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Biomedical subjects

A Hempel

Publications and source records attributed to A Hempel.

At least 37 records · Page 2Linked to original sources
PubMed1997

ANP protects against reoxygenation-induced hypercontracture in adult cardiomyocytes.

It was investigated whether atrial natriuretic peptide (ANP) or the related peptide urodilatin can be used for protecting cardiomyocytes against reoxygenation-induced hypercontracture. Isolated ventricular cardiomyocytes (from adult rats) were used as the experimental model. When the cells were submitted to substrate-free anoxia (135 min) and subsequent reoxygenation (30 min), the onset of reoxygenation provoked their hypercontracture. It was studied whether the temporary presence of ANP or urodilatin (1 nM to 1 microM) or 8-bromo-guanosine 3',5'-cyclic monophosphate (8-BrcGMP; 1 microM to 1 mM) during the last 15 min of anoxia and the first 15 min of reoxygenation prevented hypercontracture. It was found that ANP (1 microM) prevented hypercontracture in 82 +/- 8% (SD), urodilatin (1 microM) in 80 +/- 9%, and 8-BrcGMP (1 mM) in 72 +/- 10% of the cells (n = 40 cells). When ANP (1 microM) was added during the last 15 min of anoxia and the first 15 min of reoxygenation, the cellular concentration of cGMP increased from 0.41 +/- 0.04 to 2.80 +/- 0.81 pmol/mg protein (n = 6 cultures). The results show that the reoxygenation-induced hypercontracture in cardiomyocytes can be attenuated by the temporary presence of the stimulators of particulate guanylate cyclase, ANP or urodilatin.

Aerobiosis↗
PubMed1997

High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha.

Endothelial cell permeability is impaired in diabetes mellitus and may be increased by high extracellular glucose concentrations. High glucose activates protein kinase C (PKC), a family of kinases vital to intracellular signaling. We tested the hypothesis that high glucose concentration activates PKC in endothelial cells and leads to an increase in endothelial cell permeability via distinct PKC isoforms. Porcine aortic endothelial cells were used, and the PKC isoforms alpha, delta, epsilon, zeta, and theta were identified in these cells. Glucose caused a rapid dose-dependent increase in endothelial cell permeability, with an EC50 of 17.5 mmol/L. Phorbol 12-myristate 13-acetate (TPA) induced an increase in permeability very similar to that elicited by glucose. The effect of glucose and TPA was totally reversed by preincubating the cells with the PKC inhibitors staurosporine (10(-8) mol/L) and Goe 6976 (10(-8) mol/L). Downregulation of PKC by preincubation with TPA for 24 hours also abolished the effect of glucose and TPA on endothelial cell permeability. High glucose (20 mmol/L) caused an increase in PKC activity at 2, 10, and 30 minutes. Cell fractionation and Western blot analysis showed a glucose-induced translocation of PKC alpha and PKC epsilon. Confocal microscopy confirmed the translocation and showed an association of PKC alpha and PKC epsilon with nuclear structures and the cell membrane. Specific antisense oligodesoxynucleotides (ODNs) against PKC alpha reduced the expression of the isoform, abolished the effects of glucose on endothelial cell permeability completely, and reduced the TPA effect significantly. In contrast, specific antisense ODNs against PKC epsilon had no effect on glucose-induced permeability and only a minor effect on the TPA-induced increase in permeability. We conclude that an increase in extracellular glucose leads to a rapid dose-dependent increase in endothelial cell permeability via the activiation of PKC and that this effect is mediated by the PKC isoform alpha.

Animals↗
PubMed1996

Molecular structure and antioxidant specificity of purpurogallin in three types of human cardiovascular cells.

Purpurogallin (PPG) in an active cytoprotector found in certain oak barks. We have shown that PPG prolongs the survival of cultured cardiocytes from rats and rabbits against different oxidants better than do antioxidants such as Trolox (a hydrophilic analogue of vitamin E) in a morphometric assay system. First, we verified by X-ray crystallography that PPG is a bicyclic molecule comprising a phenolic ring fused with a seven-membered ring in a highly planar conformation. In analogues of PPG wherein the two double bonds in the seven membered ring of the parent molecule are saturated or where the four OH groups of the parent compound are substituted by four OCH3 groups, the derivatives are less planar and less protective of the human cells than native PPG. Second, PPG in a concentration-dependent manner protected myocytes and endothelial cells of humans against oxyradicals generated with any one of the following oxyradical generators: (a) xanthine oxidase plus hypoxanthine, (b) menadione, or (c) paraquat. In each case, PPG was more cytoprotective than comparative antioxidants. Also, PPG protected erythrocytes against peroxyl radicals better than the two PPG derivatives mentioned. Third, the cytoprotective action of PPG detected in vitro was accompanied by declines of malondialdehyde. Finally, we observed that PPG chelated ferrous ions and, therefore, can suppress the formation of radicals in the Fenton reaction. Thus, PPG with its molecular architecture and presumably its affinity for ferrous ions protects multiple types of cardiovascular cells against oxyradicals.

Animals↗
PubMed1996

Functional antagonism between cAMP and cGMP on permeability of coronary endothelial monolayers.

The role of the intracellular second messengers guanosine 3', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) in the control of macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was determined as passage of fluorescein isothiocyanate (FITC)-labeled albumin across the monolayers. Activation of adenylyl cyclase by the beta-adrenoceptor agonist isoproterenol (Iso; 10(-5) M) and the A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-7) M) induced an increase in cellular cAMP contents that was accompanied by an increase in albumin flux. Effects of Iso and NECA on cellular cAMP level and albumin flux could be antagonized by a stimulator of the particular guanylyl cyclase, atrial natriuretic peptide (ANP; 10(-7) M), and stimulators of the soluble guanylyl cyclase, 3-morpholinosydnonimine (SIN-1; 10(-7) M) and sodium nitroprusside (SNP; 10(-6) M). ANP, SIN-1, and SNP also reduced cAMP content and basal macromolecule flux in unstimulated monolayers. 8-Bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP; 5 x 10(-6) M), a stimulator of protein kinase G, reduced the increase in albumin flux under Iso (10(-5) M), NECA (10(-7) M), or 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP; 5 x 10(-6) M). The present study shows that cGMP and cAMP are functional antagonists in the control of macro molecule permeability.

Adenylyl Cyclases↗
PubMed1996

Neuropeptide Y reduces macromolecule permeability of coronary endothelial monolayers.

The effect of neuropeptide Y (NPY) on cellular adenosine 3',5'-cyclic monophosphate (cAMP) contents and macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was continuously determined as passage of albumin across the monolayers. NPY (10(-10)-10(-7) M) decreased albumin flux and cellular cAMP content in a dose-dependent manner, with a half-maximal effect on albumin flux at 1.4 x 10(-9) M and on cAMP contents at 0.7 x 10(-9) M. A maximum effect of NPY was observed at 10(-7) M, decreasing albumin flux by 71 +/- 8% and cellular cAMP contents by 80 +/- 9% (mean +/- SD, n = 6, P < 0.05) compared with control. The effect of NPY on albumin flux was not altered in the presence of 10(-5) M indomethacin (an inhibitor of cyclooxygenase) and 10(-5) M NG-nitro-L-arginine (an inhibitor of nitric oxide synthase). NPY (10(-7) M) also antagonized the increase of albumin flux and cAMP content induced by 10(-6) M isoproterenol. Pretreatment of endothelial monolayers with pertussis toxin (1 microgram/ml for 2 h) abolished the effect of NPY on albumin flux and cAMP contents. This study shows that NPY can modulate macromolecule permeability of endothelial monolayers by reducing the cellular cAMP contents. Together with the effect of pertussis toxin, the data suggest that NPY exerts its antiadrenergic effect on cAMP metabolism and endothelial barrier function by receptors linked to adenylyl cyclase via an inhibitory guanosine-binding protein in coronary endothelial cells.

Adenylate Cyclase Toxin↗
PubMed1996

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Adult↗
PubMed1995

Participation of acetylpseudouridine in the synthesis of a peptide bond in vitro.

Uracil, uridine, and pseudouridine were acetylated by refluxing in acetic anhydride, and the products of acetylation were incubated with a synthetic peptide (1-21) that corresponds to the N-terminal 21 amino acid residues of human myelin basic protein. Peptide bond formation, at the N alpha terminus in peptide 1-21, was obtained with acetyluracil and acetylpseudouridine, but not with acetyluridine. Transfer of an acetyl group from acetyluracil and acetylpseudouridine depended on acetylation in the N-heterocycle. X-ray crystallographic analysis definitively established N-1 as the site of acetylation in acetyluracil. Mass spectrometry of the acetylation products showed that one acetyl group was transferred to peptide 1-21, in water, by either acetyluracil or acetylpseudouridine at pH approximately 6. Release of the acetyl group by acylaminopeptidase regenerated peptide 1-21 (mass spectrometry) and automated sequencing (for five cycles) of the regenerated (deacetylated) peptide demonstrated that the N terminus was intact. The findings are discussed in the context of a possible role for pseudouridine in ribosome-catalyzed peptidyltransfer, with particular reference being made to similarities between the possible mechanism of acyl transfer by acetyluracil/pseudouridine and the mechanism of carboxyl transfer by carboxylbiotin in acetyl CoA carboxylase. The possibility that idiosyncratic appearance of a wide range of acyl substituents in myelin basic protein could be related to a peculiar involvement of ribosomal pseudouridine is mentioned.

Acetylation↗
PubMed1995

Molecular properties and myocardial salvage effects of morin hydrate.

Morin hydrate is a bioactive pigment found in yellow Brazil wood. Recently, we reported that morin hydrate prolongs the survival of three types of cells from the human circulatory system against oxyradicals generated in vitro. The protection excels that given by equimolar concentrations of ascorbate, mannitol, and Trolox. Here, we demonstrate that, in vivo, morin hydrate at 5 mumol/kg actually reduced by > 50% the tissue necrosis in post-ischemic and reperfused rabbit hearts. Mechanistically, morin hydrate not only scavenges oxyradicals, but also moderately inhibits xanthine oxidase, a free-radical generating enzyme from the ischemic endothelium. Among other possibilities, morin hydrate appears to chelate some metal ions (e.g. Fe2+) in oxyradical formation, although this needs to be examined further. Nuclear magnetic resonance (at 500 mHz) and electron-impact mass spectrometry also supported a molecular formula of C15H10O7 for morin hydrate. Only by X-ray crystallography was it clearly revealed that there are two water molecules attached by intermolecular hydrogen bonds to a morin molecule. Also, the three rings of morin hydrate approach coplanarity. This conformation favours a delocalization of electrons after oxyradical reduction, making morin an effective antioxidant. Thus, we have documented some of the molecular properties and myocardial salvage effects of morin hydrate.

Animals↗
PubMed1995

Combined homicide-suicides: a review.

Although the rate of combined homicide-suicides is low compared with that for suicide alone or homicide, homicide-suicides generate much public concern. In some cases, the homicide-suicide involves annihilation of an entire family or multiple non-family members. A difficult phenomenon to study--in part because the perpetrator is dead--it is, nonetheless, crucial to attempt to advance our understanding of this tragic phenomenon from a psychiatric view. This literature review then addresses demographic variables; proposes two classifications, one based on psychopathology, the other on the relationship between offender and victim; and suggests a three dimensional analytical approach to understanding homicide-suicide: 1) psychopathology and ego deficits of the perpetrator, 2) cumulative and precipitating stressors, and 3) motivation and vector of destructive urges against self and the other victim(s). Finally, some implications for mental health clinicians and forensic experts are offered. In attempting to understand acts of homicide-suicide, inquiry into the following dimensions should be useful: Ego Weakness. What type of mental disorder(s), psychopathology, or personality traits may have contributed to the homicidal-suicidal behavior? Stressors. What type of acute and chronic stressors did the individual experience leading up to this act? Vectors. Whom did the individual select to kill and why? Were some victims more clearly primary and others secondary or incidental?

Adult↗
PubMed1993

Glucosidase inhibitors: structures of deoxynojirimycin and castanospermine.

High-resolution structures of the glucosidase inhibitors deoxynojirimycin (dNM) and castanospermine (CAST) have been determined by X-ray diffraction. The crystal parameters are a = 10.751(3) and 8.788(3) A, b = 9.263(3) and 8.172(3) A, c = 7.719(2) and 6.507(2) A, and space group P2(1)2(1)2(1) and P2(1) for dNM and CAST, respectively. (beta = 105.44(8) degrees for CAST.) The absolute configuration of CAST has also been established. Stereochemical comparisons with natural glucosidase substrates such as maltose and methyl glucoside show great similarities in the positioning of functional groups, and indicate the basis for enzyme inhibition. Conformational comparison between dNM and CAST suggests the greater activity of CAST may be due to the fixed axial positioning of the O6 atom; the results have implications for the design of analogues for potential anti-HIV and other antiviral therapies.

1-Deoxynojirimycin↗
PubMed1992

A 3-year cohort study on short-term effects of air pollution in Germany. 1. Influences of medication and season.

A 3-year cohort study which started in September 1987 investigates the effect of air pollution in adult patients with chronic obstructive airway disease. Of 108 patients recruited during the pilot phase in 1987 only eight patients had left the study prematurely. The most important components of the study are the daily peakflow measurements and a diary on medication and symptoms. In a preliminary analysis the influence of medication and season has been analyzed for the period September 1988 to June 1989 for 53 patients. In general, the reactions to seasonal changes were small. However, a significant decrease in peak-flow values by about 5% was found for the months of May and June compared to December for patients with chronic bronchitis, emphysema and asthma.

Aged↗
PubMed1991

L-alanyl-L-alanyl-L-alanine: parallel pleated sheet arrangement in unhydrated crystal structure, and comparisons with the antiparallel sheet structure.

The tripeptide L-alanyl-L-alanyl-L-alanine has been crystallized from a water/dimethylformamide solution in an unhydrated form, with cell dimensions a = 11.849, b = 10.004, c = 9.862 A, beta = 101.30 degrees, monoclinic space group P21 with 4 molecules per cell (2 independent molecules in the asymmetric unit). The structure was determined by direct methods and refined to a discrepancy index R = 0.057. The tri-L-alanine molecules are packed in a parallel pleated sheet arrangement with unusually long amide nitrogen-carbonyl oxygen contacts within sheets. Comparisons are made with the antiparallel pleated sheet structure of tri-L-alanine hemihydrate, previously crystallized from the same solvent system.

Amino Acid Sequence↗
PubMed1990

[Treatment indications of hypertensive blood pressure dysregulation (a 7-year follow-up)].

The results of the present course investigations by means of bicycle ergometry over seven years on patients with vitality-limiting load hypertension in normotensive and initial situation of the borderline blood pressure, respectively, render necessary from the point of view of the authors an increase of the former indications to treatment. Situative measurement of blood pressure only at rest are hereby not sufficient and demand a bicycle-ergometric objectivation of the possible hypertensive dysregulation of blood pressure in patients with anamnestically restricted range of physical efficacy. In patients with exclusively under load increased vitality-limiting blood pressure values the ergometry represents the diagnostic method of choice.

Adult↗
PubMed1990

Age-dependent excretion of alanine aminopeptidase, alkaline phosphatase, gamma-glutamyltransferase and N-acetyl-beta-D-glucosaminidase in human urine.

Urinary excretion of alanine aminopeptidase, alkaline phosphatase, gamma-glutamyltransferase and N-acetyl-beta-D-glucosaminidase was determined in gel-filtered samples of morning random urine specimens of 442 subjects of various ages (5 days to 58 years). Enzyme excretion related to urinary creatinine (enzyme/creatinine ratio; U/mmol creatinine) significantly decreased with increasing age. Sex-related differences of some enzyme excretions were found in age groups over 6 years. From these investigations, we calculated upper reference intervals (97.5 percentiles) for 5 age-dependent groups of children and adolescents and for one group of adults.

Acetylglucosaminidase↗
PubMed1989

Crystallographic resolution and crystal and molecular structures of stereoisomers of 1,3,5-triglycidyl-s-triazinetrione.

The crystal and molecular structures of alpha and beta isomers of the antineoplastic alkylating agent 1,3,5-triglycidyl-s-triazinetrione (TGT) have been determined by X-ray diffraction. Although the isomers differ chemically only in the order of a carbon and an oxygen atom in one of the glycidyl epoxide rings, the molecular conformations and crystal packing arrangements are very different. The different physical and biological properties of the two stereoisomers can be explained on the basis of the structures. The sample of alpha-TGT was found to be a mixture of alpha and beta forms, and it is suggested that use of pure alpha-TGT may lead to better therapeutic results.

Chemical Phenomena↗
PubMed1988

Trimetrexate: molecular structures and conformational similarities in two crystal forms.

The structure of the non-classical quinazoline antifolate trimetrexate (TMQ) has been determined in two crystal forms, TMQ acetate monohydrate, and hydrated TMQ free base. Trimetrexate has an extended conformation in both structures, and the quinazoline and phenyl rings are mutually perpendicular. Protonation occurs at N1 in the acetate salt. The TMQ conformation is similar to corresponding parts of quinespar, the only other quinazoline antifolate structurally determined, and the hydrated strontium salt of methotrexate.

Antineoplastic Agents↗