Carvedilol: a beta blocker with antioxidant property protects against gentamicin-induced nephrotoxicity in rats

Gentamicin is an antibiotic effective against gram negative infections, whose clinical use is limited by its nephrotoxicity. Since the pathogenesis of gentamicin-induced nephrotoxicity involves oxygen free radicals, the antioxidant carvedilol may protect against gentamicin-induced renal toxicity. We therefore tested this hypothesis using a rat model of gentamicin nephrotoxicity. Carvedilol (2 mg/kg) was administered intraperitoneally 3 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA) were carried out, after the last dose of gentamicin. Kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity as evidenced by increase in blood urea, serum creatinine and decreased in creatinine clearance. Blood urea and serum creatinine was increased by 883% and 480% respectively with gentamicin compared to control. Carvedilol protected the rats from gentamicin induced nephrotoxicity. Rise in blood urea, serum creatinine and decrease in creatinine clearance was significantly prevented by carvedilol. There was 190% and 377% rise in plasma and kidney tissue MDA with gentamicin. Carvedilol prevented the gentamicin induced rise in both plasma and kidney tissue MDA. Kidney from gentamicin treated rats, histologically showed necrosis and desquamation of tubular epithelial cells in renal cortex, whereas it was very much comparable to control with carvedilol. In conclusion, carvedilol with its antioxidant property protected the rats from gentamicin-induced nephrotoxicity.     

Exercise capacity, energy metabolism, and beta-adrenoceptor blockade. Comparison between a beta 1-selective and a non-selective beta blocker

The effects of beta 1 and beta 1/2 blockade on exercise capacity were studied in 9 healthy normotensive subjects. Progressive maximal bicycle ergometer tests, followed by an endurance test at 80% of maximal work load, were performed during randomized, double-blind 3 day treatment periods with placebo, atenolol (beta 1) and oxprenolol (beta 1/2). The reduction of maximal work capacity (ca. 10%) was similar with atenolol and oxprenolol, despite a more pronounced maximal heart rate reduction with atenolol (from 175 +/- 2 to 132 +/- 3 beats.min-1) than with oxprenolol (to 138 +/- 2 beats.min-1). Exercise time during the endurance test was reduced from 36 +/- 4 min with placebo to 27 +/- 3 min with atenolol (p less than 0.05) and 24 +/- 3 min with oxprenolol (p less than 0.01) (atenolol vs. oxprenolol: p less than 0.05). During the endurance test, plasma glycerol and non-esterified fatty acid concentrations were reduced with both atenolol and oxprenolol. The glycerol reduction was more pronounced with oxprenolol than with atenolol, plasma NEFA concentrations being similar. Plasma glucose and lactate concentrations were reduced by oxprenolol but not with atenolol. These data show that submaximal exercise capacity at work loads representing similar relative exercise intensities is reduced during non-selective and beta 1-selective beta blockade. This reduction may be related to the effects of beta 1 blockade on energy metabolism, with possibly an additional effect of beta 2 blockade.     

A novel three-dimensional hybrid framework based on fishbone-like copper halide inorganic units

A novel inorganic-organic hybrid cuprous chloride, , has been hydrothermally synthesized and structurally characterized by the elemental analyses, IR spectrum, TG analysis and the single crystal X-ray diffraction. The structure of 1 exhibits a three-dimensional network built up from unusual fishbone-like copper(I) chloride ribbons bridged by linear isonicotinato ligands. Its luminescent property was also investigated.     

A charge-deficient analogue of spermine with chelating properties

1,12-Diamino-3,6,9-triazadodecane, a new isosteric and charge-deficient analogue of spermine, is synthesized. Unlike spermine, the new analogue is an excellent chelator of Cu2+ ions. Possible applications of this compound for studying enzymes of polyamine metabolism and cellular functions of spermine are discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.     

A click procedure with heterogeneous copper to tether technetium-99m chelating agents and rhenium complexes. Evaluation of the chelating properties and biodistribution of the new radiolabelled glucose conjugates

An efficient protocol was developed to tether chelating agents and rhenium complexes onto a glucoside scaffold with a heterogeneous copper catalyst via click chemistry. The supported catalyst avoids the formation of unwanted copper complexes during the cyclisation step. The possibility to graft a pre-chelated M(CO)₃ core by click chemistry onto a biomolecule was highlighted for the first time. ^99mTc(CO)₃-glucoconjugates displayed excellent in vitro stability, a fast in vivo blood clearance and a low specific organ uptake or long-term retention in spleen and stomach.     

DNA strand breaks and mutations caused by penbutolol, a beta blocker

Sixteen beta-adrenergic receptor blockers were screened for their mutagenic potential using Salmonella typhimurium strains TA98 and TA100. All except penbutolol were found to be nonmutagenic. Penbutolol was cytotoxic to human fibroblasts and Chinese hamster V79 cells. These effects could be due to its ability to induce DNA-strand breaks detected by hydroxyapatite chromatography, which remained unrepaired within 1 h of incubation. Under the same conditions strand-breaking activity of propranolol, timolol and indenolol could not be detected. Three potential impurities of penbutolol were ineffective in causing DNA-strand breakage and one metabolite of this drug was found to be nonmutagenic.     

A simple,cheap but reliable method for evaluation of zinc chelating properties

BackgroundZinc is an essential trace element. Both its lack and excess are associated with pathological states. The former is more common and can ensue from the excessive treatment with clinically used iron/copper chelators.Aim and methodThe aim of this work was to prepare a reliable, rapid and cheap method for the screening of zinc chelation. Spectrophotometric assessment using a known zinc indicator dithizone was selected.ResultsInitial screening performed by comparison of spectra of dithizone and its complex with zinc suggested 530 and 570 nm as suitable wavelengths for determination of zinc at pH 4.5 while 540 and 590 nm for pH 5.5–7.5. Additional research showed the lower wavelengths to be more suitable. The sensitivity of the method was always bellow 1 μM with good linearity relationship between absorbance and zinc concentration. The method suitability was confirmed by use of two known zinc chelators, ethylenediaminetetraacetic acid (EDTA) and N,N,N′,N′-tetrakis(2-pyridylmethyl)-1,2-ethylenediamine (TPEN).ConclusionThis method represents a sufficiently precise method for zinc chelation screening usable at pathophysiologically relevant pH conditions. Such method can be employed for both screening of novel zinc chelators and for testing affinity of other metal chelators for zinc.     

CGS 7525A, a new, centrally active alpha 2 adrenoceptor antagonist

CGS 7525A, a new tetracyclic compound, was evaluated for alpha 2 adrenoceptor antagonism in receptor binding assays and in behavioral and electrophysiological tests. 3H-Clonidine, but not 3H-prazosin, binding was potently inhibited in vitro by CGS 7525A. In vivo, CGS 7525A attenuated the suppressant action of clonidine on phenylquinone-induced writhing and on locus coeruleus neuronal firing rate. Mianserin was nearly equipotent with CGS 7525A in the 3H-clonidine binding assay, but considerably less potent in the measures of alpha 2 adrenoceptor antagonism in vivo. Both CGS 7525A and mianserin displaced 3H-spiroperidol binding from frontal cortex 5-HT2 binding sites. Although yohimbine resembled CGS 7525A in most respects, its activity at 5-HT2 binding sites was relatively low, CGS 7525A was not associated with any appreciable blockade of norepinephrine or serotonin uptake in vitro. Thus, CGS 7525A appears to be a promising new pharmacological tool for investigating the behavioral function of brain alpha 2 adrenoceptors.     

Higher aliphatic 2,4-diketones: a ubiquitous lipid class with chelating properties, in search of a physiological function

A group of homologous 2,4-diketones with chain lengths from C13 to C25, derived from fatty acids, is present in human and mammalian tissues and urine. The presence of this lipid class, members of which possess marked chelating properties, adequately accounts for the well-documented antiallergic activity of tissue and urine extracts on isolated smooth muscle preparations and in guinea pigs in vivo. This review summarizes the investigations leading to the discovery of this lipid class. It is postulated that the observed antiallergic activity of 2,4-diketones may be explained by the intracellular sequestration of calcium ions transiently liberated from intracellular storage pools after an agonist-receptor interaction, thus blocking response to the agonist. The true physiological function (or functions) of this lipid class has not been defined. The chelating properties of 2,4-diketones suggest their involvement in intracellular ionic interactions.     

Basal fat oxidation and after a peak oxygen consumption test in obese women with a beta2 adrenoceptor gene polymorphism

The Glu27Glu genotype in the beta2-adrenergic receptor (ADRB2) has been linked to a higher fat deposition and obesity in females. Also, in our population, it has been described that physically active women carrying the Glu allele had a higher BMI as compared to non-carriers performing the same level of activity. Since exercise may counterbalance a gene predisposition to obesity, we tested the hypothesis of a potential different metabolic response among ADRB2 Gln27Gln versus Glu27Glu obese women when submitted to a peak oxygen consumption test on a treadmill. In our study, 10 obese women with the Gln27Gln genotype were compared to 9 matched obese women bearing the Glu27Glu genotype. The ADRB2 polymorphism was identified by PCR-RFLP, fat oxidation was determined by indirect calorimetry and blood measurements were carried out following conventional procedures. The ADRB2 Glu27Glu subjects had lower plasma glycerol levels (P = 0.026), while plasma triglycerides (P <0.001) and the insulin:glucose ratio were higher (P = 0.046) as compared to the Gln27Gln group along the peak oxygen consumption trial intervention. There was a significantly lower fat oxidation (P = 0.024) in the Glu27Glu obese women during the recovery compared to Gln27Gln obese individuals. These data suggest that exercise would not benefit equally the two ADRB2 polymorphism homozygous groups, since both lipolysis and fat oxidation promoted by a peak oxygen consumption test appear to be blunted in the polymorphic Glu27Glu obese group.     

Slotoxin, alphaKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between alpha and alpha+beta (beta1 or beta4) complexes

A novel peptide from Centruroides noxius Hoffmann scorpion venom was isolated and sequenced. The 37 amino acid peptide belongs to the charybdotoxin sub-family (alphaKTx1) and was numbered member 11. alphaKTx1.11 has 75% sequence identity with iberiotoxin and 54% with charybdotoxin. alphaKTx1.11 revealed specificity for mammalian MaxiK channels (hSlo), thus, was named slotoxin. Slotoxin blocks the MaxiK pore-forming alpha subunit reversibly (K(d)=1.5 nM). Slotoxin association with alpha+beta (beta1 or beta4) channels was approximately 10 times slower than iberiotoxin and charybdotoxin, leading to a lack of effect on alpha+beta4 when tested at 100 nM for 5 min. Thus, slotoxin is a better tool to distinguish MaxiK alpha+beta complexes.     

Reduced risk of death at 28 days in patients taking a beta blocker before admission to hospital with myocardial infarction.

OBJECTIVE--To see whether patients taking an oral beta blocker at the time of admission to hospital with myocardial infarction have a reduced risk of death at 28 days. DESIGN--Retrospective analysis of data collected on patients admitted over four years. SETTING--Community based study. PATIENTS--2430 Consecutive patients living in the Perth statistical division admitted to hospital with myocardial infarction during 1984-7. MAIN OUTCOME MEASURE--Survival at 28 days among patients taking a beta blocker at onset of myocardial infarction. RESULTS--Patients were grouped into those who were and were not taking a beta blocker at the time of admission. Though patients taking a beta blocker were older and more likely to have a history of myocardial infarction, angina, or hypertension, the overall mortality at 28 days was similar in the two groups. A logistic regression model used to adjust for factors predictive of cardiac death at 28 days confirmed that patients taking a beta blocker at the time of admission had a significantly reduced risk of death (relative risk 0.50; 95% confidence interval 0.34 to 0.76). Though the incidence of fatal ventricular fibrillation was similar in the two groups, mean peak creatine kinase activity was significantly lower in the beta blocker group. CONCLUSIONS--These data support the value of long term use of beta blockers in patients at risk of myocardial infarction. They suggest that patients taking these agents before admission to hospital with myocardial infarction have a significant survival advantage at 28 days, which may be due to a reduction in infarct size.     

Inhibitory effects of beta adrenoceptor antagonist, atenolol, on the thromboxane system in the kidney of spontaneously hypertensive rats

We attempted to investigate the alterations in the vasoconstrictor thromboxane (TXA2) system in the kidney when spontaneously hypertensive rats (SHR) were treated subchronically with atenolol, a beta 1-adrenoceptor antagonist. Atenolol treatment (30 mg/kg body weight per day for 2 weeks) reduced systolic blood pressure by 11%, being accompanied by a decrease in heart rate. This treatment strikingly decreased thromboxane content in the renal cortex by 48% (p less than 0.05), whereas the tissue content was unaltered for prostaglandin E2 (PGE2) or slightly decreased for prostacyclin (PGI2). These alterations in the eicosanoid system led to an increase in the ratio of PGE2/TXA2 and of PGI2/TXA2. Similarly, thromboxane content in the renal papilla was lowered significantly with atenolol treatment, which raised the ratio of PGE2 to TXA2. Thromboxane reduction was not observed in the aortic walls and heart. However, in the vascular walls, PGI2 synthesis was markedly stimulated with atenolol treatment, resulting in an increase in the ratio of PGI2 to TXA2. Thus, these data indicate that subchronic atenolol-treatment inhibits the thromboxane system in the kidney, thereby shifting the eicosanoid system towards a vasodilator state. These alterations contribute, in part, to the anti-hypertensive properties of atenolol in genetic hypertension.     

Cloning, primary structure and properties of a novel human integrin beta subunit.

The originally described integrin beta subunits that define the three subfamilies of integrin heterodimers are beta 1, beta 2 and beta 3. In this paper, we describe the isolation of a cDNA coding for a novel human integrin beta subunit, designated as beta 5. The beta 5 cDNA was isolated from a human thymic epithelial cell library, using oligonucleotide probes that were designed from a region highly conserved among the known beta 1, beta 2 and beta 3 sequences. The beta 5 cDNA codes for 799 (or 796) amino acids, including a 23 amino acid leader sequence. There are 776 (or 773) amino acids in the mature protein, which includes a long extracellular domain of 696 amino acids, a transmembrane domain and an intracellular C-terminal domain of 57 amino acids. The beta 5 sequence resembled the known beta 3, beta 1 and beta 2 sequences by 55, 43 and 38%, respectively, including conservation of 56/56 cysteines. Rabbit antiserum was prepared against a 20 amino acid synthetic peptide predicted from the beta 5 C-terminal sequence. This serum immunoprecipitated a beta 5 protein that was 100,000 Mr (reduced) and 95,000 Mr (nonreduced). Only a single alpha subunit was detected in association with beta 5, and that alpha subunit was immunochemically indistinguishable from the alpha v subunit previously found as part of the vitronectin receptor complex. By immunoprecipitation, beta 5 was most prevalent on carcinoma cell lines, was also present on hepatoma and fibroblast cell lines, and was absent from lymphoblastoid cells and platelets.     

Interaction of human DNA polymerase beta with ions of copper, lead, and cadmium

Under appropriate conditions, divalent copper, lead, and cadmium ions significantly inhibit human DNA polymerase β (following accepted convention, the term DNA polymerase β refers to the low-molecular-weight, 3–4 S DNA polymerase of eukaryotic cells) at concentrations below 10^?5m. Each metal showed apparent linear noncompetitive inhibition kinetics with respect to the template primer and the deoxynucleoside triphosphate substrate, indicating that complex formation with these components does not account for the inhibition. Apparently, neither lead nor cadmium inhibit by displacing required zinc atoms from the polymerase. The interaction of the metals with the enzyme can be reversed or prevented by EDTA or by thiol compounds, except that inhibition by cadmium ions can be reversed by monothiols but not by dithiols. The metals probably do not inhibit through reaction with thiol groups since the inhibition is not decreased by pretreating the enzyme with N-ethylmaleimide. Although divalent zinc is moderately inhibitory in manganese activated poly(dT) synthesis on a poly(dA) template, it can fill the requirement for a divalent metal ion and, under the conditions tested, is about 60% as effective as Mn²⁺.