Lack of effect of cholinergic agents or endogenous guanosine 3':5'-monophosphate on renin release by slices of rat renal cortex in vitro

Cyclic GMP, in concentrations exceeding 50 μM, and cyclic AMP, in concentrations exceeding 1 μM, significantly increased the release of renin by slices of rat renal cortex. Stimulants of cyclic AMP accumulation, such as epinephrine or norepinephrine, 1 μM, produced a significant increase of renin release but did not alter cyclic GMP levels. In contrast, acetylcholine, carbamylcholine, bethanachol, methachol and NaN₃ increased cyclic GMP accumulation without modifying renin release. These results suggest that exogenous cyclic GMP acts as a weak agonist of cyclic AMP on renin release in renal cortex. The effects observed with exogenous cyclic GMP, however, may not represent a physiological action since various stimulants of endogenous cyclic GMP accumulation did not alter renin secretion.     

Manipulation of toxicity and tissue distribution of tubercidin in mice by nitrobenzylthioinosine 5'-monophosphate

The i.v. administration of tubercidin, an analog of adenosine, in a single dose of 45 mg/kg caused death in about 90% of B10D2F₁ mice so treated. Serum and urine analysis, as well as histological examination of tissues, related the lethality of tubercidin to hepatic injury, which was markedly reduced when mice were treated with the inhibitor of nucleoside transport, nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), at i.p. doses higher than 10 mg/kg 30 min prior to tubercidin injection. With high NBMPR-P doses (100 mg/kg, i.p.) followed by tubercidin injection (45 mg/kg, i.v.), kidney damage and high mortality occurred. The tissue distribution of ³H following [G-³H]tubercidin administration paralleled hepatic or renal injury: NBMPR-P treatment decreased the content of tubercidin-derived ³H in liver and increased that in kidney. Furthermore, the half-life of the decline in tubercidin levels in serum during the first minute after [³H]tubercidin administration was longer in NBMPR-P-treated mice (26 sec) than in untreated mice (10 sec), with the result that ³H levels in serum were more than ten times higher in the former than in the latter at an early stage during the distribution of tubercidin. Within 15 min after i.p. administration, the tissue distribution of [³H]tubercidin was complete. The i.p. administration of tubercidin caused ascites and the appearance of amylase in the peritoneal fluid evidently because of peritonitis and pancreatic injury. Administration of NBMPR-P by the i.p. route, but not by the i.v. route, prevented these injuries and shifted the ld₅₀ of i.p. injected tubercidin (5 mg/kg) to markedly higher values (a 4-fold increase with NBMPR-P at 100 mg/kg). The protection of mice by NBMPR-P against lethal injuries caused by i.p. injected tubercidin was consistent with the inhibition by NBMPR-P of tubercidin accumulation in mesentery and pancreas. The tissue specificity of the NBMPR-P influence on the tissue distribution of tubercidin may reflect differences in NBMPR-P pharmacokinetics and/or in properties of the nucleoside permeation mechanism among various tissues.     

Inhibition of deoxyribonucleic acid polymerases of human leukemic leukocytes by 2',3'-dideoxythymidine triphosphate

The effects of 2',3'-dideoxythymidine 5'-triphosphate (d₂TTP) on the activities of DNA polymerases α and β isolated from leukocytes of a patient with acute myelogenous leukemia have been examined. DNA polymerase β was more sensitive than DNA polymerase a to d₂TTP inhibition; the concentration of d₂TTP required for a 50 per cent inhibition of enzyme activity was 20-fold lower for DNA polymerase β than for DNA polymerase α in assays with activated DNA template. A similar difference in sensitivity was observed also when synthetic primer templates such as (dT) ~₁₅· (dA)_n or (dT) ~ ₁₅· (A)_n were used. However, with (dG) ~₁₅ · (dC)_n primer template, neither DNA polymerase α nor DNA polymerase β activity was inhibited by d₂TTP. Kinetic analysis with activated DNA template showed that the d₂TTP inhibition was competitive with dTTP but noncompetitive with dGTP; the values of the K_m for dTTP and K_m for d₂TTP for the DNA polymerase α were approximately the same, while for DNA polymerase β the K_m was twenty times more than K_i. Neither DNA polymerase α nor DNA polymerase β had any exonuclease activity and, therefore, the resistance of DNA polymerase α to d₂TTP inhibition was not due to exonuclease activity. The extent of d₂TTP inhibition was not altered significantly by changes in the concentration of either the template or the enzyme. Preincubation of the inhibitor with either the template or the enzyme was not necessary for inhibition. The compound was inhibitory even when added after the initiation of the reaction.     

重症监护室护士离职意愿现状及研究进展

近年来,由于社会环境、个人原因等因素的影响,护士的离职意愿水平逐年升高,而重症监护室（ICU）护士由于工作性质的特殊性,离职率更是显著高于其他临床科室,因此,为进一步认识并把握我国ICU护士离职意愿的现状,为采取针对措施降低ICU护士离职率提供理论依据,本文将从离职意愿概念及相关模型、ICU护士离职意愿发展现状、影响因素和措施建议等方面进行综述,为有关临床研究提供参考。     

Inhibition of nucleoside phosphorylase cleavage of 5-fluoro-2'-deoxyuridine by 2,4- pyrimidinedione derivatives

Several 2,4-pyrimidinedione (uracil) derivatives were evaluated as inhibitors of the pyrimidine nucleoside phosphorylases that cleave 5-fluorn-2'-deoxyuridine (FUdR) to 5-fluorouracil. Pyrimidinediones substituted at either N-1 or C-5, or both, markedly inhibited the phosphorolysis of FUdR by the uridine-deoxyuridine phosphorylases of Ehrlich ascites and Novikoff hepatoma cells. The most potent inhibitors were 5-benzyluracil derivatives substituted with alkoxy groups on the meta-position of the benzyl moiety; the most active of these was 5-{[3-(phenylmethoxy)phenyl]methyl}uracil. The same derivatives, however, did not inhibit the phosphorolysis of FUdR by the thymidine phosphorylases of murine liver, human leukocytes and HeLa (S3) cells. 6-Anilino and 6-(1-naphthylmethylamino) derivatives of uracil, which have been shown by others to inhibit the cleavage of FUdR by the thymidine phosphorylase activity of Escherichia coli, did not inhibit any of the mammalian thymidine or uridinedeoxyuridine phosphorylase activities. By contrast, pyrimidinediones substituted with smaller, non-hydrophobic groups at either C-5 or C-6, or both, inhibited the cleavage of FUdR by both the mammalian thymidine and uridine-deoxyuridine phosphorylases. The most active of these, 6-aminothymine, was also the best inhibitor of thymidine phosphorylase. Our results demonstrate differences in the active sites of the various pyrimidine nucleoside phosphorylases, and should provide a basis for the design of more potent and specific inhibitors of the nucleoside phosphorylase(s) responsible for the cleavage of FUdR in man.     

Adenosine 5'-triphosphate-citrate lyase activity in mammalian spermatozoa: A new radiometric method and characterization of the enzyme in spermatozoa

A simple radiochemical method was developed for determining the ATP-citrate lyase activity in mammalian spermatozoa. The determination of enzyme activity was followed by the measurement of the incorporation of the [1-¹⁴C]acetyl group from [1,5-¹⁴C]citrate into [1-¹⁴C]acetylcoenzyme A (ACoA). Separation of ¹⁴C-labeled ACoA from the reactants and their products was achieved by rapid anion exchange chromatography. The optimum pH was 6.4 for rat spermatozoal ATP-citrate lyase. The activity was not altered by dithiothreitol. MgCl₂ (l0mM) caused a 50 per cent inhibition in the enzyme activity. ATP-citrate lyase activities in rat and human spermatozoa were 154 ± 14 and 90 ± 12 nmoles of ACoA formed/mg of protein/5 min. Citrate may serve as an acetyl source for acetylcholine formation by spermatozoa.     

γ-l-glutamyl-5-hydroxy-l-tryptophan, but not γ-l-glutamyl-l-tryptophan, causes sodium retention in normal man

1 This randomized, placebo-controlled, cross-over study compared the relative effectiveness of γ-l-glutamyl-5-hydroxy-l-tryptophan (glu-5-HTP) and γ-l-glutamyl-l-tryptophan (glu-TRP) in terms of their ability to act as substrates for renal 5-hydroxytryptamine (5-HT) synthesis and their actions on urinary sodium excretion.
2 Urinary excretion of 5-HT and sodium were determined before, during and after 1  h intravenous infusion of an equimolar amount (45  nmol  kg⁻¹ min⁻¹) of glu-5-HTP or glu-TRP or placebo in nine healthy male subjects.
3 Cumulative urinary 5-HT excretion over the 4  h after the start of glu-5-HTP infusion was 350-fold greater than that after placebo, and this was associated with a reduction in the urinary excretion of sodium.
4 In contrast, the urinary excretion values of 5-HT and sodium after administration of glu-TRP were not significantly different from those observed on the placebo day.
5 The marked increase in urinary 5-HT excretion and the retention of sodium after administration of glu-5-HTP have been demonstrated in previous studies and result from increased intrarenal generation of 5-HT. The absence of a rise in urinary excretion of 5-HT after glu-TRP infusion suggests that there was no significant conversion of this glutamyl compound to 5-HT within the kidney. As a result, there was no effect on urinary sodium excretion.     

A novel mutant variant of the CYP2D6 gene (CYP2D6 17) common in a black African population: association with diminished debrisoquine hydroxylase activity

1The debrisoquine hydroxylase (CYP2D6) is polymorphically distributed. Not only are there differences in the proportions of extensive metabolisers to poor metabolisers in various ethnic groups, but there are also pronounced variations in the metabolic capacity among those classified as extensive metabolisers. 2The mean debrisoquine metabolic ratio of Caucasian extensive metabolisers is lower than that for a number of African populations. In the present study, we have searched for novel CYP2D6 mutations to explain the diminished enzyme activity in African populations. 3Three Zimbabwean Shona subjects with EM phenotypes (metabolic ratios for debrisoquine of 0.4, 1.5 and 10.5 respectively) were selected and the open reading frame of the CYP2D6 gene of each was sequenced. 4The subject with metabolic ratio of 10.5 was found to be homozygous for an allele with a nucleotide exchange in exon 2, ¹¹¹¹C→T causing a ¹⁰⁷Thr→Ile amino acid exchange in a conserved region of the enzyme. In addition, he was homozygous for the ²⁹³⁸C→T and ⁴²⁶⁸G→C mutations causing ²⁹⁶Arg→Ser and ⁴⁸⁶Ser→Thr amino acid substitution found in the CYP2D6*2 allele. 5Seventy-six Zimbabwean Shona subjects were subsequently genotyped for the ¹¹¹¹C→T mutation and for the intron 1 gene conversion present in the CYP2D6*2 gene. The ¹¹¹¹C→T mutation was found at an allele frequency of 34% and was only present in alleles carrying the gene conversion in intron 1 indicative for the CYP2D6*2 gene. 6This allele (CYP2D6*17), containing the ¹¹¹¹C→T, ²⁹³⁸C→T and ⁴²⁶⁸G→C mutations, was found to be strongly associated with lower capacity for debrisoquine hydroxylation. We therefore postulate that the CYP2D6*17 allele might contribute to the molecular basis of the previously established diminished debrisoquine hydroxylase activity in African Bantu populations.     

(基于)轴手性1,1’-联萘骨架膦酸酯衍生物的不对称合成

目的 轴手性联萘骨架是一类重要的手性结构类型,目前许多具有生理活性的天然产物被证实具有该核心骨架.除此之外,在有机反应中,多种具有轴手性联萘的化合物也被报道具有卓越的催化活性.鉴于该类结构的重要性,本文拟对轴手性1,1’-联萘骨架膦酸酯衍生物7的合成方法进行优化.方法 该合成方法的优化以产率为指标,主要包括反应时间、投料顺序以及反应后处理等工艺的调整.结果 优化后,减少了大量的反应时间;通过调整格氏试剂的制备方法,提高了反应的成功率;整条合成路线仅3步需经硅胶柱分离纯化;各个步骤均具有较高的收率.结论 本文提出的轴手性1,1’-联萘骨架膦酸酯衍生物7合成方法简便高效,对该结构的后续研究具有重要的参考价值.     

Effects of exogenous female sex-steroid hormones on lymphocyte β2-adrenoceptors in normal females

We have previously shown that lymphocyte β₂-adrenoceptors (AR) are under cyclical control of sex-steroid hormones with greater receptor density during the luteal phase of the menstrual cycle. It has also been postulated that abnormal cyclical regulation of β₂-AR might be a possible mechanism for premenstrual asthma. The effects of exogenous female sex-steroid hormones on lymphocyte β₂-AR function were studied in eight normal healthy females. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1–6). They were randomized to receive single oral doses of either ethinyloestradiol 50 μg or medroxyprogesterone 10 mg in a cross-over study. Lymphocyte β₂-AR parameters were evaluated at baseline (t₀), 24 h (t₂₄) and 72 h (t₇₂) after ingestion. Baseline levels of progesterone and oestradiol were comparable on both cycles. Receptor density (B_max) increased significantly (P<0.01) from t₀ after progesterone but not oestradiol at t₂₄: a 1.39-fold geometric mean difference (95% CI 0.96–2.00) between t₂₄vs t₀. Receptor affinity (K_d) and maximal cAMP response to isoprenaline (E_max) were not altered by either treatment. These results show that exogenous progesterone but not oestradiol, given during the follicular phase, significantly increased β₂-AR. This, therefore, suggests that endogenous progesterone is probably responsible for previously observed increase in B_max during the luteal phase of the female menstrual cycle. These findings may suggest possible therapeutic strategies for modulation of β₂-AR in premenstrual asthma.     

HPLC法测定复方首乌地黄丸中二苯乙烯苷的含量

目的：建立高效液相色谱法测定复方首乌地黄丸中制何首乌的2,3,5,4'-四羟基二苯乙烯-2-0-/3-D-葡萄糖苷（简称二苯乙烯苷）的含量。方法：采用高效液相色谱法,色谱柱为WIech UItimate R XB－C18（250mm×4.6mm,5μm）,流动相为乙腈-水（18∶82）,检测波长为320nm,流速为1.0mL·min－1。结果：二苯乙烯苷在0.052～1.05μg范围内线性关系良好（R=0.9999）。平均回收率为99.42%（RSD=0.52%n=6）。结论：此方法简单,快速,重现性好,可作为复方首乌地黄丸的质量控制方法。     

Suppression of vagus-mediated pancreatic polypeptide release by the μ-opiate receptor agonist loperamide in man

1Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the μ-opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2In groups of healthy subjects (n=6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin-hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol-stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose-dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4We conclude that loperamide causes a dose-dependent inhibition of pancreatic polypeptide release mediated by vagal-cholinergic pathways, but does not have an atropine-like peripheral action.     

Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

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Pharmacokinetics of trapidil,an antagonist of platelet derived growth factor,in healthy subjects and in patients with liver cirrhosis

1Pharmacokinetic parameters of trapidil (an antagonist of platelet derived growth factor) were evaluated in 12 healthy male subjects (study I) and in a group of 10 patients with liver cirrhosis (Child B) and five control subjects, respectively (study II). 2Investigations were carried out after a single dose trapidil (200 mg) and at steady state after application of 200 mg trapidil three times daily for 5 days (study 1) or 4 days (study II). 3Study I: The concentration-time curves of the terminal elimination phase of trapidil exhibited a slight convexity which might reflect nonlinear kinetics. The AUC of trapidil obtained after the first dose (20.5 [±7.0 s.d.] μg ml⁻¹ h) was markedly higher than the AUC determined at steady state (13.2 [±3.8 s.d.] μg ml⁻¹ h), the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.58–0.73 (point estimator 0.64). 4Study II: AUC averaged (21.4 [±9.1 s.d.] μg ml⁻¹ h) in controls and (34.4 [±14.9 s.d.] μg ml⁻¹ h) in cirrhotic patients. The 90% confidence intervals for the difference group 1 vs group 2 was 0.95–2.97 (point estimator 1.48, P=0.066). At steady state, AUC averaged (13.7 [±5.7 s.d.] μg ml⁻¹ h) in controls and (20.8 [±6.8 s.d.] μg ml⁻¹ h) in cirrhotic patients (90% confidence intervals group 1 vs group 2: 0.88–2.20 [point estimator 1.45, P=0.05]). As seen in study I, the AUC of trapidil obtained after the first dose was markedly higher than the AUC determined at steady state , the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.48–0.84 (point estimator 0.66) in control subjects and 0.54–0.72 (point estimator 0.64) in cirrhotic patients, respectively. 5An inverse correlation was seen between the results of the monoethylglycin-xilidid (MEGX)-test and the AUC of trapidil (single dose: r=−0.516, P=0.048; steady state: r=−0.548, P=0.042). 6Results of study I and study II indicate an autoinduction of trapidil metabolism after repeated oral doses. Although trapidil elimination is decreased in patients with liver cirrhosis (study II), the elimination half-life at steady state is relatively short (2.4 [±1.1 s.d.] h) and therefore should prevent cumulation of trapidil even in cirrhotic patients.