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At least 19 recordsLinked to original sources
PubMed1990

Kinetic properties of cation/H(+)-exchange: calcimycin (A23187)-mediated Ca2+/2H(+)-exchange on the bilayer lipid membrane.

The calcimycin (A23187)-mediated electrically silent flux of hydrogen ions coupled with a counter transport of calcium or magnesium ions was measured by the method of local pH changes recording in the unstirred layers near the planar bilayer lipid membrane (BLM). It was shown that: (1) the pH dependence of calcimycin-mediated Ca2+/2H+ exchange had a maximum at pH 7; (2) the apparent Michaelis constant for the alkali earth cations were higher at acidic pH than the corresponding values at alkaline pH; (3) the apparent Michaelis constant for calcium was similar to that for magnesium ions in agreement with calcimycine cation binding constants; (4) the ratio of calcium and magnesium fluxes was independent of pH in the pH range from 5 to 8. (5) the flux was proportional to the calcimycin concentration at pH greater than 6.3 and proportional to the square of the carrier concentration at pH less than 5; (6) the addition of calcium ion chelator EDTA increased the flux significantly. These data were discussed in terms of the model of cation/H(+)-exchange and it was concluded that the dissociation of the cation-carrier complex at the membrane/water interface played an important role in the process of calcimycine operation. The comparison of the kinetic properties of calcimycin with the previously described kinetics of nigericin (Antonenko and Yaguzhinsky (1988) Biol. Membr. (Russian) 5, 718-728) revealed much similarity. On the other hand, a significant difference was found between the mechanism of the nigericin K/Na selectivity and calcimycin Ca/Mg selectivity.

Binding, Competitive↗
PubMed1990

[Inhibitory effect of dauricine on platelet activating factor released from calcimycin-induced mouse peritoneal macrophages].

The effects of dauricine (Dau) on the release of platelet activating factor (PAF) from mouse peritoneal macrophages stimulated by calcimycin (A-23187) was studied. The method of sodium [3H]acetate incorporating into macrophages to synthesize PAF was set up for the first time. Calcimycin (0.2 mumol/L) significantly induced mouse peritoneal macrophages to utilize sodium [3H]acetate to synthesize PAF. PAF released from macrophages medium fluid increased as the concentration of sodium [3H]acetate increased. The maximal amount of PAF released from macrophages was attained by incubating macrophages with sodium [3H]acetate (250 mumol/L) and calcimycin (2 mumol/L) over 30 min. Extracted by CHCl3:CH3OH:H2O (2:2:1.8), separated by thin layer chromatography (TLC) and determined by liquid scintillation counting, PAF released was inhibited significantly by Dau both in time (10-30 min) and dose (1-1000 mumol/L) dependent manners. The IC50 of Dau for the formation of PAF was 2.5 mumol/L. On the same condition PAF release was also significantly inhibited by quinacrine at 500 mumol/L. The results indicate that Dau is a potent inhibitor of PAF synthesis in mouse peritoneal macrophages.

Alkaloids↗
PubMed1991

Calcimycin potentiates responses of rat hippocampal neurons to N-methyl-D-aspartate.

We examined the effect of elevating intracellular calcium ([Ca2+]i) on responses to iontophoretically applied N-methyl-D-aspartate (NMDA), and quisqualate in CA1 neurons of the hippocampal slice. Topical application of calcimycin (A23187), a calcium ionophore, potentiated responses to NMDA but not to quisqualate. This potentiation was prevented by loading cells with the calcium chelator, BAPTA, suggesting that the action of calcimycin on NMDA receptors was mediated by an elevation of [Ca2+]i in the recorded cell. The potentiation was also recorded in voltage-clamped and in cesium-loaded cells, suggesting that it was not mediated by non-specific changes in voltage or input resistance of the cell that may have resulted from the rise in [Ca2+]i. We propose that intracellular calcium plays a crucial role in regulating the activity of the NMDA subtype of L-glutamate receptor.

Animals↗
PubMed1992

Inhibition of calcimycin-induced stimulation of cytosolic calcium in human PMN by a LTB4 receptor antagonist.

This study investigates the significance of PMN-derived LTB4 for PMN activation by using a selective LTB4 antagonist (SC 41930). Human PMN were stimulated by platelet-activating-factor (PAF, 3 microM), a receptor dependent agonist, or by calcimycin (A 23187, 10 microM), a receptor independent agonist. PMN activation was determined by LTB4 release and changes in free cytosolic Ca++ levels. Pretreatment of the PMN with SC 41930 (0.1-10 microM) caused a concentration-dependent inhibition of agonist induced rise in cytosolic Ca++ with both PAF and calcimycin. Interestingly, at the same concentrations of SC 41.930, there was a concentration-dependent inhibition of LTB4 release. Control experiments with a cell-free 5-lipoxygenase preparation did not show any direct effect of SC 41930 on the enzyme under conditions when nordihydroguiaretic acid was active. The data demonstrate a nonselective inhibition of agonist induced PMN activation by the LTB4 receptor antagonist SC 41930 and suggest that formation of endogenous LTB4 is involved in a positive feed-back loop that is required for maximum stimulation of PMN function even by a calcium ionophore.

Arachidonate 5-Lipoxygenase↗
PubMed1991

Effects of gossypol on phorbol ester-calcimycin-induced prostaglandin synthesis by macrophages.

Arachidonic acid metabolism via cyclooxygenase pathway in mouse resident peritoneal macrophages were stimulated by phorbol-12-myristate-13-acetate (PMA), calcimycin and exogenous arachidonic acid, respectively. Racemic, (-) and (+)-gossypol dose-dependently inhibited PMA or calcimycin-induced synthesis of prostacyclin, thromboxane A2 and prostaglandin F2 alpha, but failed to affect arachidonic acid-induced synthesis of prostaglandin. It is suggested that both (-)-gossypol and (+)-gossypol inhibit synthesis of prostaglandin at the level of arachidonic acid release, and the inhibition of prostaglandin synthesis by gossypol might not be the main mode of its antifertility action.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

[Inhibitory effect of esculentoside A on platelet activating factor released from calcimycin induced rat peritoneal macrophages].

Platelet activating factor (PAF) is a kind of inflammatory mediator. We used the method of aggregation of washed rabbit platelet to study the effect of esculentoside A (EsA) on the release of PAF from calcimycin (A23187)stimulated rat peritoneal macrophages and found that the release of PAF was inhibited by EsA in a time and dose dependent manner. The IC50 of EsA for the inhibition of PAF release was 1.5 mumol/L. Under the same condition, the release of PAF was also inhibited by mepacrine at 100 mumol/L. The results indicate that EsA is a potent inhibitor of PAF synthesis in rat peritoneal macrophages.

Animals↗
PubMed1991

[Effects of econazole and clotrimazole on TXB2 and PGE2 production in calcimycin-stimulated neutrophils and arachidonic acid-stimulated platelets].

The effects of econazole and clotrimazole which are used as antifungal agents, on TXB2 and PGE2 production in calcimycin (A-23187)-stimulated rat pleural neutrophils and arachidonic acid (AA)-stimulated washing rabbit platelets were examined by radioimmunoassay. Econazole and clotrimazole 0.05-100 mumol.L-1 inhibited TXB2 production both in rat pleural neutrophils and in rabbit platelets with a dose-dependent manner. The most potent inhibition was found in rabbit platelets. At the concentration of 50 mumol.L-1, econazole and clotrimazole were sufficient to inhibit TXB2 production in rabbit platelets by up to 99% and 98% respectively. Econazole and clotrimazole 0.05-5 mumol.L-1 also increased PGE2 biosynthesis in rabbit platelets. But econazole and clotrimazole 50 mumol.L-1 reduced the PGE2 production in rabbit platelets to 11% and 37% of the amounts of 5 mumol.L-1 econazole and clotrimazole respectively. The results suggest that econazole and clotrimazole at lower concentration may have a selective inhibitory effect on thromboxane synthetase, at higher concentration they also inhibit cyclooxygenase.

Animals↗
PubMed1992

A radioautographic study of [3H]-A 23187 (calcimycin) in components of the brain. Distribution in different cell types of the diencephalo-mesencephalic roof.

The distribution of the ionophore [3H]-A 23187 was examined by means of light and electron microscopy in elements of the central nervous system located in the diencephalo-mesencephalic roof. A 23187 is not evenly distributed in the components studied (ependyma, secretory ependyma of the subcommissural organ and neurons of the mesencephalon). At the cellular level, A 23187 appears preferentially associated with the cytoplasmic membrane as well as with the internal membranous system.

Animals↗
PubMed1992

Effects of regional ischaemia, with or without reperfusion, on endothelium dependent coronary relaxation in the dog.

OBJECTIVE: The aim was to establish whether the duration of coronary ischaemia and coronary ischaemia with reperfusion selectively reduced the magnitude of relaxation mediated by endothelium dependent relaxing factor (EDRF) in response to thrombin, compared with relaxation produced by acetylcholine and calcimycin. METHODS: Adult male dogs, anaesthetised with sodium pentobarbitone (30 mg.kg-1 intravenously) were used. Coronary artery occlusions were maintained for either 15 or 45 min; in half the dogs from each timepoint, occlusion was followed by 60 min reperfusion. At the end of each in situ period, coronary arteries were removed from both ischaemic and non-ischaemic regions, cut into rings, and hung in isolated organ baths. Dose-response relationships to the EDRF dependent vasodilators thrombin, acetylcholine, and calcimycin, and to the EDRF independent vasodilator isoprenaline, were then established. RESULTS: Thrombin (0.003-0.3 units.ml-1) caused dose dependent relaxation in all tissues. Relaxant responses (E(max)) in the non-ischaemic vessels from both 15 and 45 min treatment groups were used as control data for the responses in ischaemic vessels. Maximum responses were not different in the non-ischaemic groups from either 15 or 45 min studies, at 82.7 (SEM 3.7)% after 15 min, and 82.1(2.4)% after 45 min. There was a small but significant reduction in E(max) after 15 min and 45 min ischaemia, to 74.4(3.2)% and 74.4(3.0)% respectively. Sixty minutes reperfusion provoked a further reduction in E(max) to 64.9(3.8)% after 45 min ischaemia, but not after 15 min ischaemia [70.3(4.2)%]. Neither 15 nor 45 min interventions altered E(max) of relaxation to acetylcholine or calcimycin (greater than 88.0% in each group). Similarly there were no significant differences between groups to the relaxation stimulated by isoprenaline (E(max) greater than 90.0%). CONCLUSIONS: The data suggest that loss of EDRF dependent relaxation to thrombin is more sensitive to ischaemia than the relaxation produced by either acetylcholine or calcimycin, and appears to be manifested early in the onset of ischaemic injury.

Acetylcholine↗
PubMed1992

[Effects of ketotifen on human neutrophil respiratory burst and intracellular free calcium].

The stimulatory effect of FMLP 5 nmol.L-1, OAG 25 nmol.L-1 and calcimycin 10 nmol.L-1 on luminol-dependent chemiluminescence (CL) was observed in human neutrophils (Neu). The rest level of Neu intracellular free calcium ([Ca]i) measured by Ca(2+)-sensitive probe Quin 2/AM was calculated to be 200 +/- s 19 nmol.L-1. By the addition of FMLP 0.1 nmol.L-1 or calcimycin 0.5 nmol.L-1, the peak [Ca]i increased to 769 +/- 104 nmol.L-1 and 953 +/- 53 nmol.L-1, respectively. Ketotifen (50-300 mumol.L-1) inhibited Neu CL in a dose-dependent manner with activator FMLP. Inhibition was also seen when Neu CL was activated by calcimycin and OAG, respectively. However, ketotifen did not inhibit Neu [Ca]i increment activated by FMLP and calcimycin.

Calcimycin↗
PubMed1991

Inhibition of thrombin-induced endothelium-dependent relaxation after coronary ischemia in the dog: possible role of the coagulation cascade.

Myocardial ischemia inhibits endothelium-dependent relaxation stimulated by the coagulant peptide, thrombin. To investigate whether activation of endogenous thrombin contributed to this reduction in relaxant sensitivity, the effects of pretreatment of dogs with the coumarin anticoagulant, brodifacoum, were studied. Experiments were performed in both normal coronary vasculature and coronary vasculature exposed to 90 min of myocardial ischemia, with or without 60 min of subsequent reperfusion. Ischemia was induced in the left anterior descending artery (LAD); nonischemic vessels from the left circumflex (LCX) artery of the same animals were used as control. Thrombin caused dose-dependent relaxation in isolated LCX preconstricted with prostaglandin F2 alpha (Emax of 89.1 +/- 2.33%). Relaxation was reduced by 90 min of ischemia (Emax of 27.5 +/- 8.0%; p less than 0.05), and further reduced after subsequent reperfusion (Emax of 8.7 +/- 8.7%). However, maximum relaxations to acetylcholine, calcimycin, and isoproterenol were unchanged after ischemia (Emax greater than 90% in all groups). Brodifacoum had no effect on thrombin-induced relaxation in control vessels (Emax of 83.0 +/- 3.5%), or on relaxation in response to acetylcholine, calcimycin, or isoproterenol (Emax greater than 90%). In contrast, brodifacoum markedly reduced thrombin-induced relaxation after ischemia (Emax of 3.3 +/- 3.3%; p less than 0.05) yet significantly preserved the relaxant response to thrombin after ischemia and reperfusion (Emax of 36.6 +/- 4.3%). Infusion of the thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK), during ischemia and reperfusion also preserved in part the relaxant response induced by thrombin (Emax of 30.0 +/- 5.1%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

4-Hydroxycoumarins↗
PubMed1990

A novel method for the efficient entrapment of calcium in large unilamellar phospholipid vesicles.

A technique for the efficient entrapment of high concentrations of Ca2+ in large unilamellar phospholipid vesicles (LUVs), using the carboxylic acid antibiotic ionophore A23187 (calcimycin) is demonstrated. It is shown that rapid A23187-mediated entrapment of Ca2+, corresponding to essentially 100% sequestration of the extravesicular cation may be achieved for egg yolk phosphatidylcholine LUVs (100 nm) in the presence of a transmembrane proton gradient (acidic interior). Interior-exterior concentration cation gradients of over 400-fold may be readily achieved, with interior Ca2+ concentrations in excess of 250 mM. It is shown that the extent and efficiency of the A23187-mediated uptake process is affected by the intravesicular buffering capacity and the extravesicular Ca2+ concentration in a manner that is consistent with a Ca2(+)-H+ exchange process. In the absence of a pH gradient, or the presence of a reversed gradient (basic interior), only background levels of cation uptake are detected. The driving force for A23187-mediated uptake of Ca2+ is shown to depend on the intravesicular proton pool rather than on a chelation process. This protocol provides a novel method for the efficient entrapment of high concentrations of Ca2+ and other cations in phospholipid vesicles.

Biological Transport↗
PubMed1990

Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in carotid arteries from stroke-prone spontaneously hypertensive rats.

Endothelium-dependent relaxation of carotid arteries and changes in levels of cyclic (c)GMP between stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats have been compared. The concentration-response curve for acetylcholine (ACh)-induced relaxation was shifted to the right in carotid arteries from SHRSP. Relaxation responses produced by calcimycin (A 23187) and melittin, both endothelium-dependent agents, were depressed in carotid arteries from SHRSP. Relaxation responses produced by sodium nitroprusside and 8-Br-cGMP were similar to those in strips from WKY. ACh-induced production of cGMP was significantly decreased in carotid arteries from SHRSP when compared with the level for similarly treated strips from WKY. These results suggest that functional changes in endothelium, but not guanylate cyclase activity or cGMP sensitivity in the carotid arteries, may occur in hypertension. Thus, impaired endothelium-dependent relaxation in SHRSP may play an important role in hypertensive vascular diseases such as stroke.

Acetylcholine↗
PubMed1992

Inhibitory effects of tetrandrine on Bay k 8644-stimulated contraction of isolated rabbit aortic strips.

In the presence of KCl 19 mmol.L-1, calcium agonist Bay k 8644 0.47 mumol.L-1 elicited a strong contraction of isolated rabbit aortic strips, and this contraction was concentration-dependently inhibited by tetrandrine; but this antagonism was noncompetitive. Calcium ionophore calcimycin evoked contraction was markedly depressed by tetrandrine. The results suggested that tetrandrine might not only inhibit transmembrane influx of calcium via potential-dependent channels but also interfere with other processes related to calcium.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Protective role of heparin on in vitro functional aortic response in Watanabe heritable hyperlipidemic rabbits.

The effects of prolonged in vivo heparin treatment upon vasomotor responses and content of cholesterol and energy related compounds were studied in isolated thoracic and abdominal aortas from Watanabe heritable hyperlipidemic (WHHL) rabbits. Unfractionated heparin was administered subcutaneously (2 mg/kg twice a day) to 3-month-old WHHL rabbits for a period of 6 months. A group of WHHL rabbits was treated with saline solution and considered as control. Aortic cholesterol infiltration and serum cholesterol were not significantly decreased by the prolonged heparin treatment. In heparin-treated WHHL rabbits, the in vitro aortic endothelium-dependent relaxation produced by acetylcholine or calcimycin (A 23187) was greater than in saline-treated WHHL group. ATP-induced aorta relaxation (endothelium-dependent and endothelium-independent) did not vary significantly in the two groups of WHHL rabbits, even after mechanical removal of endothelium. Also the noradrenaline-induced aorta contraction did not vary between the two groups of WHHL rabbits. No significant variation in energy-related compounds (except for ADP) was found in the aortic arch. These results suggest that heparin produces a protective effect on aortic tissue by acting mainly at endothelial level.

Adenosine Triphosphate↗
PubMed1991

PGD2 and its mimetic ZK 110.841 are potent inhibitors of receptor-mediated activation of human neutrophils.

The action of PGD2 and its mimetic ZK 110.841 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15- dihydroxy-16,17,18,19, 20-pentanor-5,13-prostadienoic acid) was compared to PGE1 in vitro on superoxide anion generation, degranulation, leukotriene (LT) B4 release and Ca++ fluxes in human polymorphonuclear leukocytes (PMN). All compounds were potent inhibitors of formyl-methionyl-leucyl-phenylalanine (FMLP)- and platelet-activating factor (PAF)-induced superoxide anion generation, beta-glucuronidase release and Ca++ influx. The PAF-induced release of LTB4 in the presence of 10 mumoles/l arachidonic acid was significantly attenuated by these prostaglandins. This inhibition of PMN function was paralleled by an increase in cellular cAMP levels. The molar potency of the prostaglandins used was comparable, although the D-type compounds appeared slightly more potent in some PMN function tests. None of the substances affected PMN activation induced by the calcium inophore calcimycin (A23187). The data demonstrate an effective inhibition of receptor-mediated (FMLP, PAF) PMN activation by PGD2 and its mimetic ZK 110.841, suggesting either an inhibitory PGD2 receptor on human PMN or action of PGD2 at the PGE receptor. PGD2 is a labile compound in vivo and is rapidly metabolized into a number of products with different biological properties. Since ZK 110.841 lacks this instability, this compound may serve as an important tool to classify PGD2-mediated reactions.

Alprostadil↗
PubMed1991

Synthesis of platelet activating factor by ocular tissue from inflamed eyes.

Platelet activating factors (PAFs) are a family of ether lipids with properties that suggest a major role in inflammation. We have previously implicated PAFs in ocular inflammation based on the inhibition of several rabbit models of iritis with a specific PAF receptor antagonist. We have tested ocular tissues for the ability to synthesize PAF. Iris, ciliary body, cornea, and/or retina were carefully dissected from New Zealand white rabbits, and tissue from four eyes was pooled. Tissues were stimulated with calcium ionophore (10 mumol/L), and supernatants were extracted with chloroform-methanol. Platelet-aggregating activity was found in the chloroform phase in 2 of 9, 1 of 8, 0 of 9, and 3 of 9 studies involving iris, retina, ciliary body, or cornea, respectively. Twenty-four hours after the intravitreal injection of 125 ng of endotoxin, aggregating activity was consistently detectable from supernatants of stimulated iris and ciliary body, occasionally present from stimulated retina but not detectable from cornea. The shape of the aggregation curve resembled that produced by 0.5 to 2.0 ng of authentic PAF. Moreover, the aggregation could be completely inhibited by a PAF receptor antagonist and the aggregating activity chromatographed identically on high-performance liquid chromatography to a PAF standard. These studies indicate that PAF-like activity could be detected from several ocular tissues subsequent to inflammation. Iris, ciliary body, retina, vascular endothelium, and/or leukocytes could each contribute to the presence of this inflammatory mediator.

Animals↗