Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Precision-cut liver slices have been developed as an in vitro tool for assessing liver viability and function and for examining hepatotoxicants. Liver slices from a variety of species (including human) are prepared using mechanical slicers that produce reproducible slices of a uniform thickness, which allows optimum exchange of nutrients, waste, and gases. Slices are incubated in dynamic systems that allow the slices to be maintained viable in culture for 1-10 days. The viability of slices can be assessed by ion content (K+, Na+ ATPase status), intermediary metabolism, energy status (ATP), respiration, biosynthetic ability, and biotransformation activity. In addition, liver tissue slices allow the opportunity for extensive microscopic evaluation (light and electron) as well as newer technologies such as confocal microscopy. Assessment of the toxic potential of a chemical can be performed after a short-term or constant exposure by evaluating the viability parameters. Liver slices have been used extensively for rank-ordering the toxicity of chemicals as well as for examining the mechanisms of liver injury. Liver slices in culture also can be used for an examination of the induction of new enzymes such as cytochrome P-450 and the expression of stress proteins or peroxisomal enzymes. Finally, liver slices offer a system for evaluating whole or cryopreserved liver as well as regeneration of liver tissue after toxic insult. Liver slices have been shown to be a valid in vitro system for examining liver function and offer a bridge between in vivo and cell culture systems.
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PMID:Use of precision-cut liver slices as an in vitro tool for evaluating liver function. 883 81

Precocene II was more toxic in 24 hour cultures than in 72 hour cultures of rat hepatocytes. In 24 hour cultures, there was no observable toxicity at 75 microM precocene II after exposure for 6 hours, but after 24 hours, 65% of the cells were dead. In contrast, although 794 microM killed 50% of the cells in the 72 hour cultures after a 24 hour exposure, 1 mM killed 96% of the cells within 6 hours. In both 24 and 72 hour cultures, cell death was preceded by a rapid, early loss of mitochondrial membrane potential, followed by decreases in glutathione, reduced pyridine nucleotide status, and plasma membrane Na+/K+-ATPase activity. There was also a rapid loss of ATP in the 72 hour cultures but not in the 24 hour cultures; therefore, onset of cell death may be closely linked to loss of ATP. Inhibition of cytochrome P-450 prevented the toxicity, and partially protected against the loss of membrane potential and glutathione, in 24 hour cultures but was ineffective in 72 hour cultures. Therefore, in addition to depletion of glutathione, precocene II appears to damage mitochondria and plasma membrane functions and can do so by more than one pathway.
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PMID:Mechanism of toxicity of precocene II in rat hepatocyte cultures. 884 9

Dopamine decreases tubular sodium reabsorption in part by inhibition of Na+,K(+)-ATPase activity in renal proximal tubules. The signaling mechanism involved in dopamine-mediated inhibition of Na+,K(+)-ATPase is known to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K(+)-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Renal proximal tubular suspensions were prepared and Na+,K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate hydrolysis. Dopamine inhibited Na+,K(+)-ATPase activity in a concentration (1 nM-10 microM)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition of Na+,K(+)-ATPase activity in WKY rats was significantly blocked by mepacrine (10 microM), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K(+)-ATPase. Arachidonic acid (a product released by PLA2 action) inhibited Na+,K(+)-ATPase in a concentration-dependent (1-100 microM) manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 microM in WKY rats and SHR, respectively). Furthermore, lower concentrations of arachidonic acid stimulated (30% at 1 microM) Na+,K(+)-ATPase activity in SHR. This suggests a defect in the metabolism of arachidonic acid in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K(+)-ATPase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K(+)-ATPase and altered arachidonic acid metabolism may contribute to reduced dopaminergic inhibition of Na+,K(+)-ATPase activity in spontaneously hypertensive rats.
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PMID:Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na+,K(+)-ATPase in kidney of spontaneously hypertensive rats. 888 79

The cytochrome P-450 pathway is capable of metabolizing arachidonic acid to omega- and subterminal hydroxylase metabolites, 16-, 17-, 18-, 19-, and 20-hydroxyeicosatetraenoic acids (P-450 HETEs). We have quantitated, by gas chromatography-mass spectrometry (GC/MS), endogenous HETEs exiting the rabbit isolated perfused kidney elicited by hormonal stimulation. Kidneys were perfused with Krebs-Henseleit solution containing indomethacin (2.8 microM) to prevent further metabolism of HETEs by cyclooxygenase. Phenylephrine (2-3 microM) was added to the perfusate to raise perfusion pressure to approximately 80 mmHg. Angiotensin II (ANG II), arginine vasopressin (AVP), and bradykinin (BK) were injected into the renal artery and perfusates collected throughout the vasoactive response. After addition of an internal standard, deuterated 19-HETE, perfusates were extracted and purified and P-450 HETEs were derivatized for GC/MS analysis. Under basal conditions, 16-, 18-, 19-, and 20-HETEs were released (range: 50-270 pg/ml), 19-HETE being the highest and fivefold greater than 16-HETE, the lowest. Injection of 50 ng ANG II increased by two- to sixfold P-450 HETE release associated with an increase of 40 +/- 11 mmHg in perfusion pressure. An equipressor dose of AVP (50 ng) did not release P-450 HETEs nor did a 5-micrograms dose of the vasodilator peptide BK, which decreased perfusion pressure by 22 +/- 6 mmHg. Authentic 19- and 20-HETE isomers resulted in dose-dependent dilation, as did 18(R)- and 16(R)-HETEs, whereas their enantiomers and 17-HETE isomers were without effect on perfusion pressure. The vasodilator effects of 18(R)- and 16(R)-HETEs, like 20- and 19-HETEs, were inhibited by indomethacin. Furthermore, P-450 HETEs exhibited both regio- and stereoselective inhibition of proximal tubule adenosine triphosphatase (ATPase) activity. The (S) enantiomers of 16- and 17-HETE potently inhibited activity, whereas their (R) isomers and other P-450 HETEs had negligible effects on ATPase activity. The quantity of HETEs released from the kidney, either under basal conditions or when stimulated by ANG II, and their biological profile suggest that subterminal HETEs may participate in renal mechanisms affecting vasomotion and tubular transport.
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PMID:Cytochrome P-450-dependent HETEs: profile of biological activity and stimulation by vasoactive peptides. 889 75

Low concentrations of angiotensin II (Ang II) increase, whereas high concentrations inhibit the apical Na/H antiporter activity in the proximal tubule, but the respective roles of the different signaling pathways in mediating these effects remains unsettled. We studied the effects of both low and high doses of Ang II in the presence of selective signaling pathway inhibitors, on the apical Na/H antiport activity of rat proximal tubule. Experiments were carried out in intact cells of freshly prepared tubule fragments obtained from the outer third of cortex, that is, devoid of basolateral Na/H antiport activity in the absence of bicarbonate transport and H(+)-ATPase activity. In tubules acid-loaded by an NH4Cl prepulse, Na/H antiport activity was assessed by the initial rate of intracellular pH recovery (dpHi/dt), measured with BCECF. When tubules were preincubated with low dose Ang II (10(-11) M for 3 min), dpHi/dt increased by 25 +/- 8%, whereas incubation with high dose Ang II (10(-7) M for 3 min) decreased dpHi/dt by 30 +/- 4%, compared to control (P < 0.01 in both cases). Both effects were abolished in the presence of 2.10(-3) M amiloride. Low dose Ang II-induced increase in dpHi/dt was not affected by preincubation with a specific PKA inhibitor, Rp-CPT-cAMP 10(-4) M, and was completely abolished by preincubation with PKC inhibitors, staurosporine 10(-7) M, sphingosine 5.10(-6) M, or calphostin 10(-6) M. In addition, pretreatment of rats with pertussis toxin led to a partial inhibition of the effect of low dose Ang II. The high dose-Ang II-induced decrease in dpHi/dt was not affected by pretreatment with a calcium-calmodulin kinase inhibitor W-7 10(-4) M. Conversely, pretreatment with the cytochrome P-450 inhibitor econazole 10(-5) M reversed the inhibitory effect of high dose Ang II to a stimulatory effect (24 +/- 8%, P < 0.01), quantitatively similar to the effect of low dose Ang II. In addition, arachidonate was found to exert an econazole-sensitive dose-dependent inhibitory effect on dpHi/dt, and 5,6-EET 10(-6) M, a cytochrome P-450 derived-arachidonic acid metabolite, induced a 38 +/- 9% inhibition, similar to that observed with high dose Ang II alone. There was no additive effect of 5,6-EET and high dose Ang II. Finally, pretreatment with two PLA2 inhibitors (BromoPhenacylBromide, 6.10(-6) M, and oleyloxyethyl phosphorylcholine, 5.10(-6) M) reversed the inhibitory effect of high dose Ang II to a stimulatory effect (32 +/- 11% and 25 +/- 11%, respectively, P < 0.05 for both inhibitors). We conclude that, in intact rat proximal cells, low dose Ang II stimulates the apical Na/H antiport through a pertussis toxin-sensitive G protein-dependent PKC pathway, whereas high dose Ang II inhibits the Na/H antiport activity through the PLA2- and cytochrome P-450-dependent metabolites of arachidonate.
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PMID:Signaling pathways in the biphasic effect of angiotensin II on apical Na/H antiport activity in proximal tubule. 891 15

Dopamine-induced natriuretic response which results from the activation of tubular dopamine1 (DA1) receptors is diminished in spontaneously hypertensive rats (SHR). This may be a result of alterations occurring at the receptor level and within the cellular signaling pathway which ultimately causes inhibition of Na+, K(+)-ATPase. There have been reports showing that DA1 receptor induced inhibition of Na+, K(+)-ATPase is abolished in SHR which is due to a decreased activation of PLC and PKC by dopamine. Of the mechanisms, adenylyl cyclase and phospholipase C are two known enzymes linked to DA1 receptors via G proteins. Furthermore, the involvement of phospholipase A2 (PLA2) has also been reported in this process. However, the site of defect in DA1 receptor signaling pathway in SHR is still not well understood. This report will (i) review the coupling of DA1 receptor with G proteins and their levels in Wistar Kyoto (WKY) rats and SHR and (ii) discuss studies dealing with the role of PLA2 in dopamine-induced inhibition of Na+, K(+)-ATPase in WKY rat and SHR kidneys. Fenoldopam, DA1 receptor selective agonist stimulated [35S]GTP gamma S binding in a concentration (10(-9)-10(-4) M)-dependent manner in WKY rats which was attenuated in SHR. Fenoldopam (10 microM)-induced stimulation of [35S]GTP gamma S binding was significantly reduced by a DA1 receptor selective antagonist, SCH 23390 suggesting the involvement of DA1 receptor. Furthermore, the specific antipeptides Gs alpha, and Gq/11 alpha significantly blocked fenoldopam-stimulation of [35S]GTP gamma S binding suggesting the coupling of DA1 receptor with both the G proteins. Western analysis revealed a significant decrease in Gq/11 alpha but no changes in Gs alpha in SHR compared to WKY rats. Dopamine inhibited Na+, K(+)-ATPase activity in a concentration (10(-9)-10(-5) M)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition in Na+, K(+)-ATPase activity was significantly blocked by mepacrine (a PLA2 inhibitor) suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+, K(+)-ATPase. Arachidonic acid (AA), a PLA2 product, inhibited Na+, K(+)-ATPase in a concentration (1-100 microM)-dependent manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 microM in WKY and 80 microM in SHR). Furthermore, lower concentration (1 microM) of AA stimulated the enzyme activity in SHR. This suggests a defect in the metabolism of AA in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+, K(+)-ATPase between WKY rats and SHR. These data suggest that (i) the reduced activation of G proteins following DA1 receptor stimulation, (ii) reduced amount of Gq/11 alpha and (iii) a defect in the AA metabolism may be responsible for the reduced dopaminergic inhibition of sodium pump activity and a diminished natriuretic response to dopamine in SHR.
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PMID:Dopamine-1 receptor G-protein coupling and the involvement of phospholipase A2 in dopamine-1 receptor mediated cellular signaling mechanisms in the proximal tubules of SHR. 902 41

Consumption of oil extracted from accidental or deliberate contamination of argemone seed to mustard seed is known to pose a clinical condition popularly referred to as Epidemic Dropsy. Several outbreaks of Epidemic Dropsy have occurred in the past in India as well as in Mauritius, Fiji Island, and South Africa. Clinico-epidemiological manifestations of argemone oil poisoning include vomiting, diarrhea, nausea, swelling of limbs, erythema, pitting edema, breathlessness, etc. In extreme cases, glaucoma and even death due to cardiac arrest have been encountered. The toxicity of argemone oil has been attributed to two of its physiologically active benzophenanthridine alkaloids, sanguinarine and dihydrosanguinarine. Histopathological studies suggest that liver, lungs, kidney, and heart are the target sites for argemone oil intoxication. Studies have shown to elucidate the cocarcinogenic potential of argemone oil that can be correlated with the binding of sanguinarine with a DNA template. Pharmacological response in intestine revealed immediate stimulation of tone and peristaltic movements of the gut in the sanguinarine-treated animals. Argemone oil/Sanguinarine caused a decrease in hepatic glycogen levels which may be due to the activation of glycogenolysis leading to an accumulation of pyruvate in the blood of Epidemic Dropsy cases. The increase in pyruvate levels causes uncoupling of oxidative phosphorylation leading to breathlessness, as observed in patients. Sanguinarine has been shown to inhibit Na+, K(+)-ATPase activity of different organs such as brain, heart, liver, intestine, and skeletal muscle, which may be due to the interaction with the glycoside receptor site on ATPase enzyme, thereby causing a decrease in the active transport of glucose. Argemone oil/alkaloid showed a Type II binding spectra with hepatic cytochrome P-450 (P-450) protein, thereby causing loss of P-450 content and an impairment of phase I and phase II enzymes. A green fluorescent metabolite of sanguinarine, benzacridine was detected in the milk of grazing animals. The delayed appearance of this metabolite in urine and feces of experimental animals suggests the slow elimination of the alkaloid. Argemone oil enhances hepatic microsomal and mitochondrial lipid peroxidation, indicating that these two organelles are the sites of membrane damage. Furthermore, studies suggest that singlet oxygen and hydroxyl radical are involved in argemone oil toxicity. Several bioantioxidants show protective effect in argemone oil-induced toxicity in experimental animals. The line of treatment in argemone-intoxicated epidemics has so far been only symptomatic, and specific therapeutic measures are still lacking, although it has been suggested that diuretics, bioantioxidants, steroids, vitamins, calcium- and protein-rich diet had some beneficial effects on Epidemic Dropsy cases.
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PMID:Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil. 918 56

1. Relaxing factors released by the endothelium and their relative contribution to the endothelium-dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries. 2. BK produced an endothelium-dependent relaxation of arteries pre-contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 microM), produced a parallel shift to the right of the concentration-response curve to BK with a pA2 of 7.75. 3. Neither the cyclo-oxygenase inhibitor, indomethacin (10 microM) alone, the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 300 microM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 microM) alone, nor the combination of L-NAME plus Hb affected the concentration-response curve to BK. Conversely, the combination of indomethacin with either L-NAME or Hb attenuated but did not abolish the BK-induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L-NAME. Also, the presence of indomethacin plus L-NAME produced contraction of arteries with functional endothelium. 4. The indomethacin plus L-NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L-NAME did not affect the nitric oxide donor, S-N-acetylpenicillamine-induced relaxation. 5. The indomethacin plus L-NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 microM), 4-aminopyridine (100 microM), glibenclamide (10 microM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). 6. In the presence of indomethacin plus L-NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 microM) or by the inhibitor of cytochrome P450, SKF 525a (10 microM). Another cytochrome P450 inhibitor, clotrimazole (10 microM) which also inhibits K+ channels, inhibited the relaxation to BK. 7. These results show that BK induces endothelium-dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo-oxygenase derived prostanoid(s) and another factor (probably an endothelium-derived hyperpolarizing factor). They indicate that nitric oxide and cyclo-oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P-450 pathway, in these arteries.
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PMID:Characterization of endothelium-derived relaxing factors released by bradykinin in human resistance arteries. 920 31

Acute systolic arterial hypertension provokes a rapid decrease in proximal tubule sodium reabsorption and diuresis associated with inhibition of renal cortex Na,K-ATPase activity and redistribution of apical membrane Na/H exchanger (NHE-3) to heavier density membranes containing markers of intermicrovillar cleft and endosomes. Because cytochrome P-450-dependent arachidonate metabolites participate in the regulation of renal sodium transport and BP, this study tested the hypothesis that these renal responses to acute hypertension would be prevented if cytochrome P-450 metabolism were inhibited by cobalt chloride (CoCl2). Four groups of rats (n = 4 to 5) were studied: (1) sham-operated; (2) 50 mg of CoCl2/kg subcutaneously for 2 d; (3) acute hypertension by constricting arteries for 5 min; and (4) acute hypertension after CoCl2 treatment as in group 3. Renal cortex was analyzed after sorbitol density gradient fractionation. CoCl2 treatment alone did not significantly affect the rate of urine output, endogenous lithium clearance (an inverse measure of proximal tubule sodium reabsorption), maximal activity of Na,K-ATPase, or subcellular distribution of NHE-3-containing membranes. In non-CoCl2-treated animals, acute hypertension provoked a three- to fourfold increase in urine output and endogenous lithium clearance, 33% inhibition of renal cortex Na,K-ATPase activity, and redistribution of NHE-3 out of the apical membrane peak. In CoCl2-treated animals, acute urine output and endogenous lithium clearance increased only twofold during acute hypertension, there was no inhibition of Na,K-ATPase activity, and there was no redistribution of NHE-3 immunoreactivity to higher density membranes. These findings demonstrate that CoCl2 treatment both attenuates the inhibition of proximal tubule sodium reabsorption and diuresis and abolishes Na,K-ATPase inhibition and NHE-3 redistribution during acute hypertension, evidence that these responses may be mediated by cytochrome P-450 arachidonate metabolites.
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PMID:The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K-ATPase and redistribution of apical NHE-3 during acute hypertension. 955 54

The protean properties of 20-hydroxyeicosatetraenoic acid (HETE), vasoactivity, mitogenicity, and modulation of transport in key nephron segments, serve as the basis for the essential roles of 20-HETE in the regulation of the renal circulation and electrolyte excretion and as a second messenger for endothelin-1 and mediator of selective renal effects of ANG II. Renal autoregulation and tubular glomerular feedback are mediated by 20-HETE through constriction of preglomerular arterioles, responses that are maintained by 20-HETE inhibition of calcium-activated potassium channels. 20-HETE modulates ion transport in the proximal tubules and the thick ascending limb by affecting the activities of Na+-K+-ATPase and the Na+-K+-2Cl- cotransporter, respectively. The range and diversity of activity of 20-HETE derives in large measure from COX-dependent transformation of 20-HETE to products affecting vasomotion and salt and water excretion. Nitric oxide (NO) exerts a negative modulatory effect on 20-HETE formation; inhibition of NO synthesis produces marked perturbation of renal function resulting from increased 20-HETE production. 20-HETE is an essential component of interactions involving several hormonal systems that have central roles in blood pressure homeostasis, including angiotensins, endothelins, NO, and cytokines. 20-HETE is the preeminent renal eicosanoid, overshadowing PGE2 and PGI2. This review is intended to provide evidence for the physiological roles for cytochrome P-450-derived eicosanoids, particularly 20-HETE, and seeks to extend this knowledge to a conceptual framework for overall cardiovascular function.
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PMID:20-HETE and the kidney: resolution of old problems and new beginnings. 1048 76


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