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991.
- Recently, 4-chloro-3-ethyl phenol (CEP) has been shown to cause the release of internally stored Ca2+, apparently through ryanodine-sensitive Ca2+ channels, in fractionated skeletal muscle terminal cisternae and in a variety of non-excitable cell types. Its action on smooth muscle is unknown. In this study, we characterized the actions of CEP on vascular contraction in endothelium-denuded dog mesenteric artery. We also determined its ability to release Ca2+, by use of Ca2+ imaging techniques, on dog isolated mesenteric artery smooth muscle cells and on bovine cultured pulmonary artery endothelial cells.
- After phenylephrine-(PE, 10 μM) sensitive Ca2+ stores were depleted by maximal PE stimulation in Ca2+-free medium, the action of CEP on refilling of the emptied PE stores was tested, by first pre-incubating the endothelium-denuded artery in CEP for 15 min before Ca2+ was restored for a 30 min refilling period. At the end of this period, Ca2+ and CEP were removed, and the arterial ring was tested again with PE to assess the degree of refilling of the internal Ca2+ store.
- In a concentration-dependent manner (30, 100 and 300 μM), CEP significantly reduced the size of the post-refilling PE contraction (49.4, 28.9 and 5.7% of control, respectively) in Ca2+-free media. This suggests that Ca2+ levels are reduced in the internal stores by CEP treatment. CEP alone did not cause any contraction either in Ca2+-containing or Ca2+-free Krebs solution.
- Restoring Ca2+ in the presence of PE caused a large contraction, which reflects PE-induced influx of extracellular Ca2+. The contraction of tissues pretreated with 300 μM CEP was significantly less compared with controls. However, tissues pretreated with 30 and 100 μM CEP were unaffected. Washout of CEP over 30 min produced complete recovery of responses to PE in Ca2+-free and Ca2+-containing medium suggesting a rapid reversal of CEP effects.
- Concentration-response curves were constructed for PE, 5-hydroxytryptamine (5-HT) and K+ in the absence of and after 30 min pre-incubation with 30, 100 and 300 μM CEP. In all cases, CEP caused a concentration-dependent depression of the maximum response to PE (84.8, 43.4 and 11.6% of control), 5-HT (65.4, 25.7 and 6.9% of control) and K+ (77.6, 41.1 and 10.8% of control).
- Some arterial rings were pre-incubated with ryanodine (30 μM) for 30 min before the construction of PE concentration-response curves. In Ca2+-free Krebs solution, ryanodine alone did not cause any contraction. However, 58% (11 out of 19) of the tissues tested with ryanodine developed contraction (6.9±1.2% of 100 mM K+ contraction, n=11) in the presence of external Ca2+. EC50 values for PE in ryanodine-treated tissues (1.7±0.25 μM, n=16) were not significantly different from controls (2.5±0.41 μM, n=22). Maximum contractions to PE (118.5±4.4% of 100 mM K+ contraction, n=16) were also unaffected by ryanodine when compared to controls (129±4.2%, n=23).
- When fura-2 loaded smooth muscle cells (n=13) and endothelial cells (n=27) were imaged for Ca2+ distribution, it was observed that 100 and 300 μM CEP in Ca2+-free medium caused Ca2+ release in both cell types. Smooth muscle cells showed a small decrease in cell length. Addition of EGTA (5 mM) reversed the effect of CEP on intracellular Ca2+ to control values.
- These data show, for the first time in vascular smooth muscle and endothelial cells, that CEP releases Ca2+ more rapidly than ryanodine. Unlike ryanodine, CEP caused no basal contraction but depressed contractions to PE, 5-HT and K+. The lack of basal contraction may result from altered responsiveness of the contractile system to intracellular Ca2+ elevation.
992.
James J Rauh Eric Benner Michael E Schnee Daniel Cordova Caleb W Holyoke Michael H Howard Donglin Bai Steven D Buckingham Michael L Hutton Alain Hamon Richard T Roush David B Sattelle 《British journal of pharmacology》1997,121(7):1496-1505
- The radiolabelled bicyclic dinitrile, [3H]-3,3-bis-trifluoromethyl-bicyclo[2.2.1]heptane-2,2-dicarbonitrile ([3H]-BIDN), exhibited, specific binding of high affinity to membranes of the southern corn rootworm (Diabrotica undecimpunctata howardi) and other insects. A variety of γ-aminobutyric acid (GABA) receptor convulsants, including the insecticides heptachlor (IC50, 35±3 nM) and dieldrin (IC50, 93±7 nM), displaced [3H]-BIDN from rootworm membranes. When tested at 100 μM, 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane(EBOB), 4-t-butyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-thione (TBPS), 1-phenyl-4-t-butyl-2,6,7-trioxabicyclo[2.2.2]octane (TBOB) and picrotoxin failed to displace 50% of [3H]-BIDN binding to rootworm membranes indicating that the bicyclic dinitrile radioligand probes a site distinct from those identified by other convulsant radioligands.
- Dissociation studies showed that dieldrin, ketoendrin, toxaphene, heptachlor epoxide and α and β endosulphan displace bound [3H]-BIDN from rootworm membranes by a competitive mechanism.
- Rat brain membranes were also shown to possess a population of saturable, specific [3H]-BIDN binding sites, though of lower affinity than in rootworm and with a different pharmacological profile. Of the insecticidal GABAergic convulsants that displaced [3H]-BIDN from rootworm, cockroach (Periplaneta americana) and rat brain membranes, many were more effective in rootworm.
- Functional GABA-gated chloride channels of rootworm nervous system and of cockroach nerve and muscle were blocked by BIDN, whereas cockroach neuronal GABAB receptors were unaffected.
- Expression in Xenopus oocytes of either rat brain mRNA, or cDNA-derived RNA encoding a GABA receptor subunit (Rdl) that is expressed widely in the nervous system of Drosophila melanogaster resulted in functional, homo-oligomeric GABA receptors that were blocked by BIDN. Thus, BIDN probes a novel site on GABA-gated Cl− channels to which a number of insecticidally-active molecules bind.
993.
Legendre Jean-Yves Trzeciak Arnold Bur Daniel Deuschle Ulrich Supersaxo Andreas 《Pharmaceutical research》1997,14(5):619-624
Purpose. This study investigates the structure/activity relationship of a series of N-acyl-peptides (lipopeptides) for the transfection of mammalian cells.
Methods. Lipopeptides comprising 1 to 3 basic amino-acids and a single fatty acid chain were synthesized. Transfecting complexes between lipopeptide, plasmid DNA and dioleoyl phosphatidylethanolamine were prepared and applied on cells in culture. Transfection efficiency was evaluated by measuring -galactosidase activity 48 h post-transfection. Lipopeptide-DNA binding was also investigated by physical means and molecular modelling.
Results. Besides the length of the fatty acid chain, the nature of the basic amino-acid and the C-terminal group were crucial parameters for high transfection efficiency. The N-acyl-(diaminobutyric acid)n derivatives were the most potent transfecting agents among those tested and induced a -galactosidase activity 2 to 20 times higher than the N-acyl-lysine, -ornithine or -diaminopropionic acid derivatives. Furthermore, a hydrazide C-terminal modification greatly enhanced transfection efficiency for all compounds tested. The reason why , -diaminobutyric acid hydrazide-based lipopeptides were the most potent in transfection is not fully understood but could be related to their high DNA binding.
Conclusions. Poly- or oligo-diaminobutyric acid containing or not a hydrazide C-terminus could advantageously be used in peptide-based gene delivery systems. 相似文献
994.
Patterns and prognosis ofClostridium difficile colitis 总被引:2,自引:2,他引:0
Boyd C. Marts M.D. Ph.D. Walter E. Longo M.D. Anthony M. Vernava III M.D. Donald J. Kennedy M.D. Gayle L. Daniel R.N. B.S.N. Ivy Jones R.N. 《Diseases of the colon and rectum》1994,37(8):837-845
The incidence of
Clostridium difficile
colitis has increased during recent years, presumably because of liberal use of broad-spectrum antibiotic regimens. METHODS: A retrospective review to determine patterns of
C. difficile
colitis development, morbidity, and treatment results was undertaken. During an 18-month period, 90 patients were diagnosed with
C. difficile
colitis by fecal toxin assays. Patient demographics, symptoms, previously administered antibiotic regimens, diagnostic evaluations, treatment modalities, morbidity, and mortality were identified, entered into a computer data base, and analyzed. RESULTS: The mean age was 58 years; males outnumbered females 1.21. Among 90 patients, 41 (46 percent) developed
C. difficile
colitis after surgical procedures. Eighty (89 percent) patients received antibiotic therapy before developing
C. difficile
colitis: 35 (44 percent) for documented infections and 45 (56 percent) as empiric or prophylactic therapy. Cephalosporins, penicillins, quinolones, vancomycin, and aminoglycosides were the most frequently administered antibiotic classes prior to
C. difficile
colitis diagnosis. Ten (11 percent) patients developed
C. difficile
colitis without previous antibiotic therapy. Eighty-two (91 percent) patients presented with diarrhea, while eight (9 percent) had fever only. Primary
C. difficile
colitis treatment for both groups included vancomycin (66 percent), metronidazole (24 percent), or both drugs (10 percent). Ten (11 percent) patients received no treatment. No patient developed toxic colitis or megacolon. Colonoscopy was performed in four (4 percent) patients; pseudomembranes were identified in one (25 percent) patient. There was one
C. difficile
colitis recurrence after treatment, but no
C. difficile
colitis-associated morbidity. Mortality (14 patients, 16 percent) was not related to
C. difficile
colitis, but to underlying illness. No difference in patient age, sex, previous antibiotic administration, serum albumin, total days hospitalized, duration of
C. difficile
colitis antibiotic therapy,C. difficile
colitis treatment regimens, or mortality was identified between nonsurgical and surgical patients. The white blood cell count was significantly lower in the nonsurgical group however.Clostridium difficile
colitis developed most commonly after antibiotic administration with symptoms of diarrhea, but did occur without previous antibiotic administration or diarrhea. CONCLUSION: Despite the clinical setting,C. difficile
colitis had no associated morbidity and treatment was highly effective. Mortality was related to underlying medical illness, not
C. difficile
colitis.Read at the meeting of The American Society of Colon and Rectal Surgery, Chicago, Illinois, May 2 to 7, 1993. 相似文献
995.
John D. Friedman Daniel S. Berman Hosen Kiat James Bietendorf Mark Hyun Kenneth F. Van Train Fan Ping Wang 《Journal of nuclear cardiology》1994,1(4):382-388
Background
To assess the accuracy of rest and treadmill exercise first-pass radionuclide ventriculographic measurements of left ventricular ejection fraction (LVEF), 40 patients underwent treadmill exercise first-pass and bicycle exercise equilibrium radionuclide ventriculography. To determine the frequency of technically adequate treadmill exercise first-pass studies, an additional 128 consecutive patients undergoing treadmill exercise first-pass procedures during stress99mTc-labeled sestamibi myocardial perfusion studies were assessed.Methods and Results
The treadmill exercise first-pass procedure used a multicrystal camera and an241Am point source to allow for correction of patient motion. Excellent correlations were observed between resting first-pass and resting equilibrium LVEF (r=0.91; standard error of the estimate=5.6). A high correlation was also observed between treadmill exercise first-pass and bicycle equilibrium exercise LVEF measurements (r=0.85, standard error of the estimate=7.6). Treadmill first-pass LVEF systematically underestimated the bicycle equilibrium LVEF. Intraobserver agreement for rest and exercise first-pass LVEF was high (r values of 0.98 and 0.94, respectively). Of the 168 consecutive treadmill exercise first-pass studies evaluated for technical adequacy, 21 (12.5%) were deemed technically inadequate, with most of the sources of error being avoidable. The frequency of technically adequate studies was as high (87%) in high levels of exercise (Bruce stages 3 and 4) as in lower levels (88%). The findings of this study validate the first-pass treadmill exercise LVEF measurement.Conclusion
This procedure now provides the option for combining the information of peak treadmill exercise LVEF with measurements of exercise myocardial perfusion from the same injection of radioactivity. 相似文献996.
Evaluation of a novel bis-naphthalimide anticancer agent,DMP 840, against human xenografts derived from adult,juvenile, and pediatric cancers 总被引:1,自引:0,他引:1
Peter J. Houghton Pamela J. Cheshire James C. Hallman III Janet L. Gross Ronald J. McRipley Jung-Hui Sun Carl H. Behrens Daniel L. Dexter Janet A. Houghton 《Cancer chemotherapy and pharmacology》1994,33(4):265-272
The new bis-naphthalimide antitumor agent (R,R)2,2-[1,2-ethanediylbis[imino(1-methyl-2.1-ethanediyl)]-bis {5-nitro-1H-benz[de]-isoquinoline-1,3-2H) dione} dimethanesulfonate (DMP 840) was evaluated against parental and multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immunedeprived mice. In vitro, KB8-5 cells were 50-fold resistant to vincristine but only 16-fold resistant to DMP 840 as measured by clonogenic survival. For in vivo evaluation, DMP 840 was given by i. v. injection daily for 9 days or for 5 days/week for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resistance of KB cell lines in vitro, both KB3-1 and KB8-5 tumors were highly and equally sensitive to DMP 840; only KB3-1 xenografts demonstrated sensitivity to vincristine, which was consistent with the in vitro results. DMP 840 was also evaluated against a panel of human tumors comprising colon adenocarcinoma and rhabdomyosarcoma xenografts. Against eight lines of colon adenocarcinoma, DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibition of growth in two lines. DMP 840 caused complete regressions in five of six lines of advanced rhabomyosarcomas, demonstrating a broad range of effective dose levels. The pattern of activity against this tumor panel was similar but not identical to that of two inhibitors of topoisomerase I. There was no cross-resistance to DMP 840 in xenografts selected for resistance to vincristine or in a rhabdomyosarcoma selected for resistance to the topoisomerase I inhibitor topotecan. In contrast, a colon tumor selected for topotecan resistance was completely resistant to DMP 840. Slight cross-resistance to DMP 840 was demonstrated in a rhabdomyosarcoma xenograft that was selected for primary resistance to melphalan and was cross-resistant to topoisomerase I inhibitors. The pattern of activity and cross-resistance in these tumors was compared with that shown by two agents that inhibit topoisomerase I: topotecan and CPT-11.This work was supported in part by CA23099, Cancer Center Support (CORE) grant CA21675, The Du Pont Merck Pharmaceutical Company, and by American Lebanese Syrian Associated Charities (ALSAC) 相似文献
997.
998.
999.
A variety of ethyl 2-(substituted)cinnamates 1 Systematic name: ethyl 3-phenyl-2-(substituted)propenoate. were synthesized and added to vinylic monomer polymerizations. These olefins are activated towards free radical addition and contain a homolytic leaving group in the allylic position. Thus, they exhibit chemical transfer properties in free radical polymerization. The compounds studied include bromide, iodide, sulfone, mercaptan and peroxide derivatives. Cinnamic iodide, however, exhibits degradative chain transfer activity. These compounds have an advantage over simple thiols in that they permit a good control of molar mass by an addition-fragmentation mechanism involving difunctionalization of the resulting telomers. The methods of synthesis of ethyl 2-(substituted)cinnamates are discussed through the nucleophilic substitution of various anions toward the allylic bromo derivative prepared from ethyl 2-(α-hydroxybenzyl)propenoate. 相似文献
1000.
K. Jendroska W. Poewe J. Pluess H. Iwerssen-Schmidt J. Paulsen S. Barthel L. Schelosky J. Cervós-Navarro S. E. Daniel S. J. DeArmond 《Acta neuropathologica》1995,90(5):461-466
The histoblot immunostaining technique for locating and characterizing amyloidogenic proteins was used to obtain information about the relationship of cerebral ischemia/hypoxia to the accumulation of amyloid protein (Aß). We investigated brains of 131 subjects (ages 25–94 years, mean 72 years). Three distribution patterns of A immunoreactivity were identified: (1) colocalization with diffuse and neuritic plaques of Alzheimer's disease (AD) and aging; (2) diffuse punctate deposits in the cerebral cortex in association with small vessel cerebral vascular disease; and (3) cerebral cortical accumulation localized to arterial boundary zones and other regions susceptible to ischemic/hypoxic injury designated stress-induced deposits (SID). SID were not identified in tissue sections by immunohistochemical, Congo red or Bielschowsky silver techniques; no histological abnormalities were present in adjacent formalin-fixed tissue sections. SID occurred in subjects with histories of cerebral ischemia, and severe orthostatic hypotension. There was also an association with aging in general and with the incidence of neuritic plaques specifically. These latter findings are consistent with the hypothesis that brain ischemia/hypoxia plays a role in the pathogenesis of AD. 相似文献