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 vasoactive peptide endothelin-1 (ET-1) which is present in high concentrations in the colon, causes concentration-dependent electrogenic Cl- secretion in rabbit descending colon. This effect is half-maximal at 0.11 mumol/l. Like other secretagogues, ET-1 also stimulates K+ secretion. The secretory effect of ET-1 is associated with increased release of prostaglandin E2 from the serosal surface of the mucosa. ET-1-induced Cl- secretion is completely inhibited by the loop diuretic bumetanide and by indomethacin and quinacrine, inhibitors of prostaglandin synthesis. Neuronal mechanisms do not seem to be involved, as tetrodotoxin did not affect the secretory response to ET-1 significantly. On the other hand, neither the catalytic activity nor the transport function of the Na+/K(+)-ATPase of rabbit colon epithelium is affected by endothelin-1 (ET-1) in concentrations up to 10 mumol/l. It is concluded that ET-1 causes Cl- and K+ secretion by stimulating phospholipase A2 and release of prostaglandins, whereas Na+ transport is not altered.
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PMID:Endothelin-1 stimulates chloride and potassium secretion in rabbit descending colon. 132 45

Sustained GnRH-stimulated LH release requires extracellular Ca2+, but GnRH transiently increases LH release in Ca(2+)-free medium. Here we have tested the dependence of the transient effect on intracellular Ca2+ pools. In superfused pituitary cells three Ca(2+)-mobilizing stimuli (GnRH, A23187, and endothelin-1) all caused sustained increases in LH release in normal medium (plateau responses), but only transient increases in Ca(2+)-free medium (spike responses). In Ca(2+)-free medium, GnRH (10(-10) or 10(-9) M) increased LH release transiently and desensitized the cells to the LH-releasing effect of subsequent stimulation with 10(-7) M GnRH. This desensitization was reversed by brief exposure to Ca(2+)-containing medium between the two GnRH stimulation periods. Heterologous desensitization between GnRH and A23187 and between GnRH and endothelin-1 also occurred in Ca(2+)-free medium. Thapsigargin, which inhibits the endoplasmic reticulum Ca(2+)-ATPase and thereby elevates cytosolic Ca2+, stimulated LH release (EC50, approximately 20 microM) in static culture, an effect which, unlike those of GnRH and A23187, was not markedly reduced in Ca(2+)-free medium. Low doses of thapsigargin, which had no effect on LH release alone, inhibited both sustained GnRH-stimulated LH release from static cultures in normal medium and transient GnRH-stimulated LH release from cells superfused in Ca(2+)-free medium. These data suggest that the spike phase of GnRH-stimulated LH release is not only associated with but is also dependent upon the mobilization of a GnRH- and thapsigargin-sensitive intracellular Ca2+ pool and that the Ca2+ pool mediating this GnRH effect is identical to or substantially interchangeable with A23187- and endothelin-1-mobilizable intracellular Ca2+ pools. Inhibition of sustained GnRH-stimulated LH release by thapsigargin also suggests the involvement of an intracellular Ca2+ pool in this phase of GnRH action.
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PMID:Dependence of gonadotropin-releasing hormone-stimulated luteinizing hormone release upon intracellular Ca2+ pools is revealed by desensitization and thapsigargin blockade. 153 42

1. We have previously demonstrated that cerebroventricular administration of potassium chloride (KCl) solutions produces dose-dependent reductions in blood pressure and heart rate in anaesthetized rats and that these effects are significantly attenuated by ouabain, a selective inhibitor of the Na(+)-pump. These observations suggest an important relationship between Na+,K(+)-ATPase activity in the central nervous system (CNS) and neural mechanisms involved in the regulation of cardiovascular function. 2. Since endothelin-1 (ET-1) has been shown to affect various ion transport mechanisms, including the Na(+)-pump, the present studies were conducted to evaluate whether this peptide would antagonize central effects of KCl. 3. The present studies demonstrate that cumulative doses of ET-1 (0.8-3.2 pmol, intracerebrolateral ventricular administration, i.c.v.) produced significant attenuation of hypotension and bradycardia produced by i.c.v. injections of KCl (0.75 mumol/5 microL, i.c.v.); in a separate series, a single high dose of ET-1 (4.0 pmol, i.c.v.) significantly reduced cardiovascular responses to various doses of KCl (0.375, 0.75, 1.25 mumol/5 microL, i.c.v.). 4. These studies suggest that endothelin may be involved in the regulation of arterial pressure since it is present in CNS and possesses a ouabain-like effect. However, it is not conclusive that ET-1 inhibits neuronal Na(+)-pump, since alternative mechanisms can also account for the efficacy of the peptide to antagonize central effects of potassium chloride.
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PMID:Antagonism by endothelin of centrally mediated cardiovascular effects of potassium in anaesthetized rats. 155 28

Endothelin has been shown to affect a broad range of renal functions, including rat inner medullary collecting duct Na/K ATPase activity, renin release, renal blood flow, and glomerular filtration rate. The source of endothelin in the kidney has been assumed to be endothelial cells. However, the inner medulla contains the highest concentration of immunoreactive endothelin in the kidney. Additionally, MDCK cells, a distal tubule-like cell line, synthesize endothelin. In order to determine if primary renal tubule cells release endothelin, supernatants collected from rat inner medullary collecting duct cells in culture were tested for endothelin-1 detected by specific radioimmunoassay. Inner medullary collecting duct cells produced endothelin-1 in a time-dependent manner, releasing 1,016.7 +/- 60.1 pg of endothelin-1 per mg/cell protein/24 h. Inner medullary collecting duct cells expressed a 2.2-kilobase mRNA on blot hybridization with rat prepro endothelin-1 cDNA. Vasopressin, thrombin, bradykinin, and epinephrine did not affect endothelin-1 release. These data demonstrate endothelin-1 production by inner medullary collecting duct cells and suggest a possible autocrine role for the peptide.
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PMID:Endothelin synthesis by rat inner medullary collecting duct cells. 195 27

Synaptosomes obtained from rat striata lesioned by central injection of endothelin-1 (ET-1) were analyzed for the levels of lipid peroxidation products, the susceptibility to lipid peroxidation, the phospholipid and free fatty acid composition and the activity of Na+,K(+)-ATPase one hour after ET-1 treatment. The intrastriatal injection of ET-1 promoted an increase of endogenous thiobarbituric reactive substances (TBARS), as index of free radical mediated lipid damage, and a greater susceptibility to iron/ascorbate-induced lipid peroxidation. The pattern of free fatty acids showed a significant decrease of arachidonic and docosahexaenoic acid consequent to ET-1 treatment. The analysis of lipid composition showed a significant loss of phospholipids: among phospholipid species, sphingomyelin and phosphatidylethanolamine plasmalogen were particularly reduced by ET-1 treatment. The activity of membrane-bound Na+,K(+)-ATPase was also significantly reduced in synaptosomes obtained from ET-1 lesioned striata. Taken together these results indicate a significant modification of synaptosomal membrane of ET-1 treated rat striata, possibly due to a free radical mediated damage.
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PMID:Effect of endothelin-1 induced ischemia on peroxidative damage and membrane properties in rat striatum synaptosomes. 756 65

We characterized Ca2+ entry in rat aortic smooth muscle cells (SMCs) maintained in primary culture by measuring uptake of 45Ca2+ or Mn2+ from a normal balanced salt solution and the extracellular Ca(2+)-induced increase in the intracellular Ca2+ concentration ([Ca2+]i) in a medium [high pH (pH 8.8)/high Mg2+ (20 mM) medium containing a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin] that inhibits removal of Ca2+ from the cytoplasm. Such measurements in the presence or absence of a dihydropyridine (DHP) calcium channel antagonist (PN200-110) or hyperpolarizing agent (valinomycin) revealed that DHP-sensitive voltage-gated Ca2+ channels (VGCCs) are activated in these SMCs under resting conditions and that DHP-sensitive Ca2+ entry occurs mostly via these VGCCs. We found that receptor stimulation by endothelin-1 in these SMCs resulted in activation of neither DHP-sensitive nor -insensitive Ca2+ entry, but rather resulted in marked suppression of the former. Utilizing the DHP-sensitive extracellular Ca(2+)-induced increase in [Ca2+]i as a monitor of activity of the DHP-sensitive VGCCs, we investigated the effects of protein kinase activators and phosphatase inhibitors on the regulation of these VGCCs. We found that the DHP-sensitive VGCCs were inhibited by endothelin-1 through the activation of protein kinase C. We also found that they were inhibited by 8Br-cGMP, okadaic acid, and calyculin A.
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PMID:Regulation of Ca2+ entry in rat aortic smooth muscle cells in primary culture. 782 43

1. It has been shown previously that nordihydroguaiaretic acid (NDGA) inhibits endothelin-1 (ET-1)-induced contractions in rat isolated tracheal smooth muscle. To investigate the underlying mechanisms, this study examined the effects of NDGA on various aspects of the ETA and ETB receptor-effector systems which mediate ET-1-induced contractions in this preparation. 2. NDGA inhibited contractions induced by each of the isoforms of ET (ET-1, ET-2 and ET-3) but not those induced by the ETB receptor-selective agonist, sarafotoxin S6c, the cholinoceptor agonist, carbachol or the depolarizing spasmogen, KCl. 3. Quantitative autoradiographic studies of [125I]-ET-1 binding to rat tracheal smooth muscle indicated that NDGA was not an ET receptor antagonist. 4. NDGA inhibited the ETA receptor-mediated, intracellular Ca(2+)-dependent contractions induced by 100 nM ET-1 in Ca(2+)-free solution (by 75%, P < 0.01). Furthermore, NDGA markedly inhibited the contractions induced by ryanodine and cyclopiazonic acid; contractions purportedly due to Ca2+ release from intracellular stores. 5. Like NDGA, the sarcoplasmic reticulum Ca(2+)-ATPase inhibitors cyclopiazonic acid and thapsigargin inhibited contractions to ET-1, but not carbachol or KCl. However, cyclopiazonic acid, but not NDGA, also (a) induced transient contractions in rat trachea, (b) potentiated contractions induced by KCl, and (c) potentiated the extracellular Ca(2+)-dependent phase of ET-1-induced contractions, indicating that NDGA did not inhibit ET-1-induced contractions through Ca(2+)-ATPase inhibition and depletion of sarcoplasmic reticular Ca2+. 6. In control preparations, ET-1 induced a slowly developing, sustained contraction. However, in the presence of NDGA or the ETA receptor antagonist, BQ123, ET-1-induced contractions resembled the transient contractions induced by sarafotoxin S6c. In nominally Ca2+-free solution, ETA receptor mediated contractions induced by ET-1 developed very slowly and were inhibited by NDGA.7. Additional studies indicated that the inhibitory effects of NDGA on endothelin-1-induced contractions were not the result of any significant actions of NDGA on lipoxygenase, cytochrome P450, L- orT-type Ca2+-channels, Na+-channels or protein kinase C.8. In summary, NDGA selectively inhibited ET-1-induced contractions in rat tracheal smooth muscle via a lipoxygenase-independent mechanism involving inhibition of the ETA but not the ETB, receptor effector system. NDGA did not appear to inhibit the initial events in the ETA signal transduction pathway, such as receptor binding and protein kinase C activation. However, NDGA inhibited the intracellular Ca2+-dependent component of ET-1-induced contraction, possibly by inhibiting mobilisation of intracellular Ca2+. As an apparent direct consequence of inhibiting the ETA receptor-effector system, NDGA markedly changed the time course of ET-1-induced contractions; from a slowly developing and sustained contraction into a transient contraction resembling that induced by sarafotoxin S6c.
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PMID:Inhibitory effects of nordihydroguaiaretic acid on ETA-receptor-mediated contractions to endothelin-1 in rat trachea. 800 99

Endothelin is a powerful inotropic peptide that increases isometric force in isolated papillary muscle and the extent of shortening in isolated single cardiac myocytes. Its mechanism of action has been variously attributed to increased Ca2+ activation, increased Ca2+ sensitivity of the contractile proteins, and increased intracellular pH, but the physiological function of the changes in cardiac performance remains obscure. In this study, the effects of endothelin-1 on both force development and the kinetics of contraction have been examined. Isometric force, actomyosin ATPase activity, and unloaded shortening velocity were measured. The effects were dose dependent. From 1 to 50 pmol/L endothelin-1 did not alter force development in isolated trabeculae with intact endothelial cells, but actomyosin ATPase activity was increased. Between 100 pmol/L and 10 nmol/L endothelin-1 raised isometric force, decreased actomyosin ATPase activity, and decreased unloaded shortening velocity. The reduction in ATPase activity was progressively enhanced as sarcomere length was increased from 1.9 t0 2.4 microns. These results indicate that the effects of endothelin-1 on the force of contraction and the rate of ATP hydrolysis are not tightly coupled and are changed in the opposite directions by endothelin-1 over most of its effective dose-range. This raises the possibility that endothelin-1 may increase the economy of contraction. A novel function of endothelin may be the modulation of the efficiency of contraction, particularly when increased preload raises the contractile work of the heart.
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PMID:Effect of endothelin-1 on actomyosin ATPase activity. Implications for the efficiency of contraction. 863 35

1. We have investigated the effect of propofol, an intravenous anaesthetic, on the intracellular calcium concentration ([Ca2+]i), Ca2+ entry pathways and on inositol phosphate formation in vascular smooth muscle cells. [Ca2+]i and Ca2+ flux were monitored with the Ca(2+)-sensitive fluorescent dye, fura-2, and by 45Ca2+ uptake. Production of labelled inositol phosphates was analysed by anion-exchange chromatography. 2. Treatment of the cells with endothelin-1 (ET-1) increased formation of inositol phosphates and elevated [Ca2+]i due to both release of Ca2+ from intracellular pools and prolonged entry of Ca2+ from outside the cell. Propofol reduced production of inositol phosphates mediated by ET-1 and arginine vasopressin which activate phospholipase C. 3. The sustained Ca2+ entry stimulated by ET-1 was found to occur through the activation of L-type Ca channels. This was inhibited by propofol in a dose-dependent manner. 4. Activation of protein kinase C (PKC) by phorbol esters activated a pharmacologically-similar channel and produced a similar change in [Ca2+]i due to Ca2+ entry. The entry was blocked by an L-type channel antagonist, nicardipine and by the anaesthetic drug, propofol. 5. Treatment of the cells with thapsigargin, a selective inhibitor of the sarcoplasmic reticulum Ca(2+)-ATPase, also elevated [Ca2+]i by inducing the release of intracellular Ca2+ and the continued entry of extracellular Ca2+ through a nicardipine-insensitive Ca channel. Neither release nor entry induced by thapsigargin was affected by propofol. 6. These findings suggest that propofol selectively inhibits Ca2+ entry through the L-type channel induced by ET-1 and phorbol esters but has no effects on Ca2+ entry via the nicardipine-insensitive channel and on Ca2+ release from intracellular pools initiated by thapsigargin. This may represent one of the mechanisms responsible for propofol-induced vasodilatation.
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PMID:Propofol regulation of calcium entry pathways in cultured A10 and rat aortic smooth muscle cells. 882 36

The release of the vasoactive peptide endothelin-1 (ET-1) is Ca2+ dependent after thrombin stimulation; however, little is known about the pathways involved. We studied the importance of Ca(2+)-dependent signal transduction pathways on preproET-1 mRNA induction in human endothelial cells. Thrombin-mediated preproET-1 mRNA induction was inhibited after clamping of cytosolic free CA2+ concentration ([Ca2+]i) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Chelation of extracellular Ca2+ with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid also had a significant inhibitory effect on the induction of preproET-1 mRNA. The Ca2+ ionophore A23187 induced constitutive as well as thrombin-stimulated preproET-1 mRNA expression. Mobilization of Ca2+ stores into the cytosol by inhibition of endoplasmic reticulum Ca(2+)-adenosinetriphosphatase with thapsigargin was effective also in inducing preproET-1 mRNA. Calmodulin antagonists W-7 and calmidazolium, as well as Ca2+/calmodulin-dependent kinase II inhibitor KN-62, significantly reduced thrombin-induced preproET-1 mRNA. Inhibition by cyclosporin A of the Ca(2+)-calmodulin-dependent phosphatase calcineurin potentiated constitutive preproET-1 mRNA. These data suggest that, in human endothelial cells, thrombin-mediated preproET-1 gene induction is regulated by a stimulatory Ca2+/calmodulin kinase II-dependent pathway.
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PMID:Roles of calcium and kinases in regulation of thrombin-stimulated preproendothelin-1 transcription. 894 10


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