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101.
Brett Claire M. Washington Carla B. Ott Ronda J. Gutierrez Marcelo M. Giacomini Kathleen M. 《Pharmaceutical research》1993,10(3):423-426
The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na+-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na+-driven 3H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na+–uridine transport was determined. At a concentration of 100 µM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a K
i of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na+–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The K
i of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside. 相似文献
102.
A. Y. S. Chan P. Poon E. L. P. Chan S. L. M. Fung Professor R. Swaminathan 《Osteoporosis international》1993,3(6):341-344
The effect of high sodium intake on bone mineral content of rats fed a normal (0.6% Ca) or a low (0.02% Ca) calcium diet was studied. Rats on a normal calcium diet given 1.8% sodium chloride to drink showed persistent and significant hypercalciuria and subnormal bone mineral content. Total calcium content of femur was significantly lower after 4 months (p<0.02) and 12 months (p<0.001). In rats maintained on a low calcium diet (0.02% Ca), a high sodium diet for 8 weeks caused a significant loss of calcium in bone similar to that seen in animals fed a normal calcium diet for 4 months. We conclude that high sodium intake reduces bone mineral content, especially if the diet is low in calcium. 相似文献
103.
Aspirin has antisecretory and ulcerogenic properties in the gastrointestinal tract. The aim of this study was to determine the effects of acetylsalicylic acid (ASA) on the electrical and mechanical activity of the ileum in anesthetized New Zealand White rabbits. Ileal electromechanical activity was recorded from serosal electrodes and a miniature intraluminal balloon. Thirty minutes after injection of ASA (30, 60 and 100 mg/kg intravenous) significant and dose-dependent increases in the percentage of slow waves with action potentials were observed when compared with saline-injected animals. The onset of action potentials correlated with phasic increases in intraluminal pressure, indicating the onset of circular muscle contractions. Injection of 15 mg/kg ASA, sodium salicylate (100 mg/kg intravenous) or saline had no effect on baseline action potential activity. Prostaglandin E
2 (PGE
2)(5 and 10 g/kg intravenous) significantly increased slow-wave frequency and decreased ASA-induced action potential activity. This study demonstrates that (1) ASA, but not sodium salicylate, stimulates phasic ileal action potential and contractile activity and (2) in ASA-treated animals, PGE
2
produces differential effects on in vivoslow-wave frequency and action potential activity. 相似文献
104.
Robert H. Smallwood George W. Mihaly Richard A. Smallwood Denis J. Morgan 《Journal of pharmacokinetics and pharmacodynamics》1988,16(5):529-542
For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu
b
)on steady state total (C
b
)and unbound (Cu
b
)blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL
int
).For a substance of very low CL
int
,if fu
b
changes, C
t
will change and Cu
b
will remain constant, whereas if CL
int
isvery high, Cu
b
will change and C
b
will remain constant.The present study defines the effects of a change in fu
b
on C
b
and Cu
b
over the whole CL
int
range. Computer simulations were undertaken which predicted that, for a given change in fu
b
,absolute and relative changes in C
b
would decreasenonlinearly with increasing CL
int, twhile the relative change in Cu
b would increasewith CL
int
.The absolute change in Cub
would be independent of CL
int
.Significant changes in Cb and Cu
b would be observed at intermediate values of CL
int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu
b of sodium taurocholate a substance with intermediate CL
int
(such that at fu
b
=0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24-
14
C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu
b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate C
b of 22.7% and a relative decrease in Cu
b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.This study was supported by the National Health and Medical Research Council of Australia. 相似文献
105.
P. W. L. Tas H. G. Kress K. Koschel 《Journal of neural transmission (Vienna, Austria : 1996)》1989,76(2):99-107
Summary We have studied the ion flux through the sodium channels of low passage number (<50p.) and high passage number (>150p.) neuroblastoma x glioma hybrid cells using [14C] guanidinium and specific neurotoxins to induce channel opening and closing. The sodium channels of low passage number hybrid cells could be opened by veratridine alone, suggesting the presence of voltage dependent channels in agreement with electrophysiological studies reported in the literature. The sodium channels of the high passage number hybrid cells, however, needed the synergistic action of veratridine and scorpion toxin for activation suggesting that these channels are silent. The [14C] guanidinium ion flux through the sodium channels of the high passage number hybrid cells was inhibited by significantly lower concentrations of the volatile anesthetics (halothane, isoflurane and enflurane) and the lcoal anesthetics (tetracaine and bupivacaine) than the comparable flux through the sodium channels of the low passage number hybrid cells.Dedicated to Prof. Dr. E. Wecker on the occasion of his 65th birthday. 相似文献
106.
Manis PB Molitor SC Wu H 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2003,153(4):443-451
During intracellular recordings in rodent brainstem slice preparations, dorsal cochlear nucleus (DCN) pyramidal cells (PCs) exhibit characteristic discharge patterns to depolarizing current injection that depend on the membrane potential from which the responses are evoked. When depolarized from hyperpolarized potentials, PCs can respond with a short-latency action potential followed by a long silent interval (pauser) or a train of action potentials with a long latency (buildup). During the silent intervals in a pauser or a buildup response, the membrane potential slowly depolarizes towards spike threshold, often exhibiting distinct voltage oscillations of 1–2 mV before the first spike. The subthreshold voltage oscillations were investigated using whole cell recordings from DCN PCs in rat pup (P10–14) brainstem slices. The oscillations were unaffected by excitatory and inhibitory neurotransmitter antagonists, and were not temporally locked to the onset of the depolarization. The oscillations typically became larger as spike threshold was approached, and had a characteristic frequency between 40 and 100 Hz. In the presence of tetrodotoxin (TTX, 500 nM), the oscillations were significantly suppressed, and could not be evoked at any voltage below or above spike threshold. The oscillations were not blocked by phenytoin or Cd2+, but they were affected by prior activity in the neuron for approximately 1 s. We conclude that voltage-gated Na+ channels are required to generate membrane oscillations during the buildup phase. We suggest that the subthreshold oscillations play a role in controlling spike timing in PCs when the membrane potential slowly approaches, or hovers near, spike threshold. 相似文献
107.
Cellular dehydration induced by water deprivation or hypertonic saline injection reduces feeding in a variety of species. Normal feeding in rats is maintained during isotonic saline consumption by increasing the intake of saline compared to the usual intake of water. Hamsters do not show the spontaneous preference for isotonic saline noted in rats, even after adrenalectomy. In the present investigation, feeding by hamsters was depressed during both isotonic and hypertonic saline consumption compared to the usual feeding with water. Saline intakes did not exceed water intakes under similar conditions. When fluid intakes were elevated by prior fluid deprivation, feeding rates increased at all concentrations of saline after a delay proportional to the osmolality of the solution. Positive 24-hr sodium balances were always associated with saline consumption. Water and hypertonic saline injections reduced feeding, and the fluid loads were excreted very slowly. When hamsters were fluid deprived prior to injections, saline totally suppressed feeding, while water increased feeding compared to sham injected controls. It is concluded that cellular dehydration produces a reduction of feeding in hamsters drinking isotonic or hypertonic saline. Reduced feeding with isotonic saline consumption results from the failure of hamsters to increase their ad lib intake of that solution. The prolonged retention of both sodium and fluid after saline consumption or injection suggests that further saline intake may be inhibited by an expansion of the extracellular space. 相似文献
108.
In the identified neurons B1, B2 and B3 of Helix pomatia an intracellular injection of Na+ induced an outward current in 10% and an inward current in 90% of the experiments. The outward current was associated with an increase and the inward current with a decrease of the membrane conductance. Both currents reversed at membrane potentials of between -60 and -70 mV. Inward currents were also elicited by intracellular Li+ or tris-[hydroxymethyl]-aminomethane (Tris+) injection. All inward currents were reduced by extracellular administration of tetraethylammonium or quinine. It is suggested that the outward current represents a calcium-activated potassium current and that the inward current is due to a blockade of potassium channels from the intracellular side. 相似文献
109.
M. Vandenbranden J.L. de Coen R. Jeener L. Kanarek J.M. Ruyschaert 《Molecular immunology》1981,18(7):621-631
Interactions between rabbit-γ-immunoglobulins and model membranes (lipid monalayers, planar lipid bilayers, liposomes) have been investigated. No significant interaction was observed with immunoglobulins. However, immunoglobulins dialysed first vs aqueous buffer having pH 2 or 3 and then dialysed against pH 7 buffer presumably adopt a new conformation which allows their bindings to model membranes. This binding is hydrophobic and the immunoglobulin region interacting with the lipid acyl chains is probably located in the heavy chain, as suggested by labelling in this region by a photosensitive probe previously incorporated into the lipid hydrophobic core. Cleavage at the hinge region by papain or pepsin, or heating above 38°C, induces the loss of the hydrophobic conformation responsible for hydrophobic bindings. The binding capacity of immunoglobulins heated above 38°C is restored after momentary dialysis at pH 2. The possible existence of two Ig isomers is discussed in relation to the mechanism of γ-immunoglobulin passage through the endoplasmic membrane and fixation into the plasma membrane. 相似文献
110.
目的探讨阿魏酸钠注射液治疗视网膜静脉栓塞的临床效果。方法100例(100只眼)视网膜静脉栓塞患者,随机分成治疗组和对照组各50例。对照组给予常规治疗,治疗组给予阿魏酸钠注射液300mg/d静脉滴注,14d为一疗程。测定治疗前后视力、视网膜中央静脉血流速度、视网膜中央动脉平均收缩期峰值血流速度。结果应用阿魏酸钠治疗后,视力明显改善,视网膜中央静脉血流速度和收缩期峰值血流速度显著提高,与对照组治疗后相比均有显著性差异,疗效优于对照组。结论阿魏酸钠治疗视网膜静脉栓塞疗效显著。 相似文献