Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evaluation of a possible role of NaK-ATPase in transtubular sodium reabsorption is difficult, since ouabain doses that inhibit this enzyme system in vitro completely [1, 11], cannot be applied in vivo. Thus studies in the isolated perfused rat kidney were carried out [3, 11, 13, 15]. However, in this model, supramaximal doses of ouabain as used to block NaK-ATPase completely induced a potent vasoconstriction, which lowers the filtered load of sodium. Thus, a meaningful quantitative comparison of sodium transport in control and in experimental phases of ouabain inhibition has not been possible. At submaximal doses, in which filtered Na-loads are still comparable, transport activity was only reduced to approximately 50% [15]. In the following experiments we reinvestigated the relationship between inhibition of renal NaK-ATPase and the reduction of Na-reabsorption by ouabain under more appropriate conditions. Previously we have observed that verapamil (syn.: iproveratril, Isoptin), a Ca ion antagonist [2, 4, 6], effectively prevents autoregulation, and a fact which is pertinent for the present experiments, blocks this vasoconstrictive action of ouabain. Thus, using the Ca antagonist verapamil, it was possible to evaluate the inhibiting effect of this glycoside on renal sodium transport quantitatively without the hazards introduced by ouabain vasoconstriction which by the same token lowers filtered load.
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PMID:The effect of Ca ion antagonist verapamil on ouabain inhibition of renal sodium reabsorption. Studies in the isolated perfused rat kidney. 13 2

The Vmax of Ca2+ ATPase of pancreatic islets is reduced in states of chronic excess of PTH. This has been attributed to the reduced ATP content of pancreatic islet and to impaired response of the enzyme to calmodulin. It is also possible that excess PTH directly inhibits the activity of islet Ca2+ ATPase. The present study examined this issue. Small doses of 1-84 PTH (0.0625 and 0.125 x 10(-7) M) stimulated while larger doses (0.25, 0.5, 1.0, 2.0 and 4.0 x 10(-7) M) inhibited the activity of Ca2+ ATPase of intact islets. PTH has no effect on Ca2+ ATPase when the hormone was added to preparation of membrane homogenate of islets. Verapamil abolished both the stimulatory as well the inhibitory effects of PTH on Ca2+ ATPase of intact islets. The data indicate that PTH does not have a direct effect on the Vmax of islet Ca2+ ATPase of islet. Its effect on the enzyme activity of intact islet is most likely mediated through the hormone-induced calcium influx.
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PMID:Acute effect of parathyroid hormone on Ca2+ ATPase of pancreatic islets. 129 61

Phosphate depletion (PD) causes impaired insulin secretion and metabolic derangements in pancreatic islets. We studied PD, pair-weighed (PW), and PD and PW rats treated with verapamil (PD-V and PW-V) to examine the mechanisms of these derangements. Cytosolic calcium ([Ca2+]i) in PD islets was higher than that in PW, PD-V, and PW-V islets, and the values in the latter three groups were not different. Both basal and stimulated ATP in PD islets were lower than those in PW, PW-V, or PD-V islets. The maximum velocity (Vmax) of Ca(2+)-ATPase and the Km and Vmax of Na+,K(+)-ATPase were reduced in PD islets. In both PD-V and PW-V, the Vmax of Ca(2+)-ATPase was higher than that in PD, but lower than that in PW. Both initial and second phases of insulin secretion by PD islets were lower than those by PW and PW-V islets. In PD-V rats, insulin secretion was greater than that in PD rats, but only the second phase was significantly higher. The data are consistent with either of the following possibilities: 1) PD causes a change in the permeability of islets, allowing increased entry of Ca2+ into them and a fall in ATP of islets; the latter would impair the activity of both ATPases, leading to reduced Ca2+ extrusion from islets and, hence, an elevation in their [Ca2+]i; or 2) the primary defect in PD is a reduction in the activities of ATPases of islets due to the fall in ATP secondary to phosphorus deficiency. The decreased Ca2+ extrusion that ensues, even in the face of normal Ca2+ entry, will result in high [Ca2+]i. In either of these scenarios the rise in [Ca2+]i would inhibit mitochondrial oxygen consumption and ATP production, further lowering the ATP content of the islets. The higher [Ca2+]i and low ATP of PD underlie the impaired insulin secretion. Verapamil, by blocking normal or augmented Ca2+ entry into the islets, mitigates or prevents the derangements in islet function and metabolism.
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PMID:Verapamil corrects abnormal metabolism of pancreatic islets and insulin secretion in phosphate depletion. 130 29

Anthracycline accumulation was evaluated by flow cytometry or radiolabeled drug assays in cells and cytoplasts (enucleated cells) prepared from parental and multidrug-resistant human K562 leukemia cells. Treatment with energy inhibitors, such as dinitrophenol (DNP) or sodium azide/deoxyglucose, led to a marked decrease in daunorubicin accumulation in parental cells and cytoplasts. Another ionophore, monensin, also caused a significant decrease in daunorubicin accumulation; however, ATPase inhibitors ouabain, vanadate, and N-ethylamaleimide had little or no effect. The lysosomatropic agents chloroquine and methylamine caused a moderate decrease in anthracycline accumulation. Fluorescence microscopy showed that the DNP-sensitive daunorubicin uptake occurred in a nonnuclear subcellular compartment. Studies using increasing daunorubicin concentrations demonstrated fluorescence quenching that occurred in the nonnuclear, DNP-sensitive compartment. The effect of inhibitors on the accumulation of rhodamine 123 and acridine orange strongly implicated lysosomes as the principal compartment of this inhibitable daunorubicin accumulation. Cytoplasts from P-glycoprotein containing multidrug-resistant K562 cells demonstrated a verapamil-reversible, decreased daunorubicin accumulation that was observed in resistant whole cells. Verapamil pretreatment of cytoplasts from resistant cells revealed the subcellular DNP-sensitive uptake present in parental cytoplasts. These studies demonstrate that cytoplasts are an effective means to study drug transport in mammalian cells without nuclear drug binding. Parental K562 cells and cytoplasts exhibit an energy-dependent accumulation of daunorubicin into cytoplasmic organelles that is also present in resistant cells and cytoplasts when P-glycoprotein mediated efflux is inhibited.
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PMID:Energy-dependent accumulation of daunorubicin into subcellular compartments of human leukemia cells and cytoplasts. 135 Feb 80

Gentamicin and calcium compete for binding to various tissues including renal tubular brush border. Moreover, gentamicin has calcium channel blocking properties in cardiac and vascular tissue. Calcium channel blockade in vitro by nifedipine or verapamil decreases calcium uptake by renal tubular epithelial cells. To determine the acute in vivo effects of gentamicin on renal calcium handling, we administered gentamicin 10 mg/kg as an i.v. bolus to F344 rats. Within 30 min of administration fractional excretion of calcium increased from a mean of 11 +/- 2% (S.E.M.) to 128 +/- 37%. There was no change in glomerular filtration rate, or urinary sodium, potassium or phosphate excretion. Maximum calciuria occurred immediately after administration, was dose-related and was correlated to preadministration urinary calcium. Urine calcium concentration was also correlated to urinary gentamicin concentration. Urinary calcium returned to base-line values within 90 min of bolus gentamicin administration, but remained elevated if a gentamicin infusion was continued. Parathyroidectomy and dietary calcium content did not affect gentamicin calciuria. Tobramycin, a less nephrotoxic aminoglycoside in the F344 rat, had calciuric effects similar to gentamicin. Verapamil, a calcium channel blocker which is largely excluded from the urine, and potassium dichromate, a nonaminoglycoside proximal tubular nephrotoxin, had no effect on urinary calcium. The mechanism of aminoglycoside calciuria is unclear, but may be related to competition between aminoglycosides and calcium for brush border binding, intraluminal calcium channel blockade by aminoglycosides or aminoglycoside inhibition of basolateral calcium ATPase or Na-K ATPase.
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PMID:Aminoglycoside-mediated calciuresis. 162 95

The relationship between variations in diaphragmatic contractility and corresponding changes in total tissue levels of 45Ca and adenosine 3',5'-cyclic monophosphate (cAMP) was examined. The contractile performance of perfused contracting rat diaphragms was manipulated with theophylline (10(-4) M), induced fatigue, or both. The increased contractility associated with theophylline was related to significant increases in 45Ca levels without changes in cAMP levels. Fatigue-diminished contractility was associated with increases in both 45Ca and cAMP levels. The increased 45Ca and cAMP levels associated with fatigue persisted, even in the presence of theophylline. Calcium channel blockade with 10(-4) M verapamil blocked the positive inotropic influence of theophylline as well as the theophylline-associated increase in 45Ca levels. Verapamil had no effect on either the fatigue-associated decreases in contractility or the fatigue-enhanced 45Ca uptake. The results of this study strongly suggest that the enhanced contractility associated with theophylline is related to its influence on cellular calcium metabolism. The elevated level of isotopic calcium measured in fatigued muscle probably represents calcium sequestered in the sarcoplasmic reticulum, the result of cAMP-enhanced Ca-adenosine triphosphatase activity.
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PMID:Theophylline, fatigue, and diaphragm contractility: cellular levels of 45Ca and cAMP. 165 Jul 69

Phosphate depletion (PD) is associated with a rise in resting levels of [Ca2+]i in pancreatic islets. It is not known whether this derangement occurs in other cells, and the mechanisms by which PD affects [Ca2+]i have not been delineated. This study examined the effect of PD on [Ca2+]i of brain synaptosomes and evaluated potential mechanisms that may lead to rise in their [Ca2+]i. [Ca2+]i levels in synaptosomes of PD rats (460 +/- 18.3 nM) were higher (P less than 0.01) than those of pair-weighed (PW) rats (358 +/- 12.5 nM). Verapamil treatment of PD rats (PD-V) normalized [Ca2+]i in their synaptosomes (361 +/- 8.5 nM). In verapamil-treated PW rats (PW-V), synaptosomal [Ca2+]i (359 +/- 8.3 nM) was not affected. ATP content and Na(+)-K(+)-ATPase activity of synaptosomes were lower (P less than 0.01) in PD rats than in PW, PD-V, and PW-V rats. The values of these parameters from the latter three groups were not different. Km of synaptosomal Ca2(+)-ATPase was not affected by PD but Vmax of this enzyme (2.5 +/- 0.33 mumol Pi.mg protein-1.h-1) was lower (P less than 0.05) than in PW (5.4 +/- 0.66 mumol Pi.mg protein-1.h-1), PD-V, and PW-V rats. Our data indicate that PD raises [Ca2+]i in brain synaptosomes and suggest that PD increases calcium entry into synaptosomes. This would inhibit mitochondrial ATP production, with a consequent fall in ATP content of synaptosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphate depletion increases cytosolic calcium of brain synaptosomes. 184 11

Verapamil, a potent calcium channel blocker, was administered orally at three different doses to guinea pigs for both short- (4 weeks) and long-term (12 weeks) effects. The drug treatment stimulated Ca(++)-transport and Ca(++)-activated ATPase in isolated plasma membrane vesicles of guinea pig spermatozoa. Ca(++)-uptake studies exhibited partial to complete restoration of stimulated Ca(++)-transport during recovery period, whereas the CA(++)-activated ATPase system remained stimulated even after 4 and 6 weeks of withdrawal of the drug treatment. The lack of inhibitory effect of verapamil on Ca(++)-uptake ruled out the involvement of calcium channels in spermatozoal calcium uptake in guinea pigs. The stimulatory effect of the drug on CA(++)-uptake, on the other hand, might indicate the possible capability of this lipophilic compound to induce favourable changes in the lipid microenvironment of the membrane, wherein the integral membrane proteins operate.
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PMID:Verapamil stimulates Ca(++)-uptake and Ca(++)-ATPase in plasma membrane vesicles of guinea pig spermatozoa. 213 44

Inside-out vesicularized membrane fragments from human erythrocytes were prepared to study the effects of various Ca2+ channel entry blockers of plasma membrane Ca2+ transport and (Ca2+ + Mg2+)-ATPase activity concomitantly. Verapamil and diltiazem (0.01 to 5 mM) inhibited both (Ca2+ + Mg2+)-ATPase activity and initial rates of 45Ca2+ net uptake analogously. In general, the parameter affected most by these drugs, using either Ca2+ transport or (Ca2+ + Mg2+)-5'-adenosine-triphospho-hydrolase (EC 3.6.1.3) ([Ca2+ + Mg2+]-ATPase) measurements, was the stimulation by calmodulin. However, the specificity and selectivity of inhibition appeared to be highly concentration and membrane preparation dependent. Verapamil and diltiazem inhibited the calmodulin-Ca2+ transport concentration-effect relationship by changing its apparent affinity as well as the maximal velocity of the process. In a "white ghost" membrane preparation, bepridil inhibited calmodulin activation with a high degree of selectivity as opposed to its effects on calmodulin activation in the vesicular preparation. Nifedipine failed to exhibit any specificity and modestly inhibited basal and calmodulin-activated inside-out vesicular Ca2+ transport and (Ca2+ + Mg2+)-ATPase alike. Our results suggest that verapamil, diltiazem and bepridil (0.01 to 0.3 mM), but not nifedipine (1 nM to 0.01 mM), in relatively high concentrations can antagonize the calmodulin-stimulated Ca2(+)-pump, i.e. the ATPase as well as the transport process. The inhibitors differed with regard to potency, selectivity, and the type of inhibition they produced.
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PMID:Inhibition of erythrocyte Ca2(+)-pump by Ca2+ antagonists. 214 81

The inhibitory effects of Ca channel antagonists on gastric acid secretion [[14C]-aminopyrine (AP) uptake ratio] have been analyzed in isolated rabbit parletal cells (PC). Secretagogue-stimulated AP uptake was inhibited by verapamil and diltiazem in a dose-dependent manner with IC50 values of 15 and 100 microM, respectively, both in the presence and absence of extracellular Ca. In contrast, nifedipine had no effect on AP accumulation. Verapamil decreased histamine-stimulated respiration with the same IC50 as observed for AP uptake. Imidazole, a weak base, by buffering the acid spaces in PC, reversed the inhibitory effect of verapamil on respiration. In the bullfrog gastric mucosa, forskolin-stimulated proton transport was inhibited by verapamil (10(-4) M) from the luminal but not the serosal side. This inhibitory effect was reversed by either elevating KCl concentration in, or removing the drug from, the secretory solution. Verapamil inhibited gastric microsomal H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) and PC K(+)-stimulated p-nitrophenyl phosphatase activities with a higher potency than diltiazem. Inhibition of these enzymes by verapamil and diltiazem was pH dependent. The drugs competed with K+ in both H+,K(+)-ATPase and K(+)-stimulated p-nitrophenyl phosphatase reactions. Our data suggest that inhibition of the gastric proton pump by verapamil or diltiazem is not due to their Ca channel antagonism but to their interaction with the luminal high affinity K(+)-site of the H+,K(+)-ATPase under acidic conditions.
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PMID:Mechanisms of gastric proton pump inhibition by calcium channel antagonists. 215 90


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