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)

The effect of drugs from the class of cardiac (methyldigoxin, verapamil, propranolol), antiepileptic (carbamazepine), sedative (diazepam) and antihistaminic (promethazine) drugs on Na,K-ATPase activity of plasma membranes was studied in rat brain synaptosomes. Methyldigoxin in a concentration of 0.1 mmol/l inhibits enzyme activity by 80 %. Verapamil, propranolol and promethazine in concentrations of 20, 20 and 2 mmol/l respectively, entirely inhibit the ATPase activity. Carbamazepine and diazepam in concentrations of 0.02-60 mmol/l have no effect on the activity of this enzyme. According to the drug concentrations that inhibit 50 % of enzyme activity (IC(50)), the potency can be listed in the following order: methyldigoxin promethazine verapamil ? propranolol. From the inhibition of commercially available purified Na,K-ATPase isolated from porcine cerebral cortex in the presence of chosen drugs, as well as from kinetic studies on synaptosomal plasma membranes, it may be concluded that the drugs inhibit enzyme activity, partly by acting directly on the enzyme proteins. Propranolol, verapamil and promethazine inhibitions acted in an uncompetitive manner. The results suggest that these three drugs may contribute to neurological dysfunctions and indicate the necessity to take into consideration the side effects of the investigated drugs during the treatment of various pathological conditions.
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PMID:Selective inhibition of brain Na,K-ATPase by drugs. 1608 3

Calcium channel antagonists have been shown to be effective in the management of coronary vascular diseases. Although initially restricted to the treatment of angiopectoris could prevent cardiovascular complication in patients with diabetes. In view of a possible role of electrolytes in the therapeutic effects of verapamil, the present study concern effects of verapamil on serum, red cell, tissue electrolytes and Na-K-ATPase activity in both male and female rats. Verapamil (30 mg/kg body weight) was administered intraperitoneally to the test group. Control group received same volume of deionize water. A slight decreased Na-K-ATPase activity was observed in both sexes. Verapamil treatment decreases serum sodium and magnesium levels in both male and female rats. However serum potassium was slightly increased in both sexes. Verapamil treatment in red cells decreases sodium and increases potassium content in both sexes. Verapamil administration decreases sodium and calcium content in heart, liver and kidney tissues in both sexes, whereas an increased content of potassium and magnesium was observed in these tissues except liver in which the magnesium content was slightly decreased in both male and female rats. The results showed that the changes in electrolyte levels are more pronounced in female than in male rats. The results reported in the present study suggests that the drug has been shown to inhibit aldosterone biosynthesis to a variable degree. Although the antihypertensive effect of verapamil is considered to be mainly due to its vasodilation or by inhibition of vasoconstriction. It is suggested that verapamil lower blood pressure by correcting a pathophysiological derangements of electrolytes present in hypertension. The cellular mechanism involved is the altered serum, intracellular, tissue electrolytes and ATPase activity.
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PMID:Antihypertensive and metabolic effects of verapamil: role of Na-K-ATPase and electrolytes homeostasis in male and female rats. 1641 92

P-glycoprotein (P-gp; ABCB1) actively transports a broad range of structurally unrelated compounds out of the cell. An important step in the transport cycle is coupling of drug binding with ATP hydrolysis. Drug substrates such as verapamil bind in a common drug-binding pocket at the interface between the TM (transmembrane) domains of P-gp and stimulate ATPase activity. In the present study, we used cysteine-scanning mutagenesis and reaction with an MTS (methanethiosulphonate) thiol-reactive analogue of verapamil (MTS-verapamil) to test whether the first TM segment [TM1 (TM segment 1)] forms part of the drug-binding pocket. One mutant, L65C, showed elevated ATPase activity (10.7-fold higher than an untreated control) after removal of unchanged MTS-verapamil. The elevated ATPase activity was due to covalent attachment of MTS-verapamil to Cys65 because treatment with dithiothreitol returned the ATPase activity to basal levels. Verapamil covalently attached to Cys65 appears to occupy the drug-binding pocket because verapamil protected mutant L65C from modification by MTS-verapamil. The ATPase activity of the MTS-verapamil-modified mutant L65C could not be further stimulated with verapamil, calcein acetoxymethyl ester or demecolcine. The ATPase activity could be inhibited by cyclosporin A but not by trans-(E)-flupentixol. These results suggest that TM1 contributes to the drug-binding pocket.
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PMID:Transmembrane segment 1 of human P-glycoprotein contributes to the drug-binding pocket. 1649 38

SAMMA is licensed for development as a contraceptive microbicide. Understanding mechanisms of its biological activity is prerequisite to designing more active second generation products. This study examined Ca(2+) involvement in SAMMA-induced premature acrosomal loss (SAL) in noncapacitated human spermatozoa. SAMMA causes acrosomal loss (AL) in a dose-dependent manner (ED(50) = 0.25 microg/mL). SAL requires extracellular Ca(2+) (ED(50) = 85 microM). SAL is inhibited by verapamil (nonspecific voltage-dependent Ca(2+) channel blocker; IC(50) = 0.4 microM), diphenylhydantoin and NiCl(2) (T-type [Ca(v)3.x] channel blockers; IC(50) 210 microM and 75 microM, respectively). Verapamil blockade of L-type (Ca(v)1.x) channels is use-dependent; activated channels are more sensitive to inhibition. However, verapamil inhibition of SAL does not increase after repeated SAMMA stimulation. SAL is unaffected by 10 microM nifedipine (selective L-type channel blocker). This contrasts to 40% inhibition (P < .001) of AL induced by 1 microM thapsigargin (Ca(2+)-ATPase inhibitor; releases intracellular Ca(2+) stores, promotes capacitative Ca(2+) entry). SAL is unaffected by 1 microM BAPTA-AM (intracellular Ca(2+) chelator), and 50 microM 2-APB (blocks InsP3 receptors and store-operated channels). This contrasts with thapsigargin-induced AL, inhibited nearly 65% by BAPTA-AM (P < .005) and 91% by 2-APB (P, .001). The results suggest that SAL is mediated by Ca(2+) entry through channels pharmacologically similar to the T-type (Ca(v)3.2) class. This process appears distinct from that caused by physiological stimuli such as progesterone or zona pellucida-derived proteins. SAMMA's contraceptive activity may be caused by induction of premature AL through dysregulation of Ca(2+) signaling.
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PMID:SAMMA induces premature human acrosomal loss by Ca2+ signaling dysregulation. 1658 17

The impact of P-glycoprotein (P-gp) on the distribution of nortriptyline (NT) and its metabolites between brain, liver and serum was studied experimentally. The interaction of NT with P-gp in vitro was confirmed by measurement of P-gp stimulated ATPase activity (Km = 257.6 microM, Vmax = 51.0 nmol phosphate released/mg protein-min). Administration of NT (5 mg/kg, s.c.) to mdrla knockout mice resulted in enhanced brain-serum (1.6-fold, p = 0.012) and liver-serum (1.4-fold, p = 0.019) ratios, as compared to the wild-type mice. For a series of NT doses (2.5, 5, 10, 25, 30 mg/kg, i.p.) inhibition of P-gp with cyclosporine A (CsA, 200 mg/kg, i.p.) in rats led to NT brain- and liver-serum ratios that were on average 1.3- (p = 0.005) and 2.1- (p = 0.001) fold higher than those of the controls, respectively. Verapamil (50 mg/kg) (NT, 5 mg/kg) increased the ratios by a factor of 1.6 (p <0.001) and 10.3 (p <0.001) for brain and liver, respectively. Finally, co-administration of methadone (1 mg/kg) did not alter the brain-serum ratio of NT, but in the liver a slight increase (1.5-fold, p = 0.035) was observed. In conclusion, verapamil yielded complete inhibition of P-gp at the blood-brain barrier and CsA had an effect corresponding to about 50% inhibition. The results show that P-gp influences the penetration of NT into the brain, and that drug-drug interactions may take place.
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PMID:The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites. 1684 11

The oral uptake of zolmitriptan, a novel and highly selectively 5-HT 1B/1D receptor agonist, was evaluated in the human epithelial cell line caco-2 that possesses intestinal enterocyte-like properties when cultured in vitro. The study demonstrated that zolmitriptan uptake significantly depended upon the extracelluar temperature and pH in the Caco-2 cell. The zolmitriptan uptake at 39 degrees C was 2.1 fold as that at 23 degrees C and the zolmitriptan uptake at pH 8.0 was 2.7 fold as that at pH 6.0. The uptake rates of zolmitriptan on both sides increased with increasing zolmitriptan concentration from 0.1 to 10 mmol x L(-1), and it shows concave concentration-dependency at high concentration. The uptake rates of zolmitriptan on the basolateral side (BL) were 3-7 times higher than that on the apical side (AP). Verapamil, nimodipine, nifedipine, flunarizine, amiloride and sumatriptan significantly increased the uptake rates of zolmitriptan on the apical sides. Propafenone significantly inhibited the uptake rate of zolmitriptan on both sides. Propranolol and aspirin have no significant effect. The results indicated that the zolmitriptan uptake in Caco-2 cells was temperature, pH and concentration dependent, and was partially counteracted by the action of an outwardly directed efflux pump, presumably p-glycoprotein. Absorption interactions should be considered when P-gp substrates or inhibitors, Na+ -H+ exchange inhibitors, P-gp ATPase agonists or inhibitors are co-administered with zomitriptan in clinical practice.
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PMID:Zolmitriptan uptake by human intestinal epithelial Caco-2 cells. 1706 26

This study tested whether sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist BQ-123 (1 microM) completely relaxed constriction to 10 nM endothelin-1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 microM), a sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase inhibitor, during the plateau of endothelin-1 constriction enhanced the constriction by approximately 30%. BQ-123 relaxed the endothelin-1 plus cyclopiazonic acid constriction by only approximately 10%. In contrast, prazosin (1 microM), an alpha-adrenergic receptor antagonist, still completely relaxed the 0.3 muM phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by approximately 30%, whereas Ni(2+) and 2-aminoethoxydiphenyl borate, nonselective cation channel and store-operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase activity selectively decreases the ability of endothelin receptor antagonist to inhibit the endothelin A receptor. The decreased antagonism may be related to the opening of store-operated channels and subsequent greater internalization of endothelin A receptor.
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PMID:Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibition prevents endothelin A receptor antagonism in rat aorta. 1717 80

T-wave alternans, an important arrhythmogenic factor, has recently been described in human fetuses. Here we sought to determine whether alternans can be induced in the embryonic mouse hearts, despite its underdeveloped sarcoplasmic reticulum (SR) and, if so, to analyze the response to pharmacological and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca-ATPase 2a expression in embryonic mouse hearts at embryonic day (E) 10.5 to E12.5, compared with neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Ca(i)) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Ca(i) transient alternans occurred during rapid pacing at an average cycle length of 212 +/- 34 ms in 57% (n = 15/26) of E10.5-E12.5 hearts. Maximum APD restitution slope was steeper in hearts developing alternans than those that did not (2.2 +/- 0.6 vs. 0.8 +/- 0.4; P < 0.001). Disabling SR Ca(i) cycling with thapsigargin plus ryanodine did not significantly reduce alternans incidence (44%, n = 8/18, P = 0.5), whereas isoproterenol (n = 14) increased the incidence to 100% (P < 0.05), coincident with steepening APD restitution slope. Verapamil abolished Ca(i) transients (n = 9). Thapsigargin plus ryanodine had no major effects on Ca(i)-transient amplitude or its half time of recovery in E10.5 hearts, but significantly depressed Ca(i)-transient amplitude (by 47 +/- 8%) and prolonged its half time of recovery (by 18 +/- 3%) in E11.5 and older hearts. Embryonic mouse ventricles can develop cardiac alternans, which generally is well correlated with APD restitution slope and does not depend on fully functional SR Ca(i) cycling.
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PMID:Cardiac alternans in embryonic mouse ventricles. 1802 42

The ATP-binding cassette (ABC) transporter protein subfamily B1 line (ABCB1) transporter P-glycoprotein (P-gp) plays an important role in the blood-brain barrier limiting a broad spectrum of substrates from entering the central nervous system. In the present study, the transport activity of P-gp for sertraline, desmethylsertraline, bupropion, and the major metabolites of bupropion, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB) was studied using an ATPase assay in expressed human P-gp membranes by measuring concentrations of inorganic P(i) in expressed human P-gp membranes. Verapamil was included as a positive control. The Michaelis-Menten equation was used for characterizing the kinetic data. Sertraline and desmethylsertraline showed high affinity for P-gp. The V(max)/K(m) values of sertraline (1.6 min(-1) x 10(-3)) and desmethylsertraline (1.4 min(-1) x 10(-3)) were comparable with that of verapamil (1.7 min(-1) x 10(-3)). Bupropion and its three metabolites showed very weak affinity for P-gp, with V(max)/K(m) values lower than 0.01 min(-1) x 10(-3). The results of the present study indicate that sertraline and desmethylsertraline have high affinity for P-gp, whereas bupropion and its three major metabolites TB, EB, and HB have very weak affinity for P-gp. These findings may help to explain observed drug-drug interactions among antidepressants.
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PMID:Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. 1823 78

Overexposure to cadmium (Cd) can induce kidney damage, which was related to the oxidative damage and disturb intracellular Ca2+ homeostasis. Chlorpromazine (CPZ), targeting calmodulin (CaM), and the Ca2+ channel blocker Verapamil (Ver) are involved in intracellular Ca2+ homeostasis processes. The aim of the study was to investigate the kidney damage caused by Cd administrated for 6 weeks and to evaluate the effects of pre-treatment with either chlorpromazine or verapamil on Cd-induced kidney damage. Thirty-two Wistar rats were divided randomly into 4 groups by weight, i.e., control group, Cd-treated group, and CPZ or Ver pre-treated group. The Cd-treated group rats were subcutaneously (s.c.) injected with 7micromol CdCl2/kg body weight/day. The CPZ and Ver pre-treated group rats were intraperitoneally (i.p.) injected with 5mg CPZ/kg body weight/day, 4mg Ver/kg body weight/day, respectively, 1h before the s.c. administration of 7micromol CdCl2/kg body weight/day. The control group rats were injected s.c. with saline at the same time. The volume of injection was 2ml/kg body weight, 5 times per week, for up to 6 weeks. After 6 weeks, Cd concentrations in the renal cortex and urine were significantly higher in Cd-treated group than that in controls. Cd concentrations of the urine in CPZ and Ver pre-treated groups were significantly lower than that in Cd-treated group, but there were no significant changes in the renal cortex. Compared with the controls, urinary NAG, ALP activities, and the levels of GSH, MDA, and the activities of PKC, Na(+)-K(+)-ATPase, and Ca(2+)-ATPase in rats from the Cd-treated group were significantly increased. SOD activity was suppressed by Cd. Urinary NAG activity and the level of GSH and the activities of PKC and Ca(2+)-ATPase in both CPZ and Ver pre-treated groups were significantly lower than that in Cd-treated rats. The present results showed that Cd-induced kidney damage was related to the oxidative damage and disturb intracellular Ca2+ homeostasis. Both CPZ and Ver possess some ability to prevent cadmium-induced kidney damage via antioxidative action and by maintaining calcium homeostasis.
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PMID:Protective effects of Chlorpromazine and Verapamil against cadmium-induced kidney damage in vivo. 1918 51


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