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991.
Summary Strips of the porcine small intestine were incubated in vitro and the outflow of 5-hydroxytryptamine (5-HT) was determined by HPLC with electrochemical detection.Spontaneous outflow of 5-HT from the porcine small intestine was reduced by about 70% after removal of the extracellular calcium or by addition of 1 mM gadolinium. Tetrodotoxin reduced the outflow of 5-HT by 30%, an effect which has previously been shown to be caused by inhibition of an excitatory cholinergic input. The sodium channel opener veratridine (up to 100 M) did not affect the outflow of 5-HT. -Conotoxin GVIA (500 nM) or nifedipine (10 M) reduced the outflow of 5-HT only by about 50%, and their effects were not additive. The inhibitory effects of -conotoxin GVIA occurred also in the presence of tetrodotoxin. Elevation of extracellular potassium to 40 mM caused a marked and sustained increase in 5-HT outflow. High potassium evoked release of 5-HT was blocked by -conotoxin GVIA, nifedipine and gadolinium. When -conotoxin GVIA and nifedipine were present in combination, their inhibitory effects on the high potassium evoked 5-HT release vanished. BAY K 8644 (1–10 M) did not facilitate 5-HT release, but markedly reduced the spontaneous and high potassium evoked release of 5-HT.In conclusion, the enterochromaffm cells are endowed with multiple calcium channels, but voltage-sensitive calcium channels of a neuronal L-type which are sensitive to dihydropyridines and -conotoxin GVIA appear to play a major role.Abbreviations 5-HT
5-hydroxytryptamine
- 5-HIAA
5-hydroxyindoleacetic acid
- TTx
tetrodotoxin
Correspondence to K. Racke at the above address 相似文献
992.
Summary Rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline were used to investigate whether the NMDA-evoked noradrenaline release is modulated by agonists or antagonists at presynaptic 2-adrenoceptors.In experiments on slices, noradrenaline and the preferential 2-adrenoceptor agonists talipexole (former B-HT 920) and clonidine inhibited the NMDA evoked tritium overflow whereas the selective 1-adrenoceptor agonists cirazoline and methoxamine were ineffective. The 2-adrenoceptor antagonists rauwolscine and idazoxan facilitated the NMDA-evoked tritium overflow whereas the preferential 1-adrenoceptor antagonist prazosin was ineffective. The concentration-response curve of talipexole for its inhibitory effect on NMDA-evoked overflow was shifted to the right by idazoxan (apparent pA2 = 7.5). The EC50 of NMDA (97 mol/l) for its stimulating effect on tritium overflow was not substantially changed by blockade of 2-autoreceptors with 1 mol/l rauwolscine (EC50 of NMDA in the presence of the 2-adrenoceptor antagonist, 155 mol/l), but the maximal overflow of tritium was increased 2.5 fold by this rauwolscine concentration. In experiments on synaptosomes, talipexole and noradrenaline inhibited the NMDA-evoked tritium overflow. The inhibitory effect of talipexole was abolished by idazoxan which, given alone, was ineffective, as was prazosin. Talipexole did also not produce an inhibition when tritium overflow was evoked by NMDA in the presence of -conotoxin GVIA 0.1 mol/l; the latter, by itself, decreased the response to NMDA by about 55%. It is concluded that the NMDA-evoked noradrenaline release in the cerebral cortex is modulated via presynaptic 2-adrenoceptors on the noradrenergic neurones. Stimulation of these autoreceptors in slices by endogenous noradrenaline does not result in a decreased potency of NMDA, but in a decreased maximum effect, in stimulating noradrenaline release. The inhibitory effect of 2-adrenoceptor agonists on the NMDA-evoked release is at least partially due to a functional interaction between the NMDA receptors and 2-autoreceptors at the level of the same varicosities. The results obtained with -conotoxin GVIA suggest that Ca2+ influx via the N-type voltage-sensitive calcium channel (VSCC) occurs in response to NMDA receptor stimulation and contributes substantially to the induction of NMDA-evoked noradrenaline release. The inhibitory effect of 2-adrenoceptor stimulation on this release appears to be ultimately due to an inhibition of the influx of Ca2+ via the N-type VSCC.
Correspondence to: M. Göthert at the above address 相似文献
993.
To clarify the role of endogenous histamine in learning and memory, the effect of -fluoromethylhistidine on active avoidance response in rats was studied. -Fluoromethylhistidine (20–100 mg/kg or 10–50 µg) significantly (P<0.05 orP<0.01) prolonged the response latency in active avoidance response when administered by either intraperitoneal or intracerebroventricular injection. These effects were dose-related and long lasting. A prolongation of the response latency induced by an intraperitoneal injection of -fluoromethylhistidine (100 mg/kg) was antagonized by intracerebroventricular injection of histamine (10 and 20 ng) in a dose-dependent manner. In addition, the acquisition of this response was retarded by a consecutive intracerebroventricular injection of -fluoromethylhistidine (50 µg), whereas histamine (100 ng) facilitated the response acquisition when administered by the same route. Both intraperitoneal (100 mg/kg) and intracerebroventricular injection of -fluoromethylhistidine (50 µg) significantly (P<0.05 orP<0.01) decreased the brain histamine content, especially in the hippocampus and hypothalamus. When -fluoromethylhistidine (50 µg) was injected intracerebroventricularly, there is a high correlation between a prolongation of the response latency and a decrease in histamine content of these brain areas. Based on these findings, it was concluded that an intimate relation may exist between a prolongation of response latency in the active avoidance response and a decrease in the brain histamine content; endogenous histamine may play an important role in learning and memory recollection in rats. 相似文献
994.
Summary In the present study the actions of -hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABAB-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.).Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABAB-receptors.
Correspondence to: G. Engberg at the above address 相似文献
995.
M. Kathmann E. Schlicker M. Detzner H. Timmerman 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(5):498-503
Summary We determined the affinities of nordimaprit, homodimaprit, clobenpropit and imetit for H3 binding sites (labelled by 3H-N-methylhistamine) in rat brain cortex homogenates and their potencies at presynaptic H3A receptors on noradrenergic nerve endings in mouse brain cortex slices.
3H-N-Methylhistamine bound saturably to rat brain cortex homogenates with a Kd of 0.70 nmol/l and a Bmax of 98 fmol/mg protein. Binding of 3H-N-methylhistamine was displaced monophasically by dimaprit (pKi 6.55), nordimaprit (5.94), homodimaprit (6.44), clobenpropit (9.16), imetit (9.83), R-(–)--methylhistamine (8.87) and histamine (8.20), and biphasically by burimamide (pKi high 7.73, pKi low 5.97). In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically (0.3 Hz) evoked tritium overflow was inhibited by imetit (pIC35 8.93),R-(–)--methylhistamine (7.87) and histamine (7.03). The effect of histamine was attenuated by nordimaprit, homodimaprit, clobenpropit and N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ); EEDQ (but not nordimaprit, homodimaprit and clobenpropit) attenuated the effect of histamine also in slices pre-exposed to the drug 60–30 min prior to superfusion. The concentration-response curve of histamine was shifted to the right by homodimaprit and clobenpropit; Schild plots yielded straight lines with a slope of unity for both drugs (pA2 5.94 and 9.55, respectively). Nordimaprit depressed the maximum effect of histamine (pD2 5.55) and also slightly increased the concentration of histamine producing the half-maximum effect.In conclusion, nordimaprit and homodimaprit possess similar affinities for H3 binding sites like dimaprit; nordimaprit and homodimaprit as well as clobenpropit and imetit do not differentiate between H3A and H3B binding sites. Nordimaprit is a reversible noncompetitive H3 receptor antagonist, homodimaprit and clobenpropit are reversible competitive H3 receptor antagonists and imetit is an H3 receptor agonist.
Correspondence to: E. Schlicker at the above address 相似文献
996.
C. Damase-Michel M. A. Tran M. E. Llau F. Chollet J. M. Senard B. Guiraud-Chaumeil J. L. Montastruc P. Montastruc 《European journal of clinical pharmacology》1993,44(2):199-201
Summary We have studied the sympathetic response to blockade of presynaptic 2-adrenoceptors in essential hypertension by measuring plasma concentrations of noradrenaline after a single oral dose of yohimbine, an 2-adrenoceptor antagonist.Mean baseline plasma noradrenaline and adrenaline concentrations were similar in the hypertensive and normotensive groups. Yohimbine (0.2 mg×kg–1 orally) caused a lesser increase in the plasma concentrations of noradrenaline in hypertensive patients (+67%) than in normotensive subjects (+178%) and a pressor response in hypertensive (but not in normotensive) patients.These results are consistent with an alteration in the balance of -adrenoceptors (for example presynaptic 2-adrenoceptor desensitization and post-synaptic 1-adrenoceptor hyper-responsiveness) which would help to develop and/or maintain arterial hypertension. 相似文献
997.
Bela Szabo Tobias Auberle Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(3):249-257
Summary Inhibition of uptake, in the central nervous system leads to a decrease of sympathetic outflow to many tissues; central a2-adrenoceptors are involved in this decrease. The aim of the present study was to compare the effects of the selective uptake, inhibitor (+)-oxaprotiline on the plasma kinetics of noradrenaline and adrenaline in anaesthetized and in conscious rabbits. [3H]Noradrenaline and [3H]adrenaline were infused iv. The arterial plasma concentrations of endogenous and radiolabelled noradrenaline and adrenaline were measured, and the clearance from and spillover into the plasma of noradrenaline and adrenaline were calculated.Results obtained in conscious and anaesthetized rabbits were similar. (+)-Oxaprotiline 0.2, 0.6 and 1.8 mg kg–1 iv. dose-dependently reduced the clearance of [3H]noradrenaline from the plasma. The clearance of [3H]adrenaline was reduced less. The spillover of endogenous noradrenaline was decreased by up to 35%. In contrast, the spillover of adrenaline tended to be enhanced. Prazosin 0.1 and 1 mg kg–1 was injected iv. in a second part of each experiment. It lowered the blood pressure and caused a marked increase in noradrenaline spillover but no increase or even a decrease in adrenaline spillover.The results are compatible with the following hypothesis. The sympathetic outflow from the central nervous system is subject to a twofold a-adrenoceptor-mediated modulation: -adrenoceptor-mediated inhibition and 1-adrenoceptor-mediated excitation. In the control of the sympathetic outflow to many extra-adrenal tissues, the 2-adrenergic inhibition prevails. Uptake1 inhibitors depress sympathetic outflow to such tissues by enhancing the 2-adrenergic inhibition. In the regulation of the sympathetic outflow to the adrenal medulla, in contrast, 2-adrenergic inhibition and 1-adrenergic excitation have a similar impact. Uptake, inhibitors, hence, cause little change in adrenaline release: the two opposing influences cancel out. Prazosin produces an increase in noradrenaline but not adrenaline release because the loss of the central 1 sympathoexcitation attenuates at best slightly the baroreflex to most extra-adrenal tissues but dampens markedly the baroreflex to the adrenal medulla.
Correspondence to B. Szabo at the above address 相似文献
998.
C. de Mey K. Beithaupt D. Palm U. Fuhr G. G. Belz 《European journal of clinical pharmacology》1993,44(4):341-348
Summary The cardiovascular effects at rest and during exercise and 1- and 2-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p. o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p. o., using a place-bo-controlled, 2-way cross-over design.The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median 1-RRA and 2-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to 1-adrenoceptors, moderately to 2-adrenoceptors, acts as 1-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect 1-adrenergic agonism, but which might reflect 2-adrenergic agonism. 相似文献
999.
J. Pfeilschifter H. Mühl W. Pignat F. M?rki H. van den Bosch 《European journal of clinical pharmacology》1993,44(Z1):S7-S9
Phospholipase A2 (PLA2) is believed to play an essential role in inflammatory processes by releasing arachidonic acid from membrane phospholipids for synthesis of important lipid mediators, such as prostaglandins, leukotrienes and platelet activating factor.We have used glomerular mesangial cells as a model system to study the regulation of PLA2 under inflammatory conditions. Potent pro-inflammatory cytokines, such as interleukin 1 (IL-1) and tumour necrosis factor (TNF), as well as agents that increase cellular cAMP levels have been found to increase Group II PLA2 gene expression in a time- and dose-dependent manner. 相似文献
1000.
Tsuyoshi Ohmura Suzu Sakamoto Haruki Hayashi Shigeru Kigoshi Ikunobu Muramatsu 《Urological research》1993,21(3):211-215
Summary The 1-adrenoceptor subtypes of dog prostate were characterized in binding and functional experiments. In saturation experiments, [3H]prazosin bound to 1-adrenoceptors with high affinity. In the displacement experiments, unlabelled prazosin and WB4101 biphasically inhibited the binding of 400 pM [3H]prazosin, suggesting the presence of at least two distinct affinity sites for prazosin or WB4101. The proportion of high-affinity sites was approximately 10%. HV723 also recognized two distinct affinity sites but the proportion of high-affinity sites was approximately 20%. From these results the presence of three distinct 1-adrenoceptor subtypes was suggested: presumably subtypes 1A (high affinity for prazosin and WB4101), 1N (high affinity for only HV723) and 1L (low affinity for the three antagonists) according to the recently proposed 1-adrenoceptor subclassification. The density of subtype 1L was much higher than that of subtypes 1A and 1N subtypes. In the functional experiments, prazosin, WB4101 and HV723 competitively antagonized the contractile response to noradrenaline with low affinities close to those estimated for the 1L subtypes. These results suggest that the contractile response to noradrenaline in the dog prostate is mediated predominantly through 1L subtype -adrenoceptors. 相似文献