glycation endproducts (AGEs) could play an important role in the etiology of the Alzheimer's syndrome. AGEs are generated by an irreversible reaction through the non-enzymatic, long-term glycosylation of proteins. They are strongly resistant to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of beta-amyloid into its unsoluble version. AGEs are also demonstrable in neurofibrillary tangles (NFTs). A further mechanism by which AGEs might be pathogenic is via their induction of oxidative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect receptor-mediated mechanisms. Further investigation of AGE-mediated mechanisms should reveal their role in the etiopathogenesis of the Alzheimer's syndrome and, finally, lead to the development of new pharmacological strategies aimed at inhibiting protein cross-linking.

Aged↗
PubMed1996

Advanced glycation endproducts-associated parameters in the peripheral blood of patients with Alzheimer's disease.

Advanced glycation endproducts (AGEs), structural components of beta-amyloid plaques and neurofibrillary tangels, have been implicated in the pathogenesis of Alzheimer's disease. AGE levels, measured by fluorescence, and their precursor molecules such as glucose and its Amadori product, fructosylamine, were measured to examine the question whether the reported increased level of AGEs in the brain is reflected in an increase in AGE-associated parameters in peripheral blood. Lactoferrin, proposed to play an important role in the interaction of AGEs with their receptors, was determined by ELISA. All AGE-associated parameters showed trends to lower values in patients with Alzheimer's disease compared with non-demented controls. Albumin and total iron were not significantly different between the groups. In contrast to diabetes and renal failure, where high levels of AGEs and their precursors are present in tissue as well as in peripheral blood, elevated CNS AGE levels in patients with Alzheimer's disease are manifested without detectable peripheral changes.

Aged↗
PubMed1996

Differential presynaptic modulation of noradrenaline release in human atrial tissue in normoxia and anoxia.

1. Presynaptic modulation of noradrenaline release in human atrial tissue specimens was investigated under normoxic and anoxic conditions. 2. Noradrenaline release was induced by electrical stimulation and release during experimental intervention (S2) was compared with release during a preceding control stimulation (S1). The results were expressed as the geometric means and 95% confidence intervals of the S2/S1 ratio. 3. The alpha 2-adrenoceptor agonist, UK 14304 (0.1 mumol-1) significantly inhibited noradrenaline release, resulting in a S2/S1 ratio of 0.49 (0.40-0.59), and the a 2-adrenoceptor antagonist, yohimbine (1 mumol l-1) increased noradrenaline release (S2/S1 1.83 [1.43-2.35]) during normoxia. Both compounds were ineffective during anoxia. 4. Adenosine (30 mumol-1) inhibited noradrenaline release with a S2/S1 ratio of 0.54 (0.42-0.66). The adenosine antagonist, 8-phenyltheophylline, alone had no effect during normoxia. During anoxia, neither adenosine nor 8-phenyltheophylline altered noradrenaline release. 5. The beta 2-adrenoceptor agonist, terbutaline (1 mumol l-1) increased (1.53 [1.14-2.01]) and the beta-adrenoceptor antagonist, pindolol (1 mumol l-1) suppressed noradrenaline release (0.62 [0.49-0.79]) under normoxic conditions. During anoxia, pindolol significantly inhibited noradrenaline release with a S2/S1 ratio of 0.66 (0.51-0.85), whereas terbutaline did not influence noradrenaline release. 6. Angiotensin II (0.1 mumol l-1 enhanced noradrenaline release resulting in a S2/S1 ratio of 1.44 (1.34-1.54), while the angiotensin II antagonist, losartan (1 mumol l-1) had no effect on noradrenaline release during normoxia. Conversely, angiotensin II did not increase noradrenaline release and losartan significantly inhibited noradrenaline release to a S2/S1 ratio of 0.60 (0.46-0.77) during anoxia. 7. In conclusion, human cardiac tissue possesses presynaptic inhibitory alpha 2-adrenoceptors and adenosine receptors, as well as facilitatory beta 2-adrenoceptors and angiotensin II receptors regulating noradrenaline release under normoxic conditions. During anoxia the responses to alpha 2-adrenoceptors and adenosine receptor stimulation are lost, whereas facilitatory responses to beta 2-adrenoceptors and adenosine II receptor stimulation are maintained and these receptors appear to be maximally stimulated. This differential presynaptic modulation in anoxia may contribute to enhanced sympathetic activity in ischaemia.

Adenosine↗
PubMed1995

Ligand binding analysis of human neuropeptide Y1 receptor mutants expressed in E. coli.

Site-directed mutants of the human neuropeptide Y1 (NPY Y1) receptor expressed as a maltose binding protein fusion protein in E. coli show identical ligand binding parameters compared with the same mutants expressed in mammalian cells using a vaccinia virus expression system. However, it was remarkable that two receptor mutants, which were initially classified as non-binding when expressed in an eukaryotic expression system, could actually be revealed to have wild-type binding activity when expressed in E. coli. Re-expression and retesting of these mutants in mammalian cells confirmed this result. This shows that bacterial expression can be used as a fast, versatile and valuable alternative to mammalian expression systems for the analysis of ligand binding sites in G-protein coupled receptors.

ATP-Binding Cassette Transporters↗
PubMed1994

The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation.

Non-enzymatic glycosylation of proteins, also called Maillard reaction, which occurs at an accelerated rate in diabetes, can lead to the formation of advanced glycosylation endproducts (AGEs). Tenilsetam (CAS 997: (+/-)-3-(2-thienyl)-2-piperazinone), a cognition-enhancing drug successfully used for treatment of patients suffering from Alzheimer's disease, when included in the Maillard reaction apparently inhibits protein crosslinking by AGEs in vitro. According to the mechanism proposed, Tenilsetam acts via covalent attachment to glycated proteins, thus blocking the reactive sites for further polymerisation reactions. A beneficial effect of Tenilsetam in Alzheimer's disease could come from the interference with AGE-derived crosslinking of amyloid plaques and a decreased inflammatory response by diminished activation of phagocytosing microglia.

Aging↗
PubMed1994

Effects of acrylamide on cotransmission in perivascular sympathetic and sensory nerves.

The effects of chronic administration of acrylamide on sympathetic and sensory nerves were examined in the mesenteric artery of rabbits. The noradrenaline (NA) content of the artery was significantly decreased and the total contractile response to electrical field stimulation (4-64 Hz) markedly reduced in the acrylamide group. This was not due to an impairment of the contractility of the smooth muscle or to alterations in the postjunctional receptors. At 16 Hz, only the purinergic component of sympathetic cotransmission was significantly reduced by acrylamide. At 64 Hz, both the purinergic and the adrenergic components were significantly decreased. Field stimulation of the artery pretreated with guanethidine and precontracted with NA produced a frequency-dependent relaxation which was prevented by capsaicin and thus mediated by perivascular sensory nerves. In contrast to its effects on sympathetic cotransmission, acrylamide resulted in a trend, although not significant, towards increased responses at each frequency studied (2-16 Hz). 2-Methylthio-ATP (2Me-S-ATP) caused significantly greater relaxation following acrylamide treatment while vasodilator responses to calcitonin gene-related peptide and substance P were unchanged. It is concluded that, in addition to its known action in producing neuropathy in myelinated somatic motor and sensory nerves, acrylamide causes damage to unmyelinated perivascular sympathetic fibres. Purinergic mechanisms may be particularly susceptible to acrylamide since both the purinergic component of sympathetic vasoconstriction and the relaxation in response to 2Me-S-ATP were affected by acrylamide treatment.

Acrylamide↗
PubMed1994

Human neuropeptide Y1 receptor expressed in Escherichia coli retains its pharmacological properties.

The coding region of the gene for the human neuropeptide Y (NPY) Y1 receptor was fused to the maltose binding protein gene. Expression of this transcription unit, after derepression with isopropyl beta-D-thiogalactopyranoside, was evidenced by the appearance of a protein of higher molecular weight, as well as the native maltose binding protein, both of which were immunoreactive with anti-maltose binding protein antibodies. Specific [125I]NPY binding activity was found associated mainly with the inner bacterial membrane fraction, suggesting that the receptor is correctly folded in this membrane. Competition binding experiments using NPY Y1- and Y2-specific ligands clearly exhibited a NPY Y1 specific pharmacological profile with Kd values indistinguishable from those of the native receptor. These results suggest that the membrane environment required by the human NPY Y1 receptor for specific high-affinity ligand binding is conserved in this heterologous bacterial system and can be used for detailed analyses of ligand-receptor interaction and drug screening.

ATP-Binding Cassette Transporters↗
PubMed1993

Two sites in the third inner loop of the dopamine D2 receptor are involved in functional G protein-mediated coupling to adenylate cyclase.

Synthetic peptides, corresponding to the amino acid sequences of the N- and C-terminal parts of the 3rd intracellular loop of the dopamine D2 receptor, attenuate dopaminergic adenylate cyclase inhibition in membranes. Both peptides also activate directly GTPase activity in membranes. We suggest a functional model for G(i)-coupled receptors where two sites in the 3rd inner loop compose the links for the receptor-G protein interaction thus providing the tools for a selective and adjustable response. Functional coupling was not affected by a peptide representing the insert in the long form of the dopamine D2 receptor (D2(long)). The selectivity pattern of conventional G protein-linked receptors also sheds some light on the recently observed interaction of beta-amyloid protein precursor (APP) complexes with G proteins.

Adenylyl Cyclase Inhibitors↗
PubMed1991

Multisite contacts involved in coupling of the beta-adrenergic receptor with the stimulatory guanine-nucleotide-binding regulatory protein. Structural and functional studies by beta-receptor-site-specific synthetic peptides.

Synthetic peptides, 12-22 amino acid residues long, comprising the presumed coupling sites of the beta-adrenergic receptor with the stimulatory guanine-nucleotide-binding regulatory protein (Gs), were examined for their ability to modulate Gs activation in turkey erythrocyte membranes. Three peptides corresponding to the second cytoplasmic loop, the N-terminal region of the third cytoplasmic loop, and the N-terminal region of the putative fourth cytoplasmic loop, compete synergistically with the hormone-stimulated receptor for Gs activation with median effector concentrations of 15-35 microM, or 3-4 microM for combinations of two peptides. One peptide, corresponding to the C-terminal region of the third cytoplasmic loop, carries the unique ability to activate the Gs-adenylate-cyclase complex independent of the signalling state of the receptor. These observations are consistent with a dynamic model of receptor-mediated G-protein activation in membranes, where domains composed of the second, third and fourth intracellular loop of the receptor bind to and are interactive with the G-protein heterotrimer, resulting in ligand-induced conformational changes of the receptor. In response to hormone binding, the extent or the number of sites involved in interaction with Gs may be readjusted using a fourth site. Modulation of coupling sites may elicit congruent conformational changes within the Gs heterotrimer, with qualitatively different effects on GTP/GDP exchange in the alpha subunit of Gs and downstream effector regulation. This model corroborates and expands a similar model suggested for activated rhodopsin-transducin interaction [König, B., Arendt, A., McDowell, J. H., Kahlert, M., Hargrave, P. A. & Hofmann, K. P. (1989) Proc. Natl Acad. Sci. USA 86, 6878-6882].

Aluminum↗
PubMed1991

Postsynaptic dopamine DA1- and DA2-receptors in jejunal arteries of rabbits.

Changes in the external diameter of rabbit isolated jejunal arteries were measured by a photoelectric device. Both norepinephrine and dopamine produced vasoconstriction; prazosin, but not idazoxan, antagonized these effects. Arteries preconstricted with norepinephrine were dilated by SKF 38393 and LY 171555. SCH 23390 antagonized both compounds, however, in the case of LY 171555 with a lower potency. Sulpiride also interacted with LY 171555. When arteries were preconstricted with PGF2 alpha in the presence of prazosin, idazoxan, and propranolol, SKF 38393 caused vasodilation, while LY 171555 and dopamine were inactive. We conclude that in jejunal arteries both DA1- and DA2-receptors may be present at the vascular smooth muscle.

Adrenergic alpha-Agonists↗
PubMed1990

Identification of a Gs-protein coupling domain to the beta-adrenoceptor using site-specific synthetic peptides. Carboxyl terminus of Gs alpha is involved in coupling to beta-adrenoceptors.

Competition between Gs-protein and the synthetic peptide, GSA 379-394, derived from the carboxyl-terminal region of the alpha s-subunit, led to complete inhibition of receptor-mediated adenylate cyclase activation in turkey erythrocyte membranes. Related peptides corresponding to the homologous carboxyl-terminal region of alpha t-, alpha il- or alpha o-subunits did not interfere with beta-receptor-Gs coupling. The direct coupling between Gs and adenylate cyclase was not influenced by any of these peptides. These results emphasize the important role of the carboxyl-terminus of G-protein alpha-subunits for the specific recognition of their corresponding receptors and for signal transduction.

Adenylyl Cyclases↗
PubMed1989

Proteolytic degradation routes for turkey beta 1-adrenoceptor probed with antipeptide antibodies against the N-terminal sequence of the receptor.

Anti-peptide antibodies, raised against the N-terminal sequence (amino acids 2-10) of the turkey beta 1-adrenoceptor [Yarden et al., Proc. Natl. Acad. Sci. USA (1986) 83, 6795-6799] recognized the 50 kDa- but not the 40 kDa-form of the receptor, thus confirming the previous assumption that the N-terminus of the 50 kDa form is lost during its conversion to the 40 kDa-form [Jür beta, R., Hekman, M. & Helmreich, E.J.M. (1985) Biochemistry 24, 3349-3354]. By in situ proteolysis small amounts of receptor fragments were formed, which could be recognized by the N-terminus specific antibody. Therefore, although the production of the stable 40 kDa receptor species by proteolytic removal of a portion of the N-terminal appears to be the predominant route, there exists an additional pathway of degradation which must involve the initial cleavage of the carboxyl terminal.

Affinity Labels↗
PubMed1989

Mapping of beta-adrenoceptor coupling domains to Gs-protein by site-specific synthetic peptides.

Peptides corresponding to the known sequence of turkey erythrocyte beta 1-adrenergic receptor were synthesized and the effects on receptor-mediated cyclase activation were measured. Peptides corresponding to the first and second intracellular loops (T61-71 and T138-159) inhibited at micromolar concentrations the hormone-dependent cyclase activation in turkey erythrocyte membranes. In contrast, the peptide corresponding to the C-terminal part of the third intracellular loop (T284-295) increased the cyclase activity in a hormone-independent manner. Peptides T338-353 and T2-10 and a number of synthetic peptides unrelated to the beta-adrenoceptor had no effect.

Adenylyl Cyclases↗
PubMed1975

Biodegradation of alpha-hexachlorocyclohexane. V. Characterization of the major urinary metabolites.

1. Free 2,4,5- and 2,4,6-trichlorophenol (TCP) have been identified by co-crystallization with authentic carrier as constituents of the urine of rats given 3-H-labelled alpha-hexachlorocyclohexane (alpha-HCH). The two TCP's constituted 7% and 63%, respectively, of the free phenol fraction which was found to account for less than 5% of all urinary metabolites. 2. 75% of the label contained in the urine of rats collected for four weeks after an i.p. dose of 14-C-alpha-HCH could be extracted into an organic solvent after alkaline and acid hydrolysis. The radioactive material thus extracted was examined by TLC and GLC. It is shown to consist mainly of chlorophenols and chlorothiophenols. 3. The extracts' major constituent was 2,4,6-TCP. Its amount was determined by GLC and was found to account for, on average, 45% of the total urinary metabolites. In conjunction with other evidence, this is considered to establish 2,4,6-TCP as the major product of alpha-HCH-biodegradation in the rat. 4. Chromatographic evidence is presented for 2,3,4,5-tetrachlorophenol and 2,4,5-TCP being other components of the chlorophenol fraction isolated from hydrolysed urine. 5. The amount of label associated with the chlorothiophenol fraction suggests a pathway involving endogenous thiol to be of significance in alpha-HCH-biodegradation in rats. Pretreatment with the drug itself increased the proportion of label associated with the fraction.

Animals↗