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PubMed1986

Stimulatory and inhibitory effects of TMB-8 on pancreatic enzyme secretion.

The putative intracellular calcium antagonist 3,4,5-trimethoxybenzoate 8-(diethylamino)-octyl ester (TMB-8) affects carbachol-induced enzyme secretion from rabbit pancreatic acini in a different way than it does that induced by either the C-terminal octapeptide of cholecystokinin (CCK-8), the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA) or the calcium ionophore, A23187. In the presence of TMB-8 the dose-response curve for carbachol-induced amylase release shifts to the right, suggesting competitive antagonism at the muscarinic receptor. The hypothesis that TMB-8 acts as a muscarinic receptor antagonist is supported by the observation that TMB-8 dose-dependently inhibits the carbachol-, but not CCK-8-induced increases in cytosolic free calcium, measured in acinar cells by means of the fluorescent calcium indicator quin2. At a concentration of 100 microM, TMB-8 maximally potentiates the secretory response to suboptimal, but not (supra)optimal, concentrations of CCK-8. At the same concentration the drug also potentiates TPA- and A23187-induced enzyme secretion. Cytosolic free calcium levels and CCK-8-induced increases in cytosolic free calcium remain unaffected by 100 microM TMB-8. The above results strongly suggest that potentiation occurs at or beyond the site of interaction between the diacylglycerol- and the Ca2+-activated pathways. At concentrations beyond 100 microM the potentiating effect of TMB-8 declines and, finally, at a concentration of 500 microM the drug completely abolishes the secretory response to CCK-8 and TPA. Basal enzyme secretion, however, remains unaffected. At 500 microM severe side effects are observed as is shown by Trypan blue uptake, lactic dehydrogenase release and release of trapped quin2. It is concluded that at lower concentrations TMB-8 does not act as a specific intracellular calcium antagonist in pancreatic enzyme secretion and that inhibitory effects obtained with rather high concentrations of this drug should be treated with caution.

Amylases↗
PubMed1989

Stimulative effects of TMB-8 and trifluoperazine on pancreatic hormone release.

The effects of 8-N-N-diethylamino octyl 3,4,5-trimethoxybenzoate (TMB-8) and trifluoperazine (TFP) on the early phase (10 min) of the release of pancreatic hormones from isolated rat islets were investigated. TMB-8 and TFP stimulated insulin, glucagon, and somatostatin release in a dose-dependent manner at a low glucose concentration (2.5 mM). The levels of glucagon and somatostatin release were also stimulated by these two agents at a high glucose concentration (10 mM). Their effects were independent of external calcium ion level. These two agents did not modify insulin release at the high glucose concentration. The stimulative effects of the two agents on the release of these hormones were partially suppressed when the islets were pretreated with 6-hydroxydopamine (6-OHDA), a chemical adrenergic denervator that acts at nerve endings. In this situation, the norepinephrine (NE) released from pancreatic islets decreased to 44% of that of non-treated islets (P less than 0.01). The addition of NE (10(-9) M) to the incubation medium increased insulin, glucagon, and somatostatin secretion by 20-30% over control levels (P less than 0.05). In conclusion, the early phase of pancreatic hormone release was stimulated by TMB-8 and TFP. Our results strongly suggest that these two drugs could be mediated by the NE released from nerve endings in the islets.

Animals↗
PubMed1992

Involvement of Ca2+ entry and inositol trisphosphate-induced internal Ca2+ mobilization in muscarinic receptor-mediated catecholamine release in dog adrenal chromaffin cells.

Catecholamine (CA) release from adrenal medulla evoked by muscarinic receptor stimulation has been studied using isolated perfused adrenal gland and cultured chromaffin cells from dogs. Muscarine and oxotremorine (1-100 microM), and bethanechol (0.1-1 mM) dose-dependently stimulated CA release. Muscarine-evoked CA release was antagonized with M1-antagonist, pirenzepine and, to a lesser extent, with atropine; and was reduced either by removal of extracellular Ca2+ or treatment with Ca2+ channel blockers. Muscarine caused an increase of 45Ca uptake and 22Na uptake. Tetrodotoxin (TTX) did not affect muscarine-evoked increase of 22Na uptake and CA release. Under the absence of extracellular Ca2+, muscarine stimulated a 45Ca efflux. Muscarine-induced CA release was attenuated by treating the cells with 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate-HCl (TMB-8) which blocks Ca2+ release from the intracellular store. A phospholipase C inhibitor, neomycin, markedly reduced muscarine-induced CA release but not nicotine- and high K(+)-evoked release. Cinnarizine, a Ca2+ channel blocker, attenuated muscarine-evoked but not caffeine-induced CA release and 45Ca efflux in the absence of extracellular Ca2+. Muscarine caused an increase in intracellular free Ca2+ concentration ([Ca2+]i) in the presence of extracellular Ca2+. It caused a similar increase, but to a lesser extent, in the absence of extracellular Ca2+. The increase of [Ca2+]i induced by muscarine without extracellular Ca2+ was reduced by neomycin and cinnarizine. Polymixin B and retinal, which reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CA release, had little effect on muscarine-induced CA release. Muscarine increased cellular Ins(1,4,5)P3 production, and atropine inhibited this increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

Mobilization of intracellular calcium as a mechanism for the positive inotropic effect by prostaglandin F2 alpha in isolated guinea pig atria.

The mechanism of the positive inotropic effect of prostaglandin F2 alpha (PGF2 alpha) was investigated using spontaneously beating isolated guinea pig atria. PGF2 alpha increased the contractile force in a concentration dependent fashion in a range between 10(-7)M to 10(-5)M. The maximal response to PGF2 alpha was obtained within 5 min and continued for at least 20 min. This positive inotropic effect of PGF2 alpha was not affected by verapamil, but was inhibited by procaine or TMB-8, potent inhibitors of Ca2+ release from intracellular Ca2+ compartments. Increase in extracellular Ca2+ concentration failed to provoke a significant positive inotropic effect by PGF2 alpha, suggesting that this response is relatively independent of extracellular Ca2+. These results suggest that the PGF2 alpha-mediated positive inotropic effect is produced by a mobilization of intracellular Ca2+.

Animals↗
PubMedDate not supplied

Intake of phenolic antioxidants from foods in Canada.

The potential dietary intake of butylated hydroxyanisole (BHA) in Canada was estimated using dietary recall data on food consumption and maximum permitted use levels for this antioxidant. Based on these estimates, it is concluded that the dietary intake of BHA and other permitted phenolic antioxidants (BHT and propyl gallate) is unlikely to exceed 1 mg/kg body weight/day and on average is less than 0.4 mg/kg body weight/day. Canadian dietary intake estimates compare favourably with those of the United States.

Adolescent↗
PubMedDate not supplied

No evidence of carcinogenicity of D-mannitol and propyl gallate in F344 rats or B6C3F1 mice.

Chronic toxicity and carcinogenicity studies were conducted on D-mannitol and propyl gallate in F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were maintained on diets containing either 0, 2.5 or 5.0% D-mannitol or 0, 0.6 or 1.2% propyl gallate for 103 wk. D-Mannitol had no effect on survival or mean body weight of rats and mice, and feed consumption was approximately the same in control and treated groups in each species. Gastric fundal gland dilation occurred at a higher incidence in treated female rats than in controls. A mild nephrosis characterized by focal vacuolization of the renal tubular epithelium was observed in an increased incidence in treated mice. No significant increase in tumour incidence was observed in any of the treated groups in comparison with the corresponding controls. Survival of rats and mice given propyl gallate was similar to that of the controls. Mean body weights were lower in chemically exposed animals, and more so for females. Male rats exposed to propyl gallate showed an increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland. Tumours of the preputial gland, islet-cell tumours of the pancreas, and phaeochromocytoma of the adrenal gland occurred at a significantly (P less than 0.05) higher incidence in the low-dose male rats. Malignant lymphoma occurred with a positive trend in male mice (control 1/50, low dose 3/49 and high dose 8/50), and the incidence in the high-dose group was significantly (P less than 0.05) higher than in the control group. However, since the incidence in the control group was much less than the historical control rate (36/398 or 9%) in this laboratory, this apparent increase was not considered to be related to propyl gallate administration. Under the conditions of these studies, neither D-mannitol nor propyl gallate was considered to be carcinogenic to F344 rats or B6C3F1 mice of either sex.

Administration, Oral↗
PubMed1984

Synthetic antioxidants: biochemical actions and interference with radiation, toxic compounds, chemical mutagens and chemical carcinogens.

Biological actions of 4 commonly used synthetic antioxidants--butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and propyl gallate--on the molecular, cellular and organ level are complied. Such actions may be divided into modulation of growth, macromolecule synthesis and differentiation, modulation of immune response, interference with oxygen activation and miscellaneous. Moreover, an overview of beneficial and adverse interactions of these antioxidants with exogenous noxae is given. Beneficial interactions include radioprotection, protection against acute toxicity of chemicals, antimutagenic activity and antitumorigenic action. Possible mechanisms of the antitumorigenic action of antioxidants are discussed. This discussion is centered around antioxidant properties which may contribute to a modulation of initiation-related events, especially their ability to interfere with carcinogen metabolism. The beneficial interactions of antioxidants with physical and chemical noxae are contrasted to those leading to unfavorable effects. These include radiosensitization, increased toxicity of other chemicals, increased mutagen activity and increased tumor yield from chemical carcinogens. At present, the latter one can most adequately be characterized as tumor promotion at least in the case of butylated hydroxytoluene. It is concluded that current information is insufficient to promote expectations as to the use of antioxidants in the prevention of human cancer.

Adult↗
PubMed1992

Effect of 2-acetylaminofluorene on intracellular free Ca2+ in isolated rat hepatocytes.

The effect of 2-acetylaminofluorene (2-AAF) on the intracellular free Ca2+ ([Ca2+]i) and viability of isolated rat hepatocytes has been investigated using the fluorescent probes quin 2 and propidium iodide respectively. At the highest concentration tested (224 microM), 2-AAF produces an elevation of [Ca2+]i which shows a biphasic profile. A small initial increase is observed during the first 5 min; this is followed by a considerable rise which reaches up to 2.5 times the control value at 15 min. These changes in intracellular calcium are not accompanied by detectable alterations in cell viability. In order to determine the mechanisms by which this effect of 2-AAF takes place, three calcium antagonists, namely verapamil, TMB-8 (8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate) and ruthenium red (RuR), have been used. The results suggest that the first phase is dependent upon internal Ca2+ store mobilization, while the second phase seems to be related to Ca2+ entry from the extracellular space. The data obtained with RuR further indicate that mitochondria may be involved in the perturbation of calcium homeostasis caused by 2-AAF. In addition, in the experiments involving antagonists, no consistent pattern emerges that suggests a close relationship between intracellular Ca2+ levels and cell viability. The present study provides further information on the mechanisms by which these well-known hepatotoxin 2-AAF may interact with liver cells. It also shows that when these cells are exposed to a toxin, short-term changes in [Ca2+]i may not be accompanied by loss of cell viability, and conversely, that changes in cell viability may occur without alterations in [Ca2+]i.

2-Acetylaminofluorene↗
PubMed1988

Angiotensin II-stimulated changes in calcium metabolism in cultured glomerulosa cells.

Studies were performed to evaluate the relationships between the effects of angiotensin II on calcium metabolism and cytosolic free calcium concentration in primary monolayer cultures of bovine adrenal glomerulosa cells. As noted previously (Kramer (1988) Am. J. Physiol. (in press], angiotensin II produced rapid dose-dependent increases in cytosolic calcium characterized by both an initial transient component and a secondary sustained component. In the absence of extracellular calcium, angiotensin II produced an initial increase in cytosolic calcium comparable to that produced in the presence of calcium, but failed to maintain a sustained calcium signal. The initial, angiotensin-stimulated increase in cytosolic calcium was inhibited by dantrolene and 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) in a concentration-dependent fashion. The onset of the angiotensin-stimulated calcium signal was accompanied by a dose-dependent increase in the rate of calcium efflux that achieved a maximum within 2-3 min and then declined to a level 2.5-3 times that from control cells. The initial rate of calcium influx was also increased about 2.5-fold by angiotensin II, an effect that was only apparent in cells that had been treated with the peptide for at least 5 min. These results indicate that the calcium signal produced by angiotensin II is initiated by the rapid mobilization of calcium from an intracellular site(s) and sustained by the continued uptake of extracellular calcium. Moreover, the kinetics of the calcium signal as well as the final, sustained calcium concentration achieved reflect the balance between intracellular calcium release, calcium influx and calcium efflux.

Angiotensin II↗
PubMed1987

Modification by alpha-tocopherol, propyl gallate and tertiary butylhydroquinone of urinary bladder carcinogenesis in Fischer 344 rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The promoting activity of 3 antioxidants, alpha-tocopherol (alpha-TP), propyl gallate (PG) and tertiary butylhydroquinone (TBHQ) in urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats was examined. Rats, 6-week-old, were treated with 0.05% BBN in the drinking water for 4 weeks and then administered 1.50, 0.75 or 0.38% alpha-TP, 1.0% PG or 2.0% TBHQ in the diet for 32 weeks. The urinary bladder of all animals was examined histologically after the total 36 experimental weeks. The incidence of papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder was significantly higher in the rats treated with BBN followed by 2.0% dietary TBHQ that in controls initiated with 0.05% BBN followed by control diet. This result indicates that TBHQ has weak promoting activity in urinary bladder carcinogenesis. alpha-TP and PG did not demonstrate a promoting effect for urinary bladder lesions.

Animals↗
PubMed1994

Prevention of heterocyclic amine formation by tea and tea polyphenols.

Heterocyclic amines (HCAs), formed during the cooking of meats and fish, are thought to be the genotoxic carcinogens associated with important types of human cancer in meat-eating populations, such as cancer of the breast, colon or pancreas. We studied the effect of black or green tea, and of the tea polyphenols theaflavine gallate (TFG, black tea) and epigallocatechin gallate (EGCG, green tea) on the formation of typical HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), using the model in vitro systems of Jägerstad. Green tea and black tea and solutions of TFG and EGCG lower the formation of PhIP by 62-85% during 1 h heating at 160 degrees C of 1 mmol creatinine, 1 mmol phenylalanine and 0.5 mmol glucose in 3.3 ml diethylene glycol-water (10:1), where the inhibitors replaced 0.3 ml of the water. The production of MeIQx and related HCAs, in the same system but with 1 mmol glycine instead of phenylalanine was likewise reduced, determined by amounts of mutagens formed. In the latter systems, the teas were not, or less effective, but the polyphenols were inhibitory. Thus, the tea products represent another approach to lower the formation of HCAs.

Antineoplastic Agents↗
PubMed1988

Intracellular Ca2+ antagonist TMB-8 blocks catecholamine secretion evoked by caffeine and acetylcholine from perfused cat adrenal glands in the absence of extracellular Ca2+.

Unlike acetylcholine, caffeine was much more effective in releasing catecholamine in the absence of extracellular Ca2+ than in its presence in perfused cat adrenal glands. The intracellular Ca2+ antagonist, TMB-8 (10(-4) M), inhibited reversibly the catecholamine secretion evoked by caffeine (40 mM) and that induced by acetylcholine (10(-4) M) in the presence of hexamethonium (10(-3) M) during perfusion with Ca2+-free Locke solution containing EGTA (10(-5) M). These results support our view that muscarinic receptor activation causes catecholamine secretion by mobilizing Ca2+ from an intracellular pool just as caffeine does.

Acetylcholine↗
PubMed1988

Muscarinic stimulation of guinea pig adrenal chromaffin cells stimulates catecholamine secretion without significant increase in Ca2+ uptake.

In isolated guinea pig adrenal chromaffin cells, not only nicotine, but also muscarine stimulated catecholamine (CA) secretion, the stimulation by muscarine being the greater. The secretions of CA by muscarine and nicotine were both dependent on the presence of Ca2+ in the medium, but only the latter was associated with a rapid increase in 45Ca2+ uptake. Experiments with the fluorescent Ca2+ indicator quin 2, showed that muscarine caused an increase in cytoplasmic free Ca2+ concentration [( Ca2+]i). Moreover, the intracellular Ca2+ antagonist 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited both CA secretion and increase in [Ca2+]i induced by muscarine. These results indicate that in isolated guinea pig adrenal chromaffin cells, nicotine stimulated CA secretion by increasing Ca2+ uptake by the cells, whereas muscarine stimulated CA secretion by mobilizing Ca2+ from the intracellular pool.

Adrenal Medulla↗
PubMed1989

[3H]acetylcholine release and the change in cytosolic free calcium level induced by high K+ and ouabain in rat brain synaptosomes.

High K+ (50 mM) increased both [3H]acetylcholine ([3H]ACh) release and cytosolic free calcium level ([Ca2+]i) in rat brain synaptosomes in the presence of extracellular Ca2+. Ouabain (5 x 10(-8) to 5 x 10(-4) M) also caused a dose-dependent increase in [3H]ACh release, but not in [Ca2+]i, in the absence of Ca2+. The effects of high K+ and ouabain on [3H]ACh and/or [Ca2+]i, were inhibited by the intracellular Ca2+ antagonist TMB-8 (10(-4) M). These results suggest that unlike high K+, ouabain increases transmitter release from nerve endings through a mechanism which is independent of [Ca2+]i, but sensitive to TMB-8.

Acetylcholine↗
PubMed1982

Requirements for different Ca2+ pools in the activation of rabbit platelets. I. release reaction and protein phosphorylation.

We examined the role of Ca2+, both extracellular and intracellular in origin, in the release reaction and protein phosphorylation in rabbit platelets stimulated with platelet activating factor (acetylglyceryl ether phosphorylcholine), thrombin, or ionophore A23187. In the presence of extracellular Ca2+, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), a putative antagonist of intracellular Ca2+ transport, blocked platelet activating factor-initiated serotonin release at a half-maximal inhibitor concentration of 40 microM, compared to 350 microM for thrombin-induced release and greater than 500 microM, for A23187-induced release. Platelet activating factor-induced phosphorylation of two platelet proteins of Mr = 41,000 (P7P) and 20,000 (P9P) was inhibited by TMB-8, an effect which was additive to that caused by removing extracellular Ca2+. TMB-8 demonstrated only minor to non-existent inhibitory effect on phosphorylation in thrombin- or A23187-stimulated platelets. In contrast to P9P phosphorylation, phosphorylation of P7P caused by platelet activating factor was more dependent on a TMB-8 sensitive step than on the availability of extracellular Ca2+. Experiments with buffers containing fixed concentrations of free Ca2+ revealed that both processes (release and phosphorylation), when stimulated by platelet activating factor and thrombin, had the same threshold requirement (1-3 microM) for extracellular free Ca2+. These studies provide evidence tht stimulation of rabbit platelets by platelet activating factor is more dependent on a TMB-8-sensitive intracellular Ca2+ source than is stimulation caused by thrombin. Furthermore, our data indicate that activation of different intracellular processes involved in platelet secretion (such as P7P and P9P phosphorylation) may require Ca2+ from different pools.

Animals↗
PubMed1986

Ca2+ and phorbol ester activation of protein kinase C at intracellular Ca2+ concentrations and the effect of TMB-8.

A calcium-activated, phospholipid-dependent protein kinase (protein kinase C) was purified to near homogeneity from human polymorphonuclear leukocytes and shown to be identical to bovine protein kinase C. The Ca2+ activation of the enzyme was studied and the Ca2+ concentrations required to activate the enzyme were compared to free cytosolic Ca2+ concentrations in resting and activated polymorphonuclear leukocytes. The free calcium concentrations in the cytosol and in the enzyme assay mixture were determined using the calcium indicator quin 2. The enzyme activity was almost totally dependent upon phosphatidylserine and could be strongly activated by Ca2+ concentrations in the micromolar range, but was not activated by phosphatidylserine at Ca2+ concentrations corresponding to the intracellular free Ca2+ concentration under resting conditions. However, at similar Ca2+ concentrations (less than 2.5 X 10(-7) M) the enzyme was highly activated by phorbol 12-myristate 13-acetate (PMA) or diolein in the presence of phosphatidylserine. It was demonstrated that PMA stimulation of human polymorphonuclear leukocytes did not induce any increase in the level of the intracellular free calcium concentration. It was concluded that PMA activation of protein kinase C occurred independently of a rise in the intracellular Ca2+ concentration. K0.5 (half-maximal activation) for the PMA activation of purified protein kinase C was shown to be equivalent to the K0.5 for PMA stimulation of superoxide (O-2) production in human polymorphonuclear leukocytes, suggesting that protein kinase C is involved in activation of the NADPH oxidase. The presumed intracellular Ca2+ antagonist TMB-8 inhibited the PMA-induced superoxide production, but neither by an intracellular Ca2+ antagonism nor by a direct inhibition of protein kinase C activity.

Animals↗
PubMed1985

Effects of Quin-2, an intracellular Ca chelator, and TMB-8, an intracellular Ca antagonist, on the short-term desensitization to histamine in guinea pig taenia caecum.

The effects of Quin-2-acetoxylmethylester, an intracellular Ca ion chelator, and 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate-HCl (TMB-8), an intracellular Ca antagonist, on short-term desensitization to histamine were tested in guinea pig taenia caecum. Desensitization was induced by incubating the muscle with 10(-4) M histamine for 30 min and the recovery from the desensitization needed ca. 90 min. Both Quin-2-acetoxylmethylester (50 microM for 120 min) and TMB-8 (5 microM for 20 min) suppressed the desensitization. Modes of action and structures of both agents are quite different but both may reduce the availability of intracellular Ca ion. It is possible that reduction of intracellular Ca ion suppressed the desensitization.

Aminoquinolines↗