Effects of smooth muscle calcium antagonists on human basophil histamine release.
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Basophils↗
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Effect of three calcium antagonists on platelet secretion and metabolism.
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Blood Platelets↗
Inhibition of agonist-induced hydrolysis of phosphatidylinositol and muscarinic receptor binding by the calcium antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate-HCl (TMB-8).
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Animals↗
Inhibition of calcium uptake and catecholamine release by 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) in cultured bovine adrenal chromaffin cells.
Effects of intracellular calcium antagonists, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) and 1-(5-(p-nitrophenyl)-furfurylidene-amino) hydantoin sodium hydrate (dantrolene sodium), on catecholamine release and 45Ca2+ uptake were studied using cultured bovine adrenal chromaffin cells. TMB-8 inhibited carbamylcholine-evoked catecholamine release and 45Ca2+ uptake in a concentration-dependent manner with a similar potency. On the contrary, dantrolene sodium did not show obvious inhibitory effects of catecholamine release and 45Ca2+ uptake. Although TMB-8 inhibited the high K+-evoked catecholamine release and 45Ca2+ uptake, the potency of the drug was approximately 100-fold less than when used to inhibit the carbamylcholine-evoked catecholamine release and 45Ca2+ uptake. The inhibitory effect of TMB-8 on the carbamylcholine-evoked catecholamine release was not overcome by an increase in an extracellular calcium concentration, and was not due to competitive antagonism at the nicotinic receptor site. Moreover, TMB-8 inhibited the carbamylcholine-stimulated 45Ca2+ efflux, but dantrolene sodium failed to affect it. These results suggest that TMB-8, a well-known intracellular calcium antagonist, prevents the cellular calcium uptake in cultured adrenal chromaffin cells, and thus prevents catecholamine release.
Adrenal Glands↗
Inhibition of the thromboplastin response of endothelial cells in vitro.
Confluent monolayers of human umbilical vein endothelial cells in culture responded with a 5-fold increase in thromboplastin (tissue factor) synthesis when exposed to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) (50 ng/ml) or endotoxin (ETX) (25 micrograms/ml) for 16 hr. This induced thromboplastin synthesis was markedly inhibited by exposure of the cells to two different phosphodiesterase inhibitors, methylisobutylxanthine (MIX) and rac-4(3-butoxy-4-methoxybenzyl)-2-imidazole idinone (RO-20-1724) and to the transmethylation inhibitors 3-deazaadenosine (DZA) and 1-homocysteine thiolactone (Hcy) in combination. It was slightly (TPA) or not at all (ETX) inhibited upon exposure of the cells to the intracellular calcium antagonist 8-(N,N-diethylamino)-octyl 3,4, 5-trimethoxybenzoate hydrochloride (TMB-8). However, in the presence of MIX TMB-8 had a moderate additional inhibitory effect on TPA-induced thromboplastin response. The thromboplastin response of endothelial cells in vitro thus probably depends on transmethylation events for its full expression. It is also strongly modulated by the intracellular level of cAMP.
1-Methyl-3-isobutylxanthine↗
Stimulation of renin secretion by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8).
The intracellular calcium antagonist 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) prevents the release of Ca2+ from cell storage sites. The effect of this compound on renin secretion from rat renal cortical slices in vitro was investigated. TMB-8 was a potent stimulant of renin secretion within the concentration range 10(-5)M to 5 X 10(-4)M with an optimum concentration of 2 X 10(-4)M. TMB-8 overcame the inhibition of renin secretion by angiotensin II, ouabain, 60 mM KCl and A23187. The results add to the existing evidence that Ca2+ is a common inhibitory messenger for a number of compounds which affect renin release and suggest a role for intracellular calcium stores in the regulation of juxtaglomerular cell Ca2+ levels.
Animals↗
AGN 2979 [3(3-methoxyphenyl)-3-(3-dimethylaminopropyl)-4, 4-dimethylpiperidine-2,6-dione]. An inhibitor of the activation of tryptophan hydroxylase.
AGN 2979 [3-(3-methoxyphenyl)-3-(3-dimethylaminopropyl)-4, 4-dimethylpiperidine-2,6-dione] blocked the increase in tryptophan hydroxylase activity that occurred when slices of brainstem were exposed to a depolarizing medium or to agents that mobilize intracellular pools of calcium, but it had no effect on the activity of enzyme prepared from slices of brainstem incubated in control medium. AGN 2979 also blocked the calcium-calmodulin-dependent activation of tryptophan hydroxylase that was seen when supernatant preparations of the enzyme were exposed to phosphorylating conditions but not the activation induced by calcium-dependent proteases that was triggered by millimolar calcium concentrations. An identical pattern of inhibition has been found with the antipsychotic drugs, haloperidol and fluphenazine [Boadle-Biber, Biochem. Pharmac. 31, 2495 (1982)]. The sensitivity to the same inhibitors of both the activation of tryptophan hydroxylase produced by pretreatment of brainstem slices and that induced by incubation of supernatant preparations of enzyme under phosphorylating conditions suggests involvement of a common mechanism of enzyme activation in response to these different treatments.
Animals↗
Effect of some drugs on thromboplastin activity in mouse trophoblast cells in vitro and in vivo.
Mouse trophoblast cells are constitutive producers of the thromboplastin apoprotein in vitro. The effects on thromboplastin activity of the three transmethylation inhibitors 3-deazaadenosine (DZA), 3-deazaaristeromycin (DZAri) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), the four calcium antagonists TMB-8, verapamil, nifedipine and felodipine, the prostaglandin E2 (PGE2), the phosphodiesterase inhibitor 1-methyl 3-isobutylxanthine (MIX) and monensin have been studied. No cytotoxic effects were detected when trypan blue exclusion, release of lactic dehydrogenase, incorporation of 14C-leucine into protein and cell morphology were monitored. TMB-8, felodipine, nifedipine and verapamil all abolished the increase in thromboplastin when added after 68 hr or 90-96 hr in culture. EHNA and DZAri had the same effect (but were only added at 90-96 hr). DZA had a similar effect when added at 68 hr and an even more marked inhibitory effect when added at 90-96 hr. Monensin prevented the increase in thromboplastin activity at 68 hr as well as at 90-96 hr. The combination of DZA and 1-homocysteine thiolactone (Hcy) further increased the inhibition, indicating that in these cases synthesis as well as degradation of thromboplastin were altered. The combination of DZA/Hcy and one of the four calcium antagonists gave no additional inhibitory effect. PGE2 had a biphasic dose-dependent effect. The increased thromboplastin activity at low concentrations of PGE2 (10 ng/ml) was inhibited by addition of one of the compounds verapamil, felodipine, nifedipine or DZA/Hcy. PGE2 at higher levels (10 micrograms/ml) significantly inhibited thromboplastin synthesis. Combination of PGE2 (10 micrograms/ml) and one of the calcium antagonists, DZA/Hcy or MIX gave no significant additive inhibitory effect.
1-Methyl-3-isobutylxanthine↗
Influence of 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) on cell cycle progression and proliferation of cultured arterial smooth muscle cells.
8-(N,N-Diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), a putative inhibitor of intracellular calcium mobilization, causes a dose-dependent inhibition of serum-induced proliferation of arterial smooth muscle cells in culture. Neither early rise in cytosolic calcium concentration nor induction of early induced cell cycle dependent genes (c-fos, ornithine decarboxylase) are inhibited after serum stimulation in presence of 100 microM TMB-8. In contrast, expression of thymidine kinase, a gene normally induced in late-G1 phase, is entirely inhibited by TMB-8. Taken together with flow cytometry studies, these results indicate that TMB-8 blocks cell cycle progression in mid- or late-G1 phase by a mechanism not directly related to early responses to serum stimulation since TMB-8 is also effective when introduced several hours after serum stimulation.
Animals↗
Effects of 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate (TMB8) on rat atrial muscle.
Rat atria loaded in vitro with the dye INDO-1 produced fluorescence signals indicative of changes in cytoplasmic calcium ion concentration ([Ca2+]c). Such atria showed systolic/diastolic fluctuations in fluorescence indicative of a systolic rise and a diastolic fall in [Ca2+] while being superfused with a solution containing a normal Ca2+ concentration. Some atria were then exposed to a low [Ca2+] in the superfusate. This caused negative inotropism and fluorescence changes indicative of a decline in [Ca2+]c. Both of these responses were reversed by adding 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate (TMB8; 2 microM) to the superfusate. Some atria were exposed instead either to a low [K+] in the superfusate or to an ouabain-containing superfusate. These atria developed a contracture, associated with fluorescence changes indicative of a rise in [Ca2+]c. The addition of TMB8 (2 microM) now relaxed the contracture, and this was associated with fluorescence changes indicative of a decline in [Ca2+]c. Atria that were exposed for 15 min to a low [Na+] in the superfusate developed a period of positive inotropism, followed by a brief period of negative inotropism on return to the normal superfusate. The period of positive inotropism was associated with fluorescence changes indicative of a rise in [Ca2+]c and the period of negative inotropism with a decline in [Ca2+]c to below baseline levels. All of these responses were less marked in atria exposed throughout to superfusates containing TMB8 (2 microM). Some atria were loaded with the dye SNARF-1. This emits fluorescence signals indicative of changes in cytoplasmic pH (pHc). These atria showed no systolic/diastolic fluctuation of fluorescence, but when superfused with a bicarbonate-free solution they displayed a change in fluorescence indicative of a decline in pHc in response to the addition of either ouabain or TMB8. Similarities were found between the effects produced by TMB8 and those produced by amiloride or dichlorobenzyl amiloride, suggesting that all three agents inhibit plasmalemmal Na+/Ca2+ and Na+/H+ exchange.
Amiloride↗
Common food additives are potent inhibitors of human liver 17 alpha-ethinyloestradiol and dopamine sulphotransferases.
Interactions between dietary xenobiotics, drugs and biologically active endogenous compounds are a potential source of idiosyncratic adverse pathology. We have examined the inhibition of the sulphation of a number of xenobiotics and endobiotics in human liver cytosol by 15 food additives and constituents. Sulphation of dehydroepiandrosterone was resistant to inhibition by all compounds tested; however, dopamine sulphotransferase (ST) activity was inhibited strongly by (+/-)-catechin, (+)-catechin, octyl gallate, tartrazine and vanillin. Sulphation of the xenobiotic steroid 17 alpha-ethinyloestradiol (EE2) was inhibited by vanillin, erythrosin B and octyl gallate. Of these compounds, only vanillin was found to be sulphated to a significant extent by both human liver and platelets, and vanillin was determined to be a substrate for the monoamine-sulphating isoenzyme of phenolsulphotransferase. Vanillin was found to inhibit 50% of liver EE2 ST activity (IC50) at a concentration of approximately 1.3 microM and the mode of inhibition was non-competitive. The implications of these results for the adverse side effects associated with food additives and oral contraceptives are discussed.
Arylsulfotransferase↗
The osmium-ethyl gallate procedure is superior to silver impregnations for mapping neuronal pathways.
Ganglia processed through the osmium-ethyl gallate procedure (OEG)19 retain more structural integrity than those processed through various silver impregnation methods. However, the OEG method continues to be neglected by most neuroanatomists. Both types of procedures have been used to trace large neuronal tracts, but during silver impregnation the neuropils lose many of their identifying characteristics. We demonstrate here the advantages of the OEG procedure by comparing it with two silver techniques, Rowell's and Holmes's. The OEG method yields consistent and reliable results and is easier to carry out than silver protocols. Most importantly, the better preservation of the neuropils has led to the discovery and study of regional specializations that were previously undetected from silver preparations.
Animals↗
Immune interferon induction by T-cell mitogens involves different T-cell subpopulations.
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Animals↗
Implications of a rise in cytosolic free calcium in the activation of RAW-264 macrophages for tumor cell killing.
The concentration of cytosolic-free calcium (Ca2+i) was determined with aequorin in RAW-264 macrophage-like cells activated in vitro for tumor cell killing with lymphokine (LK) and lipopolysaccharide (LPS). Treatments of these cells with optimal doses of stimulants, which evoked the development of cytolytic activity, also induced a rise in their Ca2+i. No rise in Ca2+i could be observed under treatments which failed to activate cells. The presence of both stimulants was an absolute requirement for evoking cytolytic activity and also a rise in Ca2+i. There was an apparent parallelism between the rate of activation and the rate of rise in Ca2+i. Cells which slowly developed their cytolytic activity exhibited a slow rise in Ca2+i, while macrophages which acquired their cytolytic activity at the faster rate also showed a more rapid increase in Ca2+i. The development of cytolytic activity in RAW-264 macrophages was inhibited by two intracellular calcium antagonists, TMB-8 and ruthenium red. This inhibition could be reversed by high concentrations of extracellular calcium. TMB-8, at the concentrations which were effective in inhibiting the activation process, also completely blocked the associated rise in Ca2+i. These results suggested that Ca2+i might play a role in the mechanism of tumoricidal transformation of RAW-264 macrophages.
Aequorin↗
Effect of propylgallate on a dipalmitoylphosphatidylglycerol and calcium mixture.
Effect of propylgallate (PrG) on the thermotropic behavior of mixtures of dipalmitoylphosphatidylglycerol (DPPG) and Ca2+ was studied by means of differential scanning calorimetry (DSC). In the case of DPPG or DPPG/Ca (molar ratio, 15 : 1), the transition temperature (Tm) of the main transition and the subtransition decreased from 40 degrees C to 29 degrees C and from 29 degrees C to 20 degrees C, respectively, with an increase in the concentration of PrG. The addition of PrG to the DPPG/Ca mixture induced a shoulder on the high temperature side in the reheating scan. Neither PrG nor low concentrations of Ca2+ bind to the Lc phase of DPPG. When the molar ratio of DPPG to Ca was 1 : 1, the subtransition did not occur, that is, only the main transition (Tm = 90 degrees C) appeared. The Tm of the main transition was slightly affected by PrG. On the addition of PrG, another metastable endothermic transition peak (Tm = 78 degrees C) appeared. It is concluded that Ca2+ and PrG inhibit each other's binding.
Calcium↗
Low temperature and muscarinic receptor activities.
Lowering temperature from 37 degrees C to 22, 18, and 14 degrees C triggered automaticity of smooth longitudinal muscle of guinea pig isolated ileum. The amplitude of the hypothermia-induced automaticity was dependent on the degree of temperature drop: the greater the temperature drop, the greater the amplitude. However, when the preparation was initially prepared and maintained at 14 degrees C and then the temperature was raised at a similar rate to 18, 22, and 37 degrees C, the automaticity was not observed. This series of observations suggests that cooling rate may be the trigger and/or part of the triggering mechanism for the observed automaticity. Mepenzolate (1.0 x 10(-6) M), a specific muscarinic receptor antagonist, blocked the automaticity suggesting the involvement of muscarinic receptors in the pathogenesis and/or the manifestation of the automaticity. Verapamil (1.0 x 10(-7) M), a calcium channel blocker which inhibits the transmembrane Ca2+ influx into smooth muscle cells during excitation, blocked the automaticity suggesting that transmembrane Ca2+ influx plays a significant role in the pathogenesis and/or manifestation of the automaticity. A specific cytoplasmic calcium channel blocker, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (1.0 x 10(-6) M) blocked the automaticity, suggesting that cytoplasmic calcium also plays a significant role in the pathogenesis and/or manifestation of the automaticity. In order to characterize the temperature-induced changes in the muscarinic receptors, an attempt was made to use the classic method of Furchgott and Burstyn to determine the dissociation constants of acetylcholine at muscarinic receptors at different temperatures. However, the alkylation of muscarinic receptors with phenoxybenzamine at lower temperatures was erratic and the recovery from the occlusion was too rapid to apply the method of Furchgott and Burstyn. We concluded that the lack of reversibility of the effects of phenoxybenzamine at 37 degrees C is due to the predominance of covalent bonding of phenoxybenzamine with the receptors, whereas at lower temperatures like 24 degrees C, the blockade of the muscarinic receptors by phenoxybenzamine is mainly due to simple occlusion.
Acetylcholine↗
Calcium antagonists and calmodulin inhibitors block cytokinin-induced bud formation in Funaria.
The plant hormone cytokinin stimulates nuclear migration followed by an asymmetric cell division in target cells of the protonema of the moss Funaria hygrometrica, leading to bud formation. The role of calcium in this developmental event was investigated by examining the effects of various calcium antagonists on the cytokinin-induced division. Calcium-free medium (buffered with EGTA), the extracellular Ca2+ antagonist La3+ (lanthanum), and the Ca2+ channel inhibitors D 600 and verapamil all block bud formation. These inhibitions are partially reversed by washing the cells or by raising the extracellular [Ca2+]. The Ca2+ ionophore A23187 partially reversed the effects of D 600 and verapamil. Bud formation is also inhibited by the intracellular Ca2+ antagonist TMB-8 (8-diethylamino)octyl 3,4,5-trimethoxybenzoate HCl), and this inhibition is partially reversed by washing or raising the extracellular [Ca2+]. The cross walls of both the filaments and bud initial cells formed during TMB-8 exposure exhibit a distorted morphology. High concentrations of TMB-8 block nuclear migration. The calmodulin inhibitor trifluoperazine stops cytokinin-induced budding more effectively than the related compound chlorpromazine. Low concentrations of these two compounds do not affect nuclear migration; however, the target cell does not enter mitosis. These results support the hypothesis that a rise in intracellular calcium mediates cytokinin-induced bud formation in Funaria. It is concluded that the proposed cytokinin-induced rise in intracellular calcium may be effected in part by the activation of calmodulin. The essential source of Ca2+ appears to be extracellular, because blocking Ca2+ uptake with Ca2+ transport inhibitors can block both nuclear migration and subsequent division.
Calcium↗
The cortical reaction in the egg of Discoglossus pictus: a study of the changes in the endoplasmic reticulum at activation.
In Discoglossus pictus previous ultrastructural observations have shown that at the animal dimple, where sperm fuse with the egg, cortical granules (CG), vacuoles, and tightly packed clusters of small cisternae are present. At fertilization the clusters open (i.e., become loose) and give rise to longer cisternae arranged in whorls and chains which migrate toward the plasma membrane. The vacuoles fuse to form cisternae and exocytose along with the CG. In the rest of the egg periphery, while exocytosis occurs, the clusters do not open as a result of activation (C. Campanella, R. Talevi, U. Atripaldi, and L. Quaglia (1986). In "Molecular and Cellular Biology of Fertilization" (J.L. Hedrick, Ed.). Plenum, New York). We have recently conducted electrophysiological studies which have detected inward currents at the dimple center, outward current at the rest of the egg surface, and an eightfold increase in [Ca2+]i which propagates from the site of activation throughout the egg (R. Nuccitelli, D. Kline, W. Busa, R. Talevi, and C. Campanella (1988). Dev. Biol. 130, 120-132). In this paper we have asked whether the anionic current and the Ca2+ increase could be causally related to the changes of the smooth endoplasmic reticulum (SER) at activation. The results obtained by activating the eggs in ion-substituted Ringers indicate that (1) the migration of cisternae is not dependent on the polarity of the activation current crossing the dimple, but is strongly impaired, together with CG exocytosis, by 5 x Cl- Ringer; (2) TMB-8, a drug which partially blocks calcium release (C. Y. Choiu and M. J. Malagodi (1975). Brit. J. Pharmacol. 53, 279-288), partially inhibits opening of cisternae clusters and the formation of an SER network in the dimple. This suggests a causal relationship between the Ca2+ rise and the cluster transformation at activation.
Animals↗