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 uptake and release of Ca2+ were studied in EGTA-skinned aortic strips from spontaneously hypertensive rats (SHR strain: SAP = 191 +/- 5 mmHg, n = 27) and normotensive control rats (WKY strain: SAP = 131 +/- 2 mmHg, n = 25). 45Ca uptake was measured as a function of time (0.5 to 30 min.), at pCa 6.6, in the presence of 10 mM of K oxalate. Skinned aortic strips of SHRs accumulated more Ca2+ after 30 min of uptake than those of WKY rats (0.66 +/- 0.05 vs 0.52 +/- 0.03 nmole.mg-1 wet tissue; p < 0.05). A lower activity of the transport system in the hypertensive group was evidenced by the fraction of these maximal uptake values accumulated after 2 minutes of uptake, 56% compared with 98% in the normotensive group. 45Ca release was assayed in skinned aortic strips preloaded for 30 minutes with 45Ca in the absence of K oxalate and desaturated with washing solutions containing 3 nM free Ca2+. 30 mM of caffeine, 5 microM of norepinephrine or 10 microM of IP3 resulted in greater increases in the rates of Ca2+ efflux in WKY than in SHR aortic strips. Net effluxes of Ca2+ upon stimulation with all these drugs were statistically significant only in the hypertensive group due to its slightly but consistently higher Ca2+ content. Changes in both rate of efflux and net efflux induced by 30 mM of caffeine could be blocked by 0.6 mM of ryanodine. The sarcoplasmic reticulum is characterized in the genetically hypertensive rats by a low transport activity of its Ca(2+)-ATPase, a high Ca2+ content and a Ca2+ release mechanism with low responsiveness to stimulation by caffeine, norepinephrine and IP3.
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PMID:Uptake and release of Ca2+ in chemically skinned aortic strips from spontaneously hypertensive (SHR) and normotensive (WKY) rats. 765 Aug 44

1. The calcium channel antagonists verapamil (100 microM) and nifedipine (100 microM) inhibited twitch response and KCl induced hypercontractility in malignant hyperpyrexia (MH)-susceptible porcine skeletal muscle. These calcium channel antagonists did not effect hypercontractility induced by 3% halothane or 2 mM caffeine. 2. The calcium channel agonist BAY K 8644 (50 microM) induced contracture in MH-susceptible muscle but did not potentiate contracture response induced by 2 mM caffeine or 3% halothane. BAY K 8644 did not increase the resting tension of control muscle or increase the sensitivity of control muscle to 4 mM caffeine, 3% halothane or 80 mM KCl. 3. The sarcoplasmic reticulum (SR) from MH-susceptible and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 4. Verapamil and diltiazem [which has been previously shown to inhibit the hypercontractility of MH-susceptible porcine muscle to caffeine, halothane and KCl (Foster and Denborough, 1989 Br. J. Anaesth. 62, 566-572)] did not effect Ca2+ uptake or Ca(2+)-dependent ATPase activities of SR longitudinal tubule membranes, from MH-susceptible or control muscle. These calcium channel antagonists did not effect Ca2+ release from terminal cisternae preparations. 5. The skeletal muscle relaxant dantrolene inhibited Ca2+ efflux and equilibrium-Ca2+ exchange associated with the terminal cisternae membrane of MH-susceptible and control skeletal muscle. 6. Calcium channel antagonists modify Ca2+ fluxes in MH-susceptible and control muscle by acting at a site distal to the SR. Calcium channel antagonists may inhibit contractile response by modifying events of excitation-contraction coupling associated with the voltage sensor molecule (dihydropyridine-receptor) of the transverse-tubule membrane, whereas dantrolene directly acts on the terminal cisternae membrane to inhibit Ca2+ efflux and equilibrium Ca2+ exchange. Different calcium channel antagonists seem to modify the voltage-sensor mechanism in different ways in MH-susceptible muscle. 7. An abnormality in the coupling mechanism of the voltage sensor-SR calcium release channel may exist in MH-susceptible muscle. This dysfunction may be an adaptation to the elevated levels of myoplasmic Ca2+ and/or the molecular defect described in the Ca2+ release channel of the SR of MH-susceptible porcine muscle. In view of these results it is unlikely that nifedipine or verapamil would be of therapeutic value for the treatment of MH.
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PMID:The effect of calcium channel antagonists and BAY K 8644 on calcium fluxes of malignant hyperpyrexia-susceptible muscle. 768 90

A study of the properties of the sarcoplasmic reticulum was performed with newborn ferret cremaster muscles at two different development stages: at 8 and 21 days. The effects of extracellular Ca2+, caffeine and cyclopiazonic acid, a specific sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, were examined on intact cremaster skeletal muscles. The uptake and release of Ca2+ were explored on saponin-skinned fibres with or without cyclopiazonic acid and some results obtained were compared with those obtained with adult cremaster muscle. The results have shown that skeletal muscle sarcoplasmic reticulum of newborn animals possesses the ability to accumulate and release Ca2+. Furthermore, application of cyclopiazonic acid modified the twitch, the caffeine responses and decreased the amount of Ca2+ taken up by the sarcoplasmic reticulum in saponin-skinned fibres. In contrast to adult skeletal muscle, in newborn cremaster muscles, the Ca2+ dependence of the twitch suggests that the Ca2+ influx at the sarcolemma level was mainly involved in the activation of the contraction. Furthermore, the results obtained in the presence of cyclopiazonic acid were in favour, as in adult muscle, of a participation of the sarcoplasmic reticulum in the relaxation process.
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PMID:Sarcoplasmic reticulum function in newborn ferret cremaster skeletal muscles. 769 97

1. The mechanism of hydralazine-induced vasorelaxation was investigated in rabbit isolated aorta, by determining its ability to interfere with force development under a variety of conditions. 2. Hydralazine relaxed phenylephrine-contracted aorta with half maximal relaxation at 17 microM and maximal relaxation above 100 microM. At 200 microM, hydralazine had little effect on contractions induced by 25 mM or 50 mM K+. 3. Hydralazine was equally effective at inhibiting contractile responses to phenylephrine in the absence or presence of extracellular Ca2+. Responses to phenylephrine in Ca(2+)-free solution were blocked to the same degree whether hydralazine was applied during filling of the sarcoplasmic reticulum (SR) Ca2+ stores or after filling was complete. Caffeine-induced contractions were less sensitive to block by hydralazine. 4. Thapsigargin, cyclopiazonic acid, ryanodine, nifedipine and diltiazem all failed to block the inhibitory effect of hydralazine on tonic contractions to phenylephrine in the presence of extracellular Ca2+. However, when cyclopiazonic acid was applied either with diltiazem or ryanodine, substantial inhibition of the hydralazine response was observed. 5. We propose that tonic contractions to phenylephrine are largely maintained by Ca2+ cycling through the SR, with Ca2+ entering the smooth muscle cell being sequestered by the SR eventually to leak out through IP3-activated channels close to the contractile proteins. Sequestration of Ca2+ would employ two pathways, one sensitive to inhibitors of the SR Ca(2+)-ATPase and the other to Ca antagonists. We further suggest that, in the presence of extracellular Ca2+ and phenylephrine, the leakage of Ca2+through IP3-activated channels is significantly reduced only if both routes for SR Ca2+ accumulation are blocked or the Ca2+-ATPase is blocked while the SR is made leaky with ryanodine.6. We conclude that the main action of hydralazine is to block the IP3-dependent release of Ca2+ from the sarcoplasmic reticulum. Thus conditions that diminish the contribution of IP3-induced Ca2+ release to tension can inhibit the hydralazine-induced vasorelaxation.
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PMID:Inhibition of calcium release from the sarcoplasmic reticulum of rabbit aorta by hydralazine. 771 24

1. The intracellular Ca2+ concentration ([Ca2+]i) was measured in mesenteric artery smooth muscle cells using the fluorescent indicator indo-1. 2. Noradrenaline (1-10 microM) produced a transient increase in [Ca2+]i. This response was unaffected by the removal of external calcium suggesting that the bulk of the increase in [Ca2+]i produced by noradrenaline is due to release from an intracellular store. 3. The maintained application of caffeine (10 mM) produced a transient rise in [Ca2+]i. The rate of relaxation was slower than that of the noradrenaline response. If caffeine was removed at the peak of the rise in [Ca2+]i then [Ca2+]i recovered more quickly than was the case in both the maintained response to noradrenaline and that to caffeine. 4. In the presence of noradrenaline, caffeine or thapsigargin elevated [Ca2+]i. However, if thapsigargin or caffeine was added first, the subsequent application of noradrenaline did not increase [Ca2+]i, suggesting that only part of the caffeine-sensitive store is sensitive to noradrenaline. 5. The recovery of [Ca2+]i during the application of caffeine was unaffected by the removal of external sodium suggesting that Na+-Ca2+ exchange is not important in the reduction in [Ca2+]i. The addition of lanthanum (1 mM) did, however, greatly slow [Ca2+]i recovery. 6. We conclude that the three major factors responsible for removing Ca2+ ions from the cytoplasm are: (i) a caffeine- and noradrenaline-sensitive store (43%), (ii) a caffeine-sensitive but noradrenaline-insensitive store (36%), and (iii) a sarcolemmal Ca(2+)-ATPase (16%). Finally, a 5% contribution remains to be accounted for.
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PMID:Factors controlling changes in intracellular Ca2+ concentration produced by noradrenaline in rat mesenteric artery smooth muscle cells. 771 20

1. A method has been developed to discriminate between the rate of ATP hydrolysis associated with calcium uptake into the sarcoplasmic reticulum (SR) and force development of the contractile apparatus in mechanically or saponin-skinned skeletal muscle fibres. The rate of ATP hydrolysis was determined in fibres of different types from the iliofibularis muscle of Xenopus laevis by enzymatic coupling of ATP re-synthesis to the oxidation of NADH. 2. The ATPase activity was determined before and after exposure of the preparations for 30 min to a solution containing 0.5% Triton X-100, which effectively abolishes the SR ATPase activity. The fibres were activated in a solution containing 5 mM caffeine to ensure that calcium uptake into the SR was maximal. 3. At saturating Ca2+ concentrations the actomyosin (AM) and SR ATPase activities in fast-twitch fibres, at 4.3 degrees C, amounted to 1.52 +/- 0.07 and 0.58 +/- 0.10 mumol s-1 (g dry wt)-1, respectively (means +/- S.E.M.; n = 25). The SR ATPase activity was 25% of the total ATPase activity. At submaximal calcium concentrations the AM ATPase activity varied in proportion to the isometric force. 4. The calcium sensitivity of the SR ATPase was larger than that of the AM ATPase and its dependence on [Ca2+] was less steep. The AM ATPase activity was half-maximal at a pCa of 6.11 (pCa = -log [Ca2+]) whereas the SR ATPase activity was half-maximal at a pCa of 6.62. 5. In Triton X-100-treated fibres, at different 2,3-butanedione monoxime (BDM) concentrations, the AM ATPase activity and isometric force varied proportionally. The SR ATPase activity determined by extrapolation of the total ATPase activity in mechanically skinned or saponin-treated fibres to zero force, was independent of the BDM concentration in the range studied (0-20 mM). The values obtained for the SR ATPase activity in this way were similar to those obtained with Triton X-100 treatment. 6. The AM ATPase activity in slow-twitch fibres amounted to 0.74 +/- 0.13 mumol s-1 (g dry wt)-1, i.e. about a factor of two smaller than in fast-twitch fibres. The SR ATPase activity amounted to 0.47 +/- 0.07 mumol s-1 (g dry wt)-1, i.e. rather similar to the value in fast-twitch fibres. The proportion of the total ATPase activity that was due to SR ATPase (40%) was larger than in fast-twitch fibres. 7. The temperature dependence of the AM and SR ATPase activities in fast-twitch fibres differed. In the temperature range 5-10 degrees C, the relative changes in AM and SR ATPase activities for a 10 degrees C temperature change (Q10) were 3.9 +/- 0.3 and 7.2 +/- 1.5, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:ATP utilization for calcium uptake and force production in skinned muscle fibres of Xenopus laevis. 773 Sep 76

We have examined the effects of the muscarinic agonists, carbachol (CCh) and oxotremorine (Oxo), on the intracellular free Ca2+ concentration ([Ca2+]i) in acutely dissociated sympathetic neurons from adult rats using fura 2-based microfluorometry. The drugs increased [Ca2+]i by 86 +/- 7 and 38 +/- 10 nM for CCh and Oxo, respectively (both 10 microM). Basal [Ca2+]i was 52 +/- 3 nM. Depletion of the caffeine-sensitive Ca2+ store or blockade of the Ca(2+)-adenosinetriphosphatase with thapsigargin did not alter the effect of either agonist on the rise in [Ca2+]i. On the other hand, the omission of Ca2+ from the perfusion solution or the use of TA-3090, a Ca2+ channel antagonist, blocked the effects of CCh and Oxo. In whole cell current-clamp recordings, the muscarinic agonists elicited a depolarization and action potential firing, which probably explained the rise in [Ca2+]i observed with microfluorimetric recording. In addition to their direct effects on the [Ca2+]i, muscarinic agonists also reduced the rise in [Ca2+]i induced by a nicotinic agonist. This inhibitory effect, observed in 68% of cells that responded to the nicotinic agonist, was blocked by atropine and pertussis toxin, whereas the muscarinic agonist-induced increase in [Ca2+]i was blocked by atropine but was pertussis toxin insensitive. These results suggest that at least two muscarinic receptors are present on sympathetic neurons and that they mediate opposite effect on the fluctuation of [Ca2+]i.
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PMID:Increase in [Ca2+]i by CCh in adult rat sympathetic neurons are not dependent on intracellular Ca2+ pools. 773 31

In chromaffin cells of adrenal medulla, heterogeneity of Ca2+ stores has been suggested with respect to the mechanisms of Ca2+ uptake and release. We have examined Ca(2+)-ATPases responsible for loading of Ca2+ stores in these cells for their sensitivity to thapsigargin, a highly selective inhibitor of the SERCA [sarco(endo)plasmic reticulum calcium ATPase] family of intracellular Ca2+ pumps. Using immunostaining, we studied the distribution of Ca(2+)-ATPases, and of receptors for inositol 1,4,5-trisphosphate (InsP3) and ryanodine, in the density-gradient fractions of microsomes from bovine adrenal medulla. In parallel, we examined distribution profiles of ATP-dependent Ca2+ uptake in the same fractions, along with subcellular markers for plasma membranes and endoplasmic reticulum (ER). Two Ca(2+)-ATPase-like proteins (116 and 100 kDa) were detected, consistent with the presence of SERCA 2b and SERCA 3 isoenzymes of Ca2+ pumps. The distribution of these putative Ca(2+)-ATPase iso-enzymes paralleled that of InsP3 and ryanodine receptors. This distribution of ER Ca(2+)-ATPases, as determined immunologically, was consistent with that of thapsigargin-sensitive, but not of thapsigargin-insensitive, ATP-dependent Ca2+ uptake. In contrast, the distribution profile of the thapsigargin-insensitive Ca2+ uptake was strongly correlated to that of plasma membranes, and co-distributed with plasma membrane Ca(2+)-ATPase detected immunologically. In isolated, permeabilized chromaffin cells, InsP3 and caffeine induced Ca2+ release following an ATP-dependent Ca2+ accumulation to the stores. This accumulation was abolished by thapsigargin. Together, these data strongly indicate that the thapsigargin-sensitive, presumably SERCA-type Ca(2+)-ATPases account for Ca2+ uptake to InsP3-sensitive, as well as to caffeine-sensitive, Ca2+ stores in bovine adrenal chromaffin cells.
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PMID:Thapsigargin-sensitive Ca(2+)-ATPases account for Ca2+ uptake to inositol 1,4,5-trisphosphate-sensitive and caffeine-sensitive Ca2+ stores in adrenal chromaffin cells. 774 6

Enzymes of the cytochrome P450 superfamily play a key role in xenobiotic metabolism. Their properties and significance are discussed with particular reference to interactions with the H+,K(+)-ATPase blocker, omeprazole. Such interactions include both inhibitory (subfamily 2C) and inducing effects (subfamily 1A). Delayed metabolic elimination of diazepam, warfarin, carbamazepin and phenytoin is probably due to omeprazole competition for the concerned isoform of subfamily 2C; however, these effects are modest to negligible in magnitude and, for phenytoin, not consistently reproducible. Also, induction of subfamily 1A is only minor as assessed from the resultant changes in N-3-demethylation of caffeine, a reaction specific to this subfamily. Concerns about a possible activation of procarcinogens that might arise from subfamily 1A induction appear ill-founded given the fact that cruciferous vegetables such as broccoli and Brussels sprouts are potent inducers, but rather seem to lower the incidence of certain types of cancer. Likewise, the idea that the toxicity of acetaminophen might increase upon subfamily 1A induction appears far-fetched, mainly because much stronger inducers of subfamily 1A (cigarette smoke and charcoaled beef) are unable to alter acetaminophen metabolism.
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PMID:Review article: omeprazole and the cytochrome P450 system. 776 37

In a freshly isolated endothelial cell preparation from rabbit aorta, the regulation of the acetylcholine (ACh)-sensitive intracellular Ca2+ store and the effects of the Ca(2+)-induced Ca2+ release agonists ryanodine and caffeine were studied using fura 2 imaging fluorescence microscopy. ACh (10 mumol/L) caused a transient release of Ca2+ from an intracellular store, presumably via an inositol tris-phosphate-sensitive mechanism. This ACh response could be repeated in the presence of extracellular Ca2+ but was obtained only once in Ca(2+)-free bathing solution, which shows that a depleted intracellular Ca2+ store can be rapidly refilled from the extracellular space. Refilling can be prevented by the endoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid (10 mumol/L), implying that Ca2+ enters the cytoplasm before accumulation in the endoplasmic reticulum. Ionomycin (10 mumol/L) caused a large Ca2+ release even after the ACh-releasable store had been emptied, indicating the existence of other ACh-insensitive stores, perhaps including the mitochondria. In one third of the cells studied, ACh induced oscillations in [Ca2+]i that were dependent on extracellular Ca2+. Also investigated were the effects of caffeine and ryanodine. In this cell preparation neither caffeine nor ryanodine induced a Ca2+ transient but instead slowly increased [Ca2+]i. It was observed that both caffeine and ryanodine were able to slowly deplete the ACh-sensitive store. These results indicate the presence of functional ryanodine receptors in native endothelial cells and demonstrate overlap between the caffeine and agonist-sensitive Ca2+ stores. We also found that caffeine was able to directly inhibit the process of ACh-induced Ca2+ release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylcholine-sensitive intracellular Ca2+ store in fresh endothelial cells and evidence for ryanodine receptors. 778 80


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