[Analysis of adenyl cyclase-cyclic AMP in the thyroid glands of normal individuals and patients with Basedow's disease (I). Autoregulation of the human thyroid].
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Adenylyl Cyclases↗
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The emergence of body temperature biorhythm in preterm infants.
The biorhythm of body temperature was studied in five hospitalized, medically stable preterm infants, gestational age 30 to 34 weeks and postnatal age 5 to 10 days. Abdominal skin temperature, as well as incubator air temperature, were measured by thermistors and recorded at one-minute intervals throughout a 24-hour day using a computerized data acquisition system. Data were analyzed using autocorrelation, a form of time series analysis. A cyclic pattern of temperature was observed in three of the five subjects. The length of time of the cycles were two, three, and six hours. Incubator air temperature did not exhibit similar cyclicity, and it is therefore assumed that incubator operation is not responsible for the observed cyclic variation in infant temperature.
Air↗
Mitomycin antibiotic reductive potential and related pharmacological activities.
Relationships of reductive potential, kinetics of enzymatic reduction, augmented oxygen consumption, and cytotoxicity were determined for seven clinically relevant mitomycin antibiotics. Potentials for one-electron reduction were obtained by cyclic voltammetry analysis in dimethyl sulfoxide with 0.1 M tetraethyl-ammonium perchlorate. These potentials were -0.55 V for N7-acetylmitomycin C, -0.61 V for mitomycin A, -0.75 V for N7-(p-hydroxyphenyl)mitomycin C, -0.79 V for N7-(dimethylamino-methylene)mitomycin C, -0.81 V for N7-(2-(4-nitrophenyldithio)-ethyl)-mitomycin C, -0.81 V for mitomycin C, and -0.89 V for porfiromycin. All seven antibiotics were reduced by xanthine oxidase and NADPH-cytochrome P450 reductase, but the rate of reduction varied for each antibiotic and each enzyme. The less negative the reductive potential of an antibiotic, the more easily that antibiotic was reduced enzymatically. These seven mitomycin antibiotics also augmented oxygen consumption by rat liver microsomes. As with their reduction by xanthine oxidase and NADPH-cytochrome P450 reductase, the less negative the reductive potential of an antibiotic, the more it augmented oxygen consumption. Cytotoxicity of each antibiotic was assessed by defining the IC50 against HCT 116 human colon carcinoma cells. A relationship between the reductive potential of these antibiotics and their cytotoxicity against HCT 116 cells was also observed.
Animals↗
[Development of clinical physiology in heart surgery].
The article deals with the analysis of the monograph Evaluation of Performance and Analysis of Cyclic Work of the Heart written by B. A. Konstantinov, V. A. Sandrikov, and V. F. Yakovlev. It discusses the possible mechanism of the maintenance of the stability of hemodynamic indices--switching into action the contractions of nonfunctioning cardiomyocytes (the factor of functional heterogeneity).
Cardiac Surgical Procedures↗
Prescriptions in general practice.
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Administration, Topical↗
Cosine analysis of heart beat data of children in a stressful situation.
The EKG of twenty-four children (mean age = = 5.7 years) was individually and continuously recorded in a dental situation. Measures of cardiac activity (heart rate [HR] and heart rate variability [HRV]) were computed by means of a CDC 1,700 and an IBM 360 computer. Histograms of heart rate (HR) and heart rate variability (HRV) measures were generated. -Successive cosine fits were fitted for each 70 beats within an interval for each individual and these cosine fits were also presented in a histogram which represented a frequency analysis of cyclic functions within individuals. Within and between subject correlations were also computed for all measures. Sinus arrhythmia seemed to account for less of the variance than a yet unexplained cosine fit function having a lower limit of 18.6 seconds in this child population. In this population many measures of HRV seem to be negatively correlated with HR.
Arrhythmia, Sinus↗
[Pharmacological analysis of the interactions between cyclic nucleotides and beta-adrenergic and serotonin receptor agonists and antagonists].
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Adrenergic alpha-Agonists↗
Possible improvement in uteroplacental blood flow during atrial natriuretic peptide infusion in preeclampsia.
OBJECTIVE: To study the effects of low doses of the hormone atrial natriuretic peptide (ANP) on uteroplacental blood flow in patients with preeclampsia. METHODS: Eleven women with preeclampsia were infused intravenously with ANP (10 ng/kg/minute). Uteroplacental blood flow index was measured using dynamic placental scintigraphy with indium-113m. Regional blood flows were assessed by pulsed Doppler ultrasound and expressed as pulsatility index (PI). Hemodynamic measurements and blood sampling for peripheral venous plasma analysis of cyclic guanosine monophosphate (cGMP), an ANP second messenger, were performed before and after 30 minutes of infusion. Nonparametric statistics were used. RESULTS: The uteroplacental blood flow index increased by 28% (-2 to 58%; mean and 95% confidence interval). The Doppler findings were unaffected. Mean arterial blood pressure decreased from 112 (108-117) to 108 (103-114) mmHg (P < .01). Cyclic GMP increased significantly from 9.2 (6.2-12.3) to 17.4 (12.3-22.6) nmol/L (P < .01). Subjects exhibiting a substantial increase in uteroplacental blood flow index (25% or more) demonstrated a significantly greater cGMP response (P < .01) than those who did not (6% or less increase). CONCLUSION: A tendency to an increased uteroplacental blood flow index combined with minor blood pressure reduction after ANP infusion suggest the possibility of uteroplacental vasodilatation.
Adult↗
[Etoposide/cis-platinum (CDDP) combined chemotherapy for ovarian cancer: evaluation of optimum schedule for CDDP administration in chronic continuous exposure of ovarian cancer cells to low-dose etoposide in vitro].
Combined chemotherapy with etoposide and cis-platinum (CDDP) is considered a second line regimen for refractory cases of ovarian cancer. In addition to the time-dependent cytocidal kinetic of etoposide, much attention has been paid to low-dose continuous administration of etoposide. In this study, ovarian cancer cells (SHIN-3) were continuously exposed to low-dose etoposide in vitro to determine the optimum schedule for CDDP administration. Etoposide concentrations of 1-3 micrograms/ml were used; per os administration of etoposide at 25 mg x 2/day has been shown to produce a continuous plasma concentration of etoposide of around 1 microgram/ml. The results were as follows: 1) The IC50 of CDDP after 72 hours of exposure was 8.0 micrograms/ml and that of etoposide after 114 hours was 3.0 micrograms/ml. 2) After 100 hours of exposure to 1 microgram/ml of etoposide, cell cyclic phase analysis showed cells predominantly in G2/M phase arrest. 3) After 24-hour administration of CDDP, it was more than 24 hours before a cytocidal effect was observed. 4) During continuous exposure of SHIN-3 to etoposide (1 microgram/ml) for 6 days, CDDP was added on the 1st, 3rd, and 5th days. The largest ratio of growth inhibition with combined treatment to that with CDDP alone was attained on the 5th day. We conclude that, in combination regimens using low-dose continuous etoposide, CDDP should be added after etoposide administration is begun.
Administration, Oral↗
Changes in cardiac autonomic control during nocturnal repetitive oxygen desaturation episodes in patients with coronary artery disease.
BACKGROUND: Periodic fluctuations in respiration such as Cheyne-Stokes respiration or the sleep apnoea syndrome are known to be associated with very-low-frequency oscillations in heart rate (cycle times about 30-120s), which may be related to periodic changes in sympathetic and vagal tone. Since disturbances in cardiac sympathovagal balance have been associated with increased cardiovascular morbidity and mortality, especially in patients with coronary artery disease (CAD), we investigated changes in cardiac autonomic control in patients with CAD during periodic breathing episodes. METHODS: Thirty-five patients with a left ventricular ejection fraction (LVEF) of > 50% and 13 patients with an LVEF of < or = 35%, who were scheduled for coronary bypass surgery, were studied using a nocturnal Holter electrocardiograph (ECG) and pulse oximetric recordings. Heart rate variability was assessed by spectral analysis during cyclic oxygen desaturation episodes, indicating periodic breathing patterns, and during control episodes with normal oxygen saturation. RESULTS: Cyclic oxygen desaturation episodes with a duration of at least 20 min were observed in 17 patients with an LVEF of > 50% and in nine patients with an LVEF of < or = 35% (minimal oxygen saturation 83.9 +/- 3.1 versus 80.4 +/- 5.6%; cycle frequency between 0.0068 and 0.0294 Hz, no significant differences between groups), all of which were associated with very-low-frequency (0.0033-0.04 Hz) oscillations in the heart rate. During cyclic desaturation episodes patients with normal, as well as those with imparied left ventricular function, had marked increases (P < 0.01) in very low frequency power, low frequency (0.04-0.15 Hz) power and the ratio of low-to-high frequency (0.15-0.4 Hz) power. The low:high frequency ratio was significantly higher in patients with an LVEF of > 50% than in patients with an LVEF of < or = 35% during cyclic desaturation episodes, but not during control episodes. CONCLUSIONS: Repetitive oxygen desaturation episodes are associated with marked changes in heart rate variability which indicate cardiac sympathetic predominance in patients with CAD. Our results suggest differences in the modulation of cardiac sympathovagal balance during periodic breathing episodes between patients with normal and imparied left ventricular function.
Adult↗
Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells.
PURPOSE: To determine the mechanistic role for adenosine and adenosine receptors in the hypoxic induction of vascular endothelial growth factor (VEGF) in retinal microvascular cells. METHODS: Bovine retinal capillary endothelial cells and microvascular pericytes were studied under normoxic (95% air, 5% CO2) or hypoxic conditions (0% to 2% O2, 5% CO2, 93% to 95% N2) using a variety of well-characterized adenosine and adenosine receptor agonists and antagonists. Vascular endothelial growth factor mRNA expression was evaluated by Northern blot analysis, VEGF protein levels were determined by Western blot analysis, and cyclic adenosine monophosphate (cAMP) accumulation was measured by radioimmunoassay. RESULTS: Inhibitors of oxidative respiration increased VEGF mRNA 5 +/- 3 times (P < 0.001) after 3 hours. Adenosine A1 receptor (A1R) agonist N6-cyclopentyl-adenosine did not increase VEGF mRNA at A1R stimulatory concentrations; however, adenosine A2 receptor (A2R) agonists DPMA, NECA, and CGS21680 increased VEGF mRNA in a dose-dependent manner with elevations of 2 +/- 0.3 (P < 0.001), 2.3 +/- 0.5 (P = 0.016), and 2 +/- 0.2 (P = 0.002) times, respectively. A2R antagonist CSC and adenosine degradation by adenosine deaminase reduced hypoxic stimulation of VEGF mRNA 68% +/- 18% (P = 0.038) and 37% +/- 6% (P = 0.025), respectively, in a dose-dependent manner. A1R antagonists DPCPX and 8-PT had no significant effect. Hypoxia and NECA increased VEGF protein secretion 4.7 times, whereas CSC inhibited hypoxia-induced VEGF protein secretion by 96%. NECA and CGS21680 increased cAMP production within 10 minutes, and cAMP stimulation increased VEGF mRNA 4.8 +/- 2.6 times (P = 0.034). CSC suppressed the hypoxic elevation of cAMP (P < 0.05). Inhibition of protein kinase A using H-89 reduced hypoxia-induced VEGF expression 61% +/- 6.3% (P = 0.043) in a dose-dependent manner. CONCLUSIONS: These data suggest that the hypoxia-induced accumulation of adenosine stimulates VEGF gene expression through stimulation of adenosine A2a receptor and subsequent activation of the cAMP-dependent protein kinase A pathway in retinal vascular cells.
Adenosine↗
The Rv0805 gene from Mycobacterium tuberculosis encodes a 3',5'-cyclic nucleotide phosphodiesterase: biochemical and mutational analysis.
Mycobacterium tuberculosis is an important human pathogen and has developed sophisticated mechanisms to evade the host immune system. These could involve the use of cyclic nucleotide-dependent signaling systems, since the M. tuberculosis genome encodes a large number of functional adenylyl cyclases. Using bioinformatic approaches, we identify, clone, and biochemically characterize the Rv0805 gene product, the first cyclic nucleotide phosphodiesterase identified in M. tuberculosis and a homologue of the cAMP phosphodiesterase present in Escherichia coli (cpdA). The Rv0805 gene product, a class III phosphodiesterase, is a member of the metallophosphoesterase family, and computational modeling and mutational analyses indicate that the protein possesses interesting properties not reported earlier in this class of enzymes. Mutational analysis of critical histidine and aspartate residues predicted to be essential for metal coordination reduced catalytic activity by 90-50%, and several mutant proteins showed sigmoidal kinetics with respect to Mn in contrast to the wild-type enzyme. Mutation of an asparagine residue in the GNHD motif that is conserved throughout the metallophosphoesterase enzymes almost completely abolished catalytic activity, and these studies therefore represent the first mutational analysis of this class of phosphodiesterases. The Rv0805 protein hydrolyzes cAMP and cGMP in vitro, and overexpression in Mycobacterium smegmatis and E. coli reduces intracellular cAMP levels. The presence of an orthologue of Rv0805 in Mycobacterium leprae suggests that the Rv0805 protein could have an important role to play in regulating cAMP levels in these bacteria and adds an additional level of complexity to cyclic nucleotide signaling in this organism.
3',5'-Cyclic-AMP Phosphodiesterases↗
Gas chromatography-mass spectrometry and gas chromatography-tandem mass spectrometry of cyclic fatty acid monomers isolated from heated fats.
The analysis of hydrogenated cyclic fatty acid monomers isolated from heated linseed and sunflower oils is achieved by gas chromatography-tandem mass spectrometry of their pentafluorobenzyl esters. Collisionally activated dissociation of the carboxylate anions produced by electron-capture ionization shows remote charge-site fragmentation that allows location of cyclopentane and cyclohexane rings by examining the resulting mass-analysed ion kinetic energy spectra. Oxidative ozonolysis of the methyl esters of the unsaturated cyclic fatty acid monomers allows location of some double bonds. However, preliminary results obtained with remote charge fragmentation of synthetic unsaturated models make this approach an alternative for double bond location in the cyclic fatty acid monomers isolated from heated fats.
Cyclopentanes↗
Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: analysis by multiple indicator dilution method.
Rilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1 (Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution method. The hepatic availabilities (F) of DG and M1, assessed from the recovery into the hepatic vein, were 0.16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first-pass elimination of M1 was greater than that of DG. The kinetic analysis based on the distributed model showed that the influx (k'1) and efflux (k'2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k'3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k'2 for each ligand were much smaller than the respective k'3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.
Administration, Oral↗
A multivariate factor analysis of the high plasma concentration of cyclic AMP in patients with chronic renal failure.
The concentration of cyclic AMP which is known as an intracellular mediator of hormone action increased in the plasma of patients with chronic renal failure (CRF). In the present study, the plasma concentration of cyclic AMP significantly correlated not only with serum, creatinine, and urea levels, but also with plasma PTH and glucagon in patients with CRF. Furthermore, plasma concentrations of PTH and glucagon correlated with the serum creatinine concentration to a significant extent. To discuss the cause of the increased cyclic AMP concentration in plasma of patients with CRF, multivariate analyses were carried out on the obtained clinical data from patients and normal subjects. In the factor analysis on the clinical data from 61 subjects, cyclic AMP, creatinine and BUN correlated with the first factor and PTH correlated with the second factor. The cumulative contribution ratio by the second factor was 76%. The results of the cluster analysis indicated that cyclic AMP, creatinine, and BUN formed a cluster and PTH glucagon made another cluster. These results suggest that the elevated plasma concentration of cyclic AMP in patients with CRF was mainly introduced not by overproduction but by the retention of cyclic AMP due to the decreased renal function.
Adult↗
Mass spectrometric analysis of head-to-tail connected cyclic peptides.
Tandem mass spectrometry is an extremely useful tool for high sensitive sequence identification of peptides. In the case of cyclic peptides fragmentation can easily be performed for sequence analysis. However, analysis is usually tedious due to the lack of a defined beginning and end of the sequence. Since cyclic peptides are a highly interesting class of compounds especially for the pharmaceutical industry, ways have to be found to identify their strictures. In this work we demonstrate how software and dedicated analytical strategies can be used for detailed analysis of these substances.
Biochemistry↗
Synthesis of a cyclic fibrin-like peptide and its analysis by fast atom bombardment mass spectrometry.
For immunochemical purposes, a cyclic 12-peptide was synthesized to model the gamma-gamma-chain cross-link site in human fibrin. The model was based upon the structure proposed by Chen & Doolittle (Biochemistry (1971) 10, 4486-4491) which is characterized by two reciprocating epsilon-(gamma-Glu)Lys bonds between adjacent fibrin gamma-chains oriented in an antiparallel manner. To achieve the antiparallel orientation of the peptide backbone, Pro and Gly were inserted at positions 6 and 7 of the linear 12-peptide: acetyl-Gly-Glu-Gln-His-His-Pro-Gly-Gly-Gly-Ala-Lys-Gly-amide. The insertions were made to facilitate a reverse turn of the peptide during the last synthetic step, which was formation of the epsilon-(gamma-Glu)Lys bond between Glu at position 2 and Lys at position 11 with diphenylphosphorylazide. The resulting cyclic peptide represented half of the symmetrical cross-linked region in clotted fibrin. Following purification by HPLC, both linear and cyclic 12-peptides were analyzed by fast atom bombardment mass spectrometry. Abundant molecular protonated ions were observed for both peptides. In addition, the amino acid sequence of the linear peptide and the location of the epsilon-(gamma-Glu)Lys bond in the cyclized peptide could be verified.
Amino Acid Sequence↗
Emergence of cyclic guanosine 3':5'-monophosphate-dependent protein kinase immunoreactivity in developing rhesus monkey cerebellum: correlative immunocytochemical and electron microscopic analysis.
The appearance of cyclic guanosine 3':5'-monophosphate-dependent protein kinase (cGK), an enzyme that may be involved in the regulation of various aspects of neuronal function and that is highly concentrated in cerebellar Purkinje cells, was studied in the developing and adult monkey cerebellum by indirect immunofluorescent staining. The appearance and distribution of cGK immunoreactivity were then correlated with the stages of Purkinje cell differentiation and with the establishment of synaptic inputs to Purkinje cells as revealed by electron microscopy and by the presence of synapsin I, a specific nerve terminal marker. In the adult monkey, in analogy with previous observations in the adult rat, cGK immunoreactivity was detected throughout the cytoplasm of all Purkinje cells and was not seen in other neurons. During ontogenesis, cGK immunoreactivity appeared for the first time in Purkinje cells at the 97th embryonic day (E97). On this day it was detectable in Purkinje cells situated in the posterior lobe concurrently with the emergence of synapsin I immunoreactivity surrounding their somata. The cGK-positive cells had entered the phase of rapid dendritic growth and had begun establishing axosomatic synapses. By E102, Purkinje cells in the posterior lobe and in most of the anterior lobe were cGK positive. By E125, all Purkinje cells had received synaptic contacts and had become cGK positive. In addition to typical Purkinje cells situated in the cortex, we found another population of cGK-positive neurons present transiently in the prospective cerebellar white matter. These neurons, which were observed only during the second half of gestation, had morphological similarities to Purkinje cells. The emergence of cGK in these neurons also coincided with their dendritic proliferation and with the appearance of synapsin I immunoreactivity around their cell bodies. Subcortical cGK-positive cells were not observed in postnatal animals. Such neurons may be Purkinje cells which, failing to reach the cortical plate, subsequently degenerate. The close temporal correlation between appearance of cGK immunoreactivity, onset of synaptic inputs, and dendritic proliferation, both in typical Purkinje cells and in the Purkinje cell-like cells in subcortical areas, suggests that expression of high levels of cGK may be an important aspect of the neuronal differentiation of these cells.
Animals↗