Ouabain appears as odorless, white crystals or crystalline powder as an octahydrate. Used to produce rapid digitalization in acute congestive heart failure. Also recommended in treatment of atrial or nodal paroxysmal tachycardia and atrial flutter. (EPA, 1998)
颜色/状态：
Crystals from water
分解：
Melts with decomposition at 190 °C.
计算性质
辛醇/水分配系数(LogP)：
-1.7
重原子数：
41
可旋转键数：
4
环数：
6.0
sp3杂化的碳原子比例：
0.9
拓扑面积：
207
氢给体数：
8
氢受体数：
12
ADMET
代谢
哇巴因...并不广泛与血浆白蛋白结合，并且...大部分以原形被排出。
Ouabain ... is not bound extensively to plasma albumin and ... /is/ excreted largely unchanged.
IDENTIFICATION AND USE: Ouabain, a solid, is a cardiac glycoside commonly used in the laboratory for electrophysiological experiments in cardiac myocytes. It has been used as medication and as a veterinary drug. HUMAN EXPOSURE AND TOXICITY: Ouabain-induced reactive oxygen species generation and cell apoptosis on human glioma cells has been described. The number of ouabain binding sites, detected using (3)H ouabain, were significantly increased in the borderline hypertensive subjects irrespective of heredity. Endogenous ouabain levels increase in human essential hypertension. ANIMAL STUDIES: Retinal activity measured by electroretinography in animals and in isolated retinas has been shown to be rapidly reduced by exposure to ouabain. Intravitreal injection in rabbits has caused rapid loss of vision. In cats circumferential artery of iris is reported to be constricted by ouabain. Ouabain is an endogenous Na(+)/K(+)-ATPase inhibitor whose chronic administration induces hypertension. Ouabain treatment in rats produced cognitive deficits independent of locomotor effects associated with bipolar disorder. ECOTOXICITY STUDIES: Ouabain inhibited the efflux of ammonia (from the basolateral to the apical side) in preparation of isolated Carcinus gills.
Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 uL of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which was not affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.
Brain-derived neurotrophic factor (BDNF) is a well-known and well-studied neurotrophin. Most biological effects of BDNF are mediated by the activation of TrkB receptors. This neurotrophin regulates several neuronal functions as cell proliferation, viability, and differentiation. Ouabain is a steroid that binds to the Na(+)/K(+) ATPase, inducing the activation of several intracellular signaling pathways. Previous data from our group described that ouabain treatment increases retinal ganglion cells survival (RGC). The aim of the present study was to evaluate, if this cardiac glycoside can have a synergistic effect with BDNF, the classical trophic factor for retinal ganglion cells, as well as investigate the intracellular signaling pathways involved. Our work demonstrated that the activation of Src, PLC, and PKCdelta participates in the signaling cascade mediated by 50 ng/mL BDNF, since their selective inhibitors completely blocked the trophic effect of BDNF. We also demonstrated a synergistic effect on RGC survival when we concomitantly used ouabain (0.75 nM) and BDNF (10 ng/mL). Moreover, the signaling pathways involved in this synergistic effect include Src, PLC, PKCdelta, and JNK. Our results suggest that the synergism between ouabain and BDNF occurs through the activation of the Src pathway, JNK, PLC, and PKCdelta.
The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on mitochondrial superoxide, lipid peroxidation, and proteins involved in cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Wistar rats received Li, VPA, or saline twice a day for 13 days. On the 7th day of treatment, the animals received a single intracerebroventricular injection of ouabain or aCSF. After the ICV injection, the treatment with mood stabilizers continued for 6 additional days. The locomotor activity of rats was measured using the open-field test. In addition, we analyzed oxidative stress parameters, specifically levels of phosphorylated p53 (pp53), BAX and Bcl-2 in the brain of rats by immunoblot. Li and VPA reversed ouabain-related hyperactivity. Ouabain decreased Bcl-2 levels and increased the oxidative stress parameters BAX and pp53 in the brains of rats. Li and VPA improved these ouabain-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. These findings suggest that the Na(+)/K(+)-ATPase can be an important link between oxidative damage and the consequent reduction of neuronal and glial density, which are both observed in BD, and that Li and VPA exert protective effects against ouabain-induced activation of the apoptosis pathway.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
Docosahexaenoic acid (DHA) may prevent heart failure or optimize drug treatments by improving cardiac contraction. We studied whether DHA-enriched avian glycerophospholipids (GPL-DHA) have cardioprotective effects in rats treated with ouabain after 4 weeks of dietary supplementation with 10, 35, or 60 mg DHA per kg body weight compared to no supplementation (DHA10, DHA35, DHA60, and control groups, respectively). The responsiveness of contraction to different doses of ouabain (10(-7) to 10(-4) M), ouabain intoxication (at 3 X 10(-4) M), and relative changes in cardiac energy metabolism were determined using (31)P NMR in isolated perfused rat hearts. The fatty acid composition of cardiac membranes was analyzed by gas chromatography. DHA accumulation in the heart was dose-dependent (+8%, +30%, and +45% for DHA10, DHA35, and DHA60, respectively). The cardiac phosphocreatine content significantly increased at baseline in DHA35 (+45%) and DHA60 groups (+85%), and at different doses of ouabain in the DHA60 group (+73% to 98%). The maximum positive inotropy achieved at 10(-4) M ouabain was significantly increased in all DHA groups compared to control (+150%, +122.5%, and +135% for DHA10, DHA35, and DHA60, respectively), and ouabain intoxication was delayed. The increase in myocardial phosphocreatine content and the improved efficacy of ouabain on myocardial contraction without toxicity suggest the potential of GPL-DHA as a dietary supplement or ingredient for functional food, and possibly as a co-treatment with digitalis drugs in humans.
Docosahexaenoic acid (DHA) might prevent heart failure or optimize drug treatments by improving cardiac contraction. We investigated whether DHA-enriched avian glycerophospholipids (GPL-DHA) exert cardioprotection in ouabain-treated rats after 4 weeks of dietary supplementation with 10, 35 or 60 mg DHA per kg body weight versus none (DHA10, DHA35, DHA60 and control groups, respectively). The contractile responsiveness to different doses of ouabain (10(-7) to 10(-4) M), ouabain intoxication (at 3 X 10(-4) M), and relative variations in cardiac energy metabolism were determined using (31)P NMR in isolated perfused rat hearts. The fatty acid composition of cardiac membranes was analyzed by gas chromatography. DHA accretion in the heart was dose-dependent (+8%, +30% and +45% for DHA10, DHA35 and DHA60, respectively). The cardiac phosphocreatine content significantly increased at the baseline in DHA35 (+45%) and DHA60 groups (+85%), and at the different doses of ouabain in the DHA60 group (+73% to 98%). The maximum positive inotropy achieved at 10(-4) M ouabain was significantly increased in all DHA groups versus control (+150%, +122.5% and +135% for DHA10, DHA35 and DHA60, respectively), and ouabain intoxication was delayed. The increase in myocardial phosphocreatine content and the improved efficacy of ouabain on myocardial contraction without toxicity suggest the potential of GPL-DHA as a dietary supplement or ingredient for functional food, and possibly as a co-treatment with digitalis drugs in humans.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
静脉注射哇巴因的效果在注射后立即开始，5分钟后达到最大值，持续5-7小时，然后迅速下降。
The effect of i.v.-administered ouabain starts immediately after injection, reaches a maximum after 5 min, last 5-7 hr and then rapidly declines.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
它从消化道吸收不良，大部分口服剂量似乎被破坏。
It is poorly absorbed from alimentary tract, where much of oral dose appears to be destroyed.
Four, 7 and 10% of (3)H-ouabain had been absorbed 1, 5 and 15 hr respectively after oral administration to guinea pigs. Percentage absorbed was constant at each of 3 dose levels. ... Similar results obtained in man. ... /It/ was absorbed from GI tract of rats by passive diffusion. Absorption of im dose probably depended more on tissue-blood flow than on rates of diffusion ... 67% of iv dose was excreted in 30-min bile of rats. ... /It/ was actively transported from liver to bile, and carbon tetrachloride pretreatment of rats reduced biliary excretion by depressing this transport.
Plasma clearance of ouabain following iv admin was much faster in rat than in rabbit or dog. Levels of radioactivity in plasma, bile, and liver ... determined 20 min after iv administration ... showed that rat exhibited overall bile to plasma concentration ratio of 1500, whereas same ratio was much less for rabbit (2.9) and dog (9.3). Liver/plasma and bile/liver concentration ratios ... were ... much greater in rat (20 and 71) than in rabbit (2.5 and 1.3) or dog (3.3 and 2.7). This species variation is thought to be important factor in resistance of rat to toxic effects of ouabain relative to rabbit and dog.
