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21.
A. J. Lawrence Elena Krstew Bevyn Jarrott 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(2):303-308
The present study has employed in vitro electrophysiology and radioligand binding assays to determine whether dopamine and
adenosine receptors interact with each other on rat vagal afferent neurons. Preincubation of the isolated rat nodose ganglion
with the adenosine A2a agonists CGS 21680 or DPMA (Both 1 μM) resulted in a functional antagonism of the ability of dopamine to depolarise the preparation.
Specifically, the concentration-response curve to dopamine was significantly shifted to the right in the presence of CGS 21680
and DPMA. On the other hand, adenosine itself, A1 and A3 receptor agonists and ATP were all incapable of modulating the electrophysiological response to dopamine. In contrast to
the nodose ganglion, CGS 21680 did not significantly affect the ability of the dopamine D2 ligands quinpirole or raclopride to displace [125I]NCQ298 binding to dopamine D2 receptors in membranes prepared from rat dorsal brain stem. These data indicate the presence of an interaction between high
affinity adenosine A2 receptors and dopamine D2 receptors on the soma of rat vagal afferent neurons, whereas the situation in the brain stem remains less clear.
Received: 17 September 1996 / Accepted: 20 October 1996 相似文献
22.
S. M. O. Hourani S. J. Bailey C. R. Johnson J. P. Tennant 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(4):464-473
The functional effects of adenosine 5’-triphosphate (ATP), uridine 5’-triphosphate (UTP), adenosine 5’-tetraphosphate (AP4) and the diadenosine polyphosphates P1,P3-diadenosine triphosphate (Ap3A), P1,P4-diadenosine tetraphosphate (Ap4A) and P1,P5-diadenosine pentaphosphate (Ap5A) were studied in two isolated smooth muscle preparations thought to contain P2Y (P2Y1) receptors, the guinea-pig taenia caeci (which relaxes to ATP) and the rat colon muscularis mucosae (which contracts to ATP).
In addition, the breakdown of these compounds by the rat colon muscularis mucosae was investigated by high pressure liquid
chromatography. In the guinea-pig taenia caeci all the purine nucleotides caused relaxation with a potency order of Ap3A=Ap4A> ATP>AP4=Ap5A, and these relaxations were antagonised by suramin with apparent pA2 values in the region of 5, consistent with activation of a P2Y1 receptor. In the rat colon muscularis mucosae the nucleotides caused contraction with a potency order of Ap3A = Ap4A>ATP=AP4 =Ap5A >UTP. However, while suramin (100 μM) inhibited responses to ATP and UTP at all concentrations of agonist, it only inhibited
contractions induced by the higher concentrations of AP4, Ap3A and Ap4A and had little effect on contractions induced by Ap5A. A higher concentration of suramin (1 mM) enhanced contractions induced by ATP but greatly inhibited those induced by UTP
and had no effect on responses to the other agonists. The A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) had no effect on responses to ATP or UTP
but inhibited responses to Ap3A, Ap4A, Ap5A and AP4. A combination of suramin (1 mM) and DPCPX (10 nM) almost abolished responses to all the agonists. ATP and UTP were rapidly
degraded by the rat colon muscularis mucosae while AP4, Ap3A, Ap4A and Ap5A were degraded more slowly, and the major product detected after breakdown of the purine nucleotides was inosine rather than
adenosine. The breakdown of all the nucleotides was inhibited by suramin (1 mM), although this inhibition did not achieve
statistical significance in the case of ATP. These results show that while the diadenosine polyphosphates appear to act as
P2 agonists in the taenia caeci, in the rat colon muscularis mucosae their major action is via adenosine A1 receptors rather than via P2 receptors. In addition, although they are more stable than ATP or UTP, their action in this
tissue is clearly affected by their degradation which complicates the effects of suramin.
Received: 23 March 1998 / Accepted: 29 June 1998 相似文献
23.
P. Schubert T. Ogata S. Ferroni A. McRae Y. Nakamura K. Rudolphi 《Journal of molecular neuroscience : MN》1996,28(1-3):185-190
In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative
diseases, we investigated the underlying molecular signaling as a possible target for a pharmacological therapy. Here, we
are particularly focusing on the endogenous modulation of the Ca2+ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline
(PPF). As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation
rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level
favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function.
On the other hand, a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties
of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine
effects and increased the intracellular level of cAMP and cGMP. Such a pharmacological glial cell conditioning, obtained by
modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which
a pathological activation of microglial cells and astrocytes is discussed to play a pathogenic role. 相似文献
24.
Martin J. Lohse Bernice Elger Jutta Lindenborn-Fotinos Karl-Norbert Klotz Ulrich Schwabe 《Naunyn-Schmiedeberg's archives of pharmacology》1988,337(1):64-68
Summary Human platelet membranes were solubilized with the zwitterionic detergent CHAPS (3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonate) and the solubilized extract subjected to gel filtration. Binding of the adenosine receptor agonist [3H]NECA (5-N-ethylcarboxamidoadeno-sine) was measured to the eluted fractions. Two [3H]NECA binding peaks were eluted, the first of them with the void volume. This first peak represented between 10% and 25% of the [3H]NECA binding activity eluted from the column. It bound [3H]NECA in a reversible, saturable and GTP-dependent manner with an affinity of 46 nmol/1 and a binding capacity of 510 fmol/mg protein. Various adenosine receptor ligands competed for the binding of [3H]NECA to the first peak with a pharmacological profile characteristic for the A2 adenosine receptor as determined from adenylate cyclase experiments. In contrast, most adenosine receptor ligands did not compete for [3H]NECA binding to the second, major peak. These results suggest that a solubilized A2 receptor-GS protein complex of human platelets can be separated from other [3H]NECA binding sites by gel filtration. This allows reliable radioligand binding studies of the A2 adenosine receptor of human platelets.Abbreviations CHAPS
3-[3-(cholamidopropyl)dimethylammoniol-l-propanesulfonate
- CIA
2-chloroadenosine
- CPA
N6-cyclopentyladenosine
- DPX
1,3-diethyl-8-phenylxanthine
- NECA
5-N-ethylcarboxamidoadenosine
- PAA
2-phenylaminoadenosine
- PIA
N6-phenyhsopropyladenosine
- XAC
8-{4-[([{(2-aminoethyl)amino}carbonyl}methyl)oxy]phenyl]-1,3-dipropylxanthine
Send offprint requests to M. J. Lohse 相似文献
25.
Karl-Norbert Klotz Martin J. Lohse Ulrich Schwabe Gloria Cristalli Sauro Vittori Mario Grifantini 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(6):679-683
Summary The tritiated analogue of 2-chloro-N6-cyclopentyladenosine (CCPA), an adenosine derivative with subnanomolar affinity and a 10000-fold selectivity for A1 adenosine receptors, has been examined as a new agonist radioligand. [3H]CCPA was prepared with a specific radioactivity of 1.58 TBq/mmol (43 Ci/mmol) and bound in a reversible manner to A1 receptors from rat brain membranes with a high affinityK
D-value of 0.2 nmol/l. In the presence of GTP aK
D-value of 13 nmol/l was determined for the low affinity state for agonist binding. Competition of several adenosine receptor agonists and antagonists for [3H]CCPA binding to rat brain membranes confirmed binding to an A1 receptor. Solubilized A1 receptors bound [3H]CCPA with similar affinity for the high affinity state. At solubilized receptors a reduced association rate was observed in the presence of MgCl2, as has been shown for the agonist [3H]N6-phenylisopropyladenosine ([3H]PIA). [3H]CCPA was also used for detection of A1 receptors in rat cardio myocyte membranes, a tissue with a very low receptor density. A KD-value of 0.4 nmol/l and aB
max-value of 16 fmol/ mg protein was determined in these membranes. In human platelet membranes no specific binding of [3H]CCPA was measured at concentrations up to 400 nmol/l, indicating that A2 receptors did not bind [3H]CCPA. Based on the subnanomolar affinity and the high selectivity for A1 receptors [3H]CCPA proved to be a useful agonist radioligand for characterization of A1 adenosine receptors also in tissues with very low receptor density.Abbreviations CHA
N6-cyclopenyadenosine
- CPA
N6-cy-clopentyladen,osine
- CCPA
2-chloro-N6-cyclopentyladenosine
- CCCPA
2-chloro-5-chloro-5-deoxy-N6-cyclopentyladenosine;
- CHAPS
3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonate
- DPCPX
8-cyclopentyl-1,3-dipropylxanthine
- NECA
N-ethylcarboxamidoadenosine
- PEI
polyethylenimine
- PIA
N6-phenylisopropyladenosine
Send offprint requests to K.-N. Klotz at the above address 相似文献
26.
Caffeine exerts a number of different effects on L-type calcium current in rat ventricular myocytes. These include: (1) a slowing of inactivation that is comparable to, but not additive to, that produced by prior treatment of the cells with ryanodine (a selective sarcoplasmic reticulum Ca2+ releaser) or high concentrations of intracellular 1,2-bis[2-aminophenoxy]ethane-N,N,N,N-tetraacetic acid (BAPTA) (a fast Ca2+ chelator), (2) a stimulation of peak I
Ca that is comparable to, but not additive to that produced by prior treatment with isobutylmethylxanthine (a selective phosphodiesterase inhibitor), and (3) a dose-dependent decrease of peak I
Ca that is not prevented by pretreatment with any of these agents. None of the caffeine actions could be mimicked or prevented by administration of 8-phenyltheophylline, a specific adenosine receptor antagonist. We conclude that only the slowing of I
Ca inactivation is due to caffeine's ability to deplete the sarcoplasmic reticulum of calcium. The stimulatory effect of caffeine on peak I
Ca is probably due to phosphodiesterase inhibition, while caffeine's inhibitory effect on I
Ca is independent of these processes and could be a direct effect on the channel. The multiplicity of caffeine actions independent of its effects on the sarcoplasmic reticulum lead to the conclusion that ryanodine, though slower acting and essentially irreversible, is a more selective agent than caffeine for probing sarcoplasmic reticulum function and its effects on other processes.The experimental part of this work was published during the postdoctoral stay of I. Zahradník in the Department of Physiology and Biophysics, The University of Texas Medical Branch, Galveston, TX 77555, USA 相似文献
27.
Rodrigo A. Cunha A. M. Sebastião 《Pflügers Archiv : European journal of physiology》1993,424(5-6):503-510
The independent release of adenosine and adenine nucleotides upon electrical stimulation was studied in the innervated sartorius muscle of the frog after blockade of the extracellular catabolism of adenosine monophosphate (AMP) through exo-AMP deaminase and ecto-5-nucleotidase. Nerve stimulation (30 min, 0.2Hz) induced the release of both adenosine (19±3 pmol) and adenine nucleotides (101±7 pmol). Experiments performed in the presence of tubocurarine (5 M) to prevent purine release due to nerve-evoked muscle twitching, or under direct stimulation of the muscle in low calcium solutions to prevent pre-synaptic release of purines, showed that there was an evoked release of adenosine and adenine nucleotides both from the nerve endings and from the twitching muscle fibres. Removal of ecto-5-nucleotidase inhibition shows that the catabolism of adenine nucleotides released during stimulation contributes in about 50% to the amount of endogenous extracellular adenosine. When only one of the enzymes catabolizing AMP (ecto-5-nucleotidase or exo-AMP deaminase) was inhibited, the evoked release of adenine nucleotides was undetectable, suggesting that each enzyme is able to catabolize all the AMP formed from adenine nucleotides released upon stimulation. It is concluded that the concentration of endogenous extracellular adenosine is under the control of the relative activities of exo-AMP deaminase and ecto-5-nucleotidase.Brief accounts of some of the results in this study have been published previously (refs. [6, 7]). 相似文献
28.
Nabil Nakhostine Daniel Lamontagne 《Pflügers Archiv : European journal of physiology》1994,428(5-6):526-532
The mechanism of hypoxia-induced coronary vasodilatation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO2 (from 520±6 to 103±9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF1 (from 1.8±0.3 to a maximum of 4.4±0.9 pmol min–1 g–1). The cyclooxygenase inhibitor, diclofenac (1 M), blocked the release of PGI2 and reduced hypoxia-induced vasodilatation (from 47±8% to 25±5%, P<0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K+ channel (KATP channel) activation in hypoxia-induced vasodilatation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (–48 ±7%) was found to be equivalent to the sum of their respective effects (–24±7 and –19±4%, respectively). Glibenclamide (0.3 M) reduced significantly hypoxia-induced vasodilatation (differential change in CPP of –27±6%) as well as the dilator response to 10 M adenosine and to the stable PGI2-analogue, iloprost. Forskolin-induced coronary vasodilatation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of KATP channels. KATP channel activation by prostacyclin and adenosine may involve both cyclic adenosine monophosphate-dependent and independent pathways. 相似文献
29.
光化学诱导的血栓形成性脑缺血及其代谢改变 总被引:4,自引:2,他引:4
本文用光化学法激发大鼠局部脑血栓形成,以组织病理学、局部脑血流量、皮层水含量、三磷酸腺苷、二磷酸腺苷,一磷酸腺苷、能量负荷、肌酸及乳酸为指标,探讨局部脑血栓形成后5天rCBF明显增高的可能机理。结果表明,血栓形成后局部脑组织ATP水平进行性减少(P<0.01)、ADP/ATP及AMP/ATP比值明显升高(P均<0.01),LA及脑水含量显著增加(P<0.01)。这些因素既是能量衰竭、无氧酵解的结果 相似文献
30.
荷人鼻咽癌裸鼠血浆MDA,cAMP/cGMP水平及PSP的影响 总被引:2,自引:1,他引:2
本实验利用BALB/C裸小鼠,复制荷人鼻咽癌裸鼠模型,检测荷瘤鼠血浆丙二醛,cAMP,cGMP和cAMP/cGMP比值,观察云芝糖肽对荷人NPC裸鼠的抑瘤作用及对荷瘤鼠血浆MDA和cAMP/cGMP等的影响。结果发现荷瘤鼠血浆MDA升高,cAMP,cGMP降低,cAMP/cGMP比值升高,高你低浓度PSP对荷人NPC裸鼠均有明显抗癌作用(P<0.01),抑瘤率59.58-95.53%;并可降低荷瘤 相似文献