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Biomedical subjects

B Mayer

Publications and source records attributed to B Mayer.

At least 127 records · Page 7Linked to original sources
PubMed1998

Arginine availability controls the N-methyl-D-aspartate-induced nitric oxide synthesis: involvement of a glial-neuronal arginine transfer.

The neuronal nitric oxide (NO) synthase generates NO from arginine. NO mediates its physiological effects mainly by stimulating the synthesis of cyclic GMP. We have investigated the role of the arginine availability on the NMDA-induced cyclic GMP accumulation in immature rat brain slices. The effect of NMDA was blocked by the inhibitor of the NO synthase, N(G)-nitro-L-arginine, and by the antagonist of ionotropic non-NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This inhibition was not due to a direct interaction of CNQX with the NMDA receptor, and it was overcome by the presence of exogenously applied arginine. CNQX also blocked the NMDA-evoked release of [3H]arginine from cerebellar slices. Moreover, the arginine uptake inhibitor L-lysine reduced the cyclic GMP response to NMDA significantly. Therefore, the extracellular arginine availability, which is dependent on the activation of ionotropic non-NMDA receptors, determines the rate of the NO biosynthesis by the neuronal NO synthase. Together with the reported release of arginine from glial cells upon activation of glial ionotropic non-NMDA receptors and the predominant glial localization of arginine, these data provide the first evidence of an essential role of the arginine transfer from glial cells to neurons for the biosynthesis of NO.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1998

Molecular actions of a Mn(III)Porphyrin superoxide dismutase mimetic and peroxynitrite scavenger: reaction with nitric oxide and direct inhibition of NO synthase and soluble guanylyl cyclase.

Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), described as a superoxide dismutase mimetic and peroxynitrite scavenger, has been used previously to investigate the cytotoxic potential of superoxide and peroxynitrite in several pathological models. Here we report on the interference of MnTMPyP with NO/cGMP signaling using cultured endothelial cells as well as purified soluble guanylyl cyclase (sGC) either activated by the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine sodium salt (DEA/NO) or reconstituted with nitric oxide synthase (NOS). MnTMPyP inhibited endothelial cGMP accumulation induced by A23187 (0.3 microM) with an IC50 of 75.0 +/- 10.4 microM but had no significant effect on the potency of the Ca2+ ionophore. Purified NOS was inhibited by MnTMPyP (IC50 = 5.5 +/- 0.8 microM) because of an interference of the Mn-porphyrin with the reductase domain of the enzyme. The most pronounced actions of MnTMPyP were direct inhibition of sGC and scavenging of NO. Purified sGC stimulated with either Ca2+/calmodulin-activated NOS (in the presence of GSH) or DEA/NO (in the absence of GSH) was inhibited with IC50 values of 0.8 +/- 0.09 microM and 0.6 +/- 0.2 microM, respectively. In the presence of GSH, MnTMPyP was reduced to the Mn(II) complex, resulting in efficient scavenging of NO under these conditions. Our data demonstrate that MnTMPyP (i) interferes with the reductase domain of NOS, (ii) scavenges NO in the presence of GSH, and (iii) is a potent direct inhibitor of sGC. These results cast doubt on the usefulness of MnTMPyP and related Mn-porphyrin complexes as probes to study the involvement of peroxynitrite/superoxide in biological systems.

Animals↗
PubMed1998

Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione.

Soluble guanylyl cyclase (sGC) is the major physiological target of sydnonimine-based vasodilators such as molsidomine. Decomposition of sydnonimines results in the stoichiometric formation of nitric oxide (NO) and superoxide (O2-), which rapidly react to form peroxynitrite. Inasmuch as sGC is activated by NO but not by peroxynitrite, we investigated the mechanisms underlying sGC activation by 3-morpholinosydnonimine (SIN-1). Stimulation of purified bovine lung sGC by SIN-1 was found to be strongly dependent on glutathione (GSH). By contrast, GSH did not affect sGC activation by NO released from 2,2-diethyl-1-nitroso-oxyhydrazine, indicating that NO/O2- released from SIN-1 converted GSH to an activator of sGC. High performance liquid chromatography identified this product as the thionitrite S-nitrosoglutathione. Further, the reaction product decomposed to release NO upon addition of Cu(NO3)2 in the presence of GSH. Activation of sGC was antagonized by the Cu(I)-specific chelator neocuproine, whereas the Cu(II)-selective drug cuprizone was less potent. Carbon dioxide (delivered as NaHCO3) antagonized S-nitrosation by peroxynitrite but not by SIN-1. Thus, NO/O2- released from SIN-1 mediates a CO2-insensitive conversion of GSH to S-nitrosoglutathione, a thionitrite that activates sGC via trace metal-catalyzed release of NO. These results may provide novel insights into the molecular mechanism underlying the nitrovasodilator action of SIN-1.

Animals↗
PubMed1998

Beta adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics.

OBJECTIVE: To examine the effect of concomitant intake of beta blockers with angiotensin converting enzyme (ACE) inhibitors, diuretics, or both on plasma renin concentrations in a population based sample (MONICA survey, Augsburg, Germany). SUBJECT AND METHODS: 728 individuals were studied, of whom 171 were treated using monotherapy (ACE inhibitor (n = 21), diuretic (n = 10), or beta blocker (n = 72)), or combination treatment (ACE inhibitor + diuretic (n = 32), ACE inhibitor + beta blocker (n = 7), diuretic + beta blocker (n = 22), ACE inhibitor + diuretic + beta blocker (n = 7)). The remaining 557 individuals were untreated. Indications for treatment were hypertension (75%), coronary artery disease with (12%) or without (3%) hypertension, or unknown (10%). RESULTS: Mean (SEM) renin concentrations in individuals treated with an ACE inhibitor (41 (8) mU/l), a diuretic (41 (10) mU/l), or the combination of an ACE inhibitor and a diuretic (54 (10) mU/l) were raised compared with untreated individuals (17 (1) mU/l; p < 0.05 each). Monotherapy with a beta blocker, however, decreased mean renin concentrations (12 (1) mU/l; p < 0.01 v untreated). Renin concentrations in individuals taking a beta blocker with either an ACE inhibitor (21 (8) mU/l), or a diuretic (22 (4) mU/l), or with both an ACE inhibitor and a diuretic (21 (7) mU/L), were significantly lower compared with renin concentrations in groups not receiving beta blocker treatment (p < 0.05 each). CONCLUSION: These data suggest that the upregulation of renin by treatment with ACE inhibitors, diuretics, or both can be largely prevented by concomitant beta blocker treatment.

Adrenergic beta-Antagonists↗
PubMed1998

Tetrahydrobiopterin, cytokines, and nitric oxide synthesis.

Nitric oxide synthases require a surprisingly rich selection of cofactors to perform the conversion of L-arginine to citrulline and nitric oxide (NO): NADPH, FAD, FMN, heme and tetrahydrobiopterin. In a previous minireview in this journal we summarized work concerning the induction of tetrahydrobiopterin biosynthesis by cytokines, which yields increased intracellular tetrahydrobiopterin concentrations supporting NO formation by intact cells (P.S.E.B.M. 203:1-12). The present review updates work on the induction of tetrahydrobiopterin biosynthesis by cytokines, and summarizes recent advances in research of tetrahydrobiopterin dependence of the NO synthase reaction. Studies using recombinant NO synthases and site-directed mutations thereof have localized several amino acids critical for tetrahydrobiopterin binding, which are discussed in reference to the recently published crystal structure of the dimer of the oxygenase domain of murine inducible NO synthase with substrate and pterin. Allosteric actions of tetrahydrobiopterin on NO synthases are stabilization of dimers, stabilization of a conformation with high-spin heme iron, and support of binding of the substrate L-arginine. Since the 4-amino analog of tetrahydrobiopterin, which is a dihydropteridine reductase inhibitor, supports these allosteric actions but inhibits the enzyme activity, tetrahydrobiopterin appears to play a redox-active role in stimulating the NO synthase reaction in addition to its allosteric actions on NO synthases. Amelioration of endothelial dysfunction by tetrahydrobiopterin in animal models and in humans in vivo has been observed. It remains to be investigated, however, to what extent the role of tetrahydrobiopterin as cofactor of NO synthases contributes to these in vivo effects of tetrahydrobiopterin.

Animals↗
PubMed1998

Dilemmas in mandatory reporting of domestic violence: carative ethics in emergency rooms.

Laws are clear when it comes to reporting child abuse, elder abuse, or maltreatment of the disabeled; however, the fuzzy area of domestic violence, or injury to women by their husbands or intimates, puzzles the system ethically and legally. Experts are divided on the issue of mandatory reporting of domestic violence by health care professionals. As exemplified by the Florida law, the crux of the problem may be twofold. First, the law requires reporting of certain incidents that are ambiguously defined. Second, reporting may be mandatory without the patient's consent. Many experts in the field of domestic violence suggest that mandated reporting by health care workers is not in the best interests of the victims; it may lead to more violence and increase the victim's reluctance to get needed health care. This victim vulnerability creates ethical dilemmas in the emergency department, often the first outside contact after a violent incident. This paper examines the implications of reporting applied to emergency practice in the context of basic ethical standards. The application of mandatory reporting laws to competent adult victims presents questions related to nonmaleficence, beneficence, autonomy, confidentiality, and a variety of contextual issues that arise from these main ethical domains.

Adult↗
PubMed1998

[Expression of Lewis blood group antigens in stomach carcinoma induces metastatic potential].

In a series of gastric cancer patients twenty-eight percent of the primary tumors expressed high levels of the Lewis carbohydrate. This correlated significantly with clinicopathological parameters of advanced disease (tumor size of > 50 mm, M1 stage, UICC stage IIIB/IV). In multivariate analysis, high Lewis expression was found to be a new independent factor of poor prognosis. In addition, Lewis was expressed on solid metastases and micrometastatic cells originating from Lewis positive primary tumors. The data suggest that Lewis positive tumor cells may have an advantage in penetrating secondary organs because, like leukocytes, they can specifically adhere to activated vascular endothelia.

Animals↗
PubMed1998

The distribution of nitric oxide synthase-I and NADPH-diaphorase containing neurons in the cerebral cortex of different strains of mice and its association with learning and memory.

We investigated the distribution of nitric oxide synthase-I (NOS-I) containing neurons within the neocortex of inbred mice belonging to the Balb/c, NMRI and DBA/2 strains which differ in learning and memory performance. The NOS-I positive neurons were detected immunohistochemically with antibodies against NOS-I and enzyme histochemically using their NADPH-diaphorase (NADPH-d) activity. The qualitative and quantitative evaluation of cortical NADPH-d and NOS-I containing neurons revealed that more than 95% of these cells contained both enzymes. Therefore, we combined the NADPH-d with the WFA-staining to evaluate and parcellate at one section. The specific differences in learning and memory tasks of the three mouse strains have been tested in previous studies. Our investigation test the hypothesis that differences in various aspects of eight-arm radial maze learning are associated with differences in the density of NOS-I positive neurons in cytoarchitectonically and functionally identified cortical areas. We found an increased density of NADPH-d neurons within the whole neocortex in the DBA/2 strain, which reached a lower learning score than the Balb/c and NMRI strains. Significantly higher densities of NADPH-d neurons appeared in the areas of the gustatory cortex, the piriform cortex, the entorhinal cortex and in area 1 of the temporal cortex in DBA/2 mice. A negative correlation exists between the learning scores and the number of NADPH-d positive neurons. If NOS-I activity influences spatial learning as determined in the eight-arm radial maze, the areas with strongly elevated NADPH-d positive neurons may demarcate task-related cortical areas affected in mice with a reduced learning capacity.

Animals↗
PubMed1998

Comparison of models used for UV index calculations.

Eighteen radiative transfer models in use for calculation of UV index are compared with respect to their results for more that 100 cloud-free atmospheres, which describe present, possible future and extreme conditions. The comparison includes six multiple-scattering spectral models, eight fast spectral models and four empirical models. Averages of the results of the six participating multiple-scattering spectral models are taken as a basis for assessment. The agreement among the multiple-scattering models is within +/- 0.5 UV index values for more than 80% of chosen atmospheric parameters. The fast spectral models have very different agreement, between +/- 1 and up to 12 UV index values. The results of the empirical models agree reasonably well with the reference models but only for the atmospheres for which they have been developed. The data to describe the atmospheric conditions, which are used for the comparison, together with the individual results of all participating models and model descriptions are available on the Internet: http://www.meteo.physik.uni-muenchen.de/++ +strahlung/cost/.

Computer Simulation↗
PubMed1998

The versatile and complex enzymology of nitric oxide synthase.

The biogenesis of nitric oxide is catalyzed by nitric oxide synthase (NOS) which forms L-citrulline and NO from L-arginine. Here we review the enzymology of NOS. We discuss its modular structure, its prosthetic groups and cofactors, and we provide a brief account of present knowledge regarding cellular targeting and regulation of the different isoforms. The various reactions which are catalyzed by NOS are reviewed, and an inventory of different inhibitor types is given. Special attention is paid to the role of the cofactor tetrahydrobiopterin (BH4) and of the dimeric structure, and to the possibility that the main product of NOS catalysis under some conditions may not be NO. Based on a number of recent observations, we postulate that neuronal NOS with one equivalent of BH4 per dimer (a state which may be physiologically relevant) catalyzes the concerted formation of peroxynitrite.

Animals↗
PubMed1998

Continuous renal replacement therapy. A national perspective AACN/NKF.

Health care providers rely on quality continuing education programs to increase their knowledge and to acquire new skills. Participation in programs such as CVVH: Implications for Clinical Practice-the Patient, the Circuit, the Team can potentially improve patient outcomes. While this study identifies critical care nurses as a receptive professional group for further CRRT training, it also indicates that additional education in this topic may benefit other members of the critical care team as well. Therefore, because the critical care nurse's role, while crucial to the clinical management of patients undergoing CRRT, does not include prescribing or initiating CRRT therapy, it is difficult to predict the impact of future workshops on the increased and sustained use of CRRT in critical care arenas. If you would like additional information on CVVH: Implications for Practice-the Patient, the Circuit, the Team, please contact the National Kidney Foundation at (800) 622-9010, or the American Association of Critical Care Nurses at (800) 899-2226.

Acute Kidney Injury↗
PubMed1997

Allosteric modulation of rat brain nitric oxide synthase by the pterin-site enzyme inhibitor 4-aminotetrahydrobiopterin.

We investigated the functional and allosteric effects of the 4-amino analogue of tetrahydrobiopterin, (6R)-2,4-diamino- 5,6,7,8-tetrahydro-6-(L-erythro-1,2-dihydroxypropyl) pteridine (4-amino-H4biopterin) on pteridine-free rat neuronal nitric oxide synthase. In the presence of added (6R)-5,6,7,8-tetrahydro-L-erythrobiopterin (H4biopterin; 10 microM), 4-amino-H4biopterin completely inhibited the conversion of both L-arginine and NG-hydroxy-L-arginine with half-maximally effective concentrations of 1.1+/-0.09 and 1.3+/-0.09 microM, respectively. Inhibition was reversible, as shown by a time-dependent restoration of citrulline formation upon dilution of the inhibitor-treated enzyme (t1/2=3.0 min). Binding of 4-amino-H4biopterin led to a complete conversion of the haem from low-spin to high-spin state, and to the formation of stable homodimers which partially survived electrophoresis under denaturating conditions. These results show that oxidation of both L-arginine and NG-hydroxy-L-arginine is pteridine-dependent, and that the allosteric effects of H4biopterin do not fully explain the essential role of the pteridine cofactor in nitric oxide biosynthesis.

Allosteric Regulation↗
PubMed1997

Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit.

The DNA-dependent protein kinase (DNA-PK) controls the repair of double-stranded DNA breaks in mammalian cells. The protein kinase subunit of DNA-PK (DNA-PKcs) is targeted to DNA breaks by association with the Ku DNA-binding heterodimer. Here we show that a Ku association site is present at the carboxyl terminus of DNA-PKcs (amino acids 3002-3850) near the protein kinase domain. Correspondingly, the nuclear c-Abl tyrosine kinase that associates with DNA-PK also binds to the kinase homology domain. The c-Abl SH3 domain binds to amino acids 3414-3850 of DNA-PKcs. c-Abl phosphorylates C-terminal fragments of DNA-PKcs, particularly amino acids 3414-3850. c-Abl phosphorylation of DNA-PKcs disassociates the DNA-PKcs.Ku complex. Thus, Ku and c-Abl provide opposing functions with regard to DNA-PK activity.

Animals↗
PubMed1997

Analysis of neuronal NO synthase under single-turnover conditions: conversion of Nomega-hydroxyarginine to nitric oxide and citrulline.

Nitric oxide synthases (NOSs) are proposed to generate NO and citrulline from L-arginine in two steps: initial N-hydroxylation to generate Nomega-hydroxyarginine (NOHA) followed by a three-electron oxidation of the hydroxylated nitrogen to form products. Both steps consume NADPH and may involve heme iron-based activation of O2. Studies done under multiple-turnover conditions suggest that 0.5 mol of NADPH is consumed to convert 1 mol of NOHA to products, implying that one electron from NADPH may be sufficient. To test this, we studied NOHA oxidation under single-turnover conditions using neuronal NOS (nNOS), whose heme iron reduction requires bound calmodulin. The heme iron in calmodulin-bound nNOS was reduced with excess NADPH under anaerobic conditions, calmodulin was then dissociated from nNOS to prevent subsequent heme iron reduction, NOHA was added, and the reaction initiated by exposure to air. Spectra obtained at each step were consistent with buildup of NOHA-bound ferrous nNOS prior to air exposure. Reactions containing graded amounts of nNOS produced L-citrulline in linear relation (1.2 +/- 0.1 mol of citrulline per mole of nNOS). Nitrite and nitrate also accumulated as NO-derived products. Control reactions that contained L-arginine instead of NOHA, no enzyme, or ferric nNOS did not generate products. Thus supplying a single electron from NADPH to the heme iron permits nNOS to catalyze one full round of citrulline and NO synthesis from NOHA upon exposure to O2. These data provide a molecular explanation for the NADPH requirement in the second step of the biosynthetic reaction, implicate ferrous-dioxy nNOS as a critical reactant in that step, and eliminate a number of possible alternative catalytic mechanisms or products.

Animals↗