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PubMed1991

[Catecholamine secretion from adrenal chromaffin cells].

The effect of palytoxin (PTX) on catecholamine (CA) secretion from cultured bovine adrenal chromaffin cells was examined. PTX (greater than 10(-10) M) induced CA secretion concentration-dependently. About 40-50% of the total cellular CA was secreted during a 20 min incubation with 3 x 10(-8) M PTX. PTX caused increases in [22Na](+)- and [45Ca](2+)-influxes into the cells, which were not affected by TTX. PTX-induced CA secretion and [22Na](+)- and [45Ca](2+)-influxes were significantly inhibited by quinidine and aprindine, antiarrhythmic drugs. Ca(2+)-channel blockers such as nifedipine, verapamil, Co2+, and Cd2+ inhibited both CA secretion and [45Ca](2+)-influx induced by PTX. These results indicated that PTX-induced CA secretion was mediated by activation of Na(+)-dependent, TTX-insensitive voltage-dependent Ca(2+)-channels. PTX-induced [22Na](+)-influx was inhibited by amiloride, an inhibitor of the Na(+)-H+ exchange system, suggesting that the Na(+)-H+ exchange mechanism might be involved in PTX-induced [22Na](+)-influx into the cells. The effects of flavonoids on CA secretion from permeabilized adrenal chromaffin cells were examined. CA secretion from the cells in response to a direct Ca2+ challenge was inhibited by quercetin (greater than 10(-5) M) and apigenin (greater than 10(-5) M). These flavonoids also inhibited phorbol ester TPA-induced CA secretion. Therefore, the inhibitory effects of flavonoids on CA secretion were thought to be attributed to their inhibitory effects on PKC.

Acrylamides↗
PubMed1979

Effects of palytoxin on mechanical and electrical activities of guinea pig papillary muscle.

Effects of palytoxin (PTX) on isolated papillary muscles of guinea pigs were studied in an attempt to elucidate the mechanical and electrical activities. Inotropic effects of PTX above 3 x 10(-9) g/ml; an early positive inotropic effect, slowly developing contracture accompanied by decline in phasic tension, appearance of aftercontractions and arrhythmias at high doses. The positive inotropic effect of PTX was enhanced in high Ca2+ medium but was not modified by propranolol. PTX induced a sustained depolarization and decrease in the amplitude, upstroke velocity and duration of action potential. During development of depolarization, arrhythmias occurred, which lasted for 5--10 min and reappeared 30--60 min after. Oscillatory afterpotential often appeared. Neither reserpine nor practolol prevented the PTX-induced arrhythmia while propranolol prevented it. Tetrodotoxin slowed the development of depolarization due to PTX and inhibited PTX-arrhythmias. In low Na+ medium, PTX exerted fewer effects on resting and action potentials and produced no arrhythmia. The results suggest that PTX-induced depolarization is responsible for the generation of contracture and arrhythmia and that the depolarization is due to the change in membrane Na permeability.

Acrylamides↗
PubMed1983

The mechanism of contractile action of palytoxin on vascular smooth muscle of guinea-pig aorta.

The mode of action of palytoxin (PTX) on the contractile responses and ion movements in guinea-pig aorta was investigated. PTX (10(-8) M) induced a contraction with a latency period of 0.5-1 min, and it reached maximum after about 20 min. This contraction was not affected by phentolamine (10(-6) M). The contraction induced by PTX was rapidly abolished by removal of external Ca. Readdition of Ca restored the contraction. Verapamil, which markedly antagonized the contraction induced by some depolarizing agents (K, Ba and tetraethylammonium), decreased the rate of rise of the PTX-induced contraction, but did not affect the sustained tension level. Removal of external Na markedly inhibited the contraction induced by PTX (10(-10) - 10(-8) M), while it had no effect on the contraction induced by histamine (10(-7) - 10(-5) M). PTX rapidly decreased tissue K content with a similar time course to that of the increase in tension. Ouabain (10(-4) M) also caused contraction and decreased tissue K content in the muscle, but the rate of these changes was much slower than the PTX-induced ones. PTX increased cellular 45Ca content in normal solution, but not in Na deficient solution. These results suggest that the PTX-induced contraction in guinea-pig aorta is due to an increase in membrane Na permeability.

Acrylamides↗
PubMed1984

Effects of palytoxin on Na, K and ATP contents of vascular smooth muscle of rabbit aorta.

Palytoxin (PTX) at concentrations higher than 10(-9) M increased tissue Na and decreased tissue K contents in the smooth muscle of rabbit aorta. The decrease in the tissue K content induced by PTX (10(-8)M) was complete within 1 hr. Saponin (1 mg/ml) and Triton X-100 (0.1% wt./vol.) also rapidly decreased the tissue K content. On the other hand, a high concentration of ouabain (10(-3)M) did not change the tissue K content within 1 hr of application, and the maximum loss of K was obtained after 6 hr. Loss of tissue Na into Na- and K-free solution from Na loaded muscle was accelerated by PTX (10(-8)M). The PTX-induced increase in loss of Na was inhibited in proportion to the decrease in the temperature from 37 to 10 degrees C, while the loss of Na in the absence of PTX was almost completely inhibited at 24 degrees C. Decrease in the wet weight of the muscle induced by hyperosmotic solution was inhibited by pretreatment with PTX (10(-8)M) or saponin (1 mg/ml) for 1 hr. PTX (10(-9) and 10(-8)M) had no effect on the ATP content of the muscle. However, PTX at concentrations above 10(-7)M reduced the ATP content, and a significant amount of ATP was detected in the incubation medium. Saponin (1 mg/ml) and Triton X-100 (0.2% wt./vol.) induced a release of Na from liposomes prepared with synthesized lecithin or total lipids of rabbit red blood cells. However, no Na leak was induced by PTX (10(-8)-10(-6)M) in these liposomes. These results suggest that PTX at low concentrations (10(-9)-10(-8)M) increases the membrane permeability of vascular smooth muscle cells to Na and K ions. At higher concentrations (10(-7)-10(-6)M). PTX seems to form pores which are permeable to a larger molecule like ATP. The results further suggest that the mode of action of PTX is different from that of saponin or detergent.

Acrylamides↗
PubMed1988

Palytoxin-induced K+ efflux from ileal longitudinal smooth muscle of the guinea-pig.

In guinea-pig ileal longitudinal smooth muscle, both palytoxin (PTX) and carbachol (CCh) increased K+ efflux with an EC50 of 1.8 X 10(-10) M and 4.1 X 10(-7) M, respectively. Atropine (10(-6) M) did not inhibit the K+ efflux due to PTX (3 X 10(-9) M), but completely inhibited the efflux due to CCh (10(-5) M). External Ca2+ removal and verapamil (10(-5) M) did not change the PTX-induced K+ efflux, although the CCh-induced K+ efflux was inhibited about 77% and 71%, respectively. PTX-induced K+ efflux was reduced to 31% by a depletion of intracellular Ca2+. Tetraethylammonium (15 mM) inhibited the K+ efflux due to PTX or CCh to 61% or 75%, respectively. The PTX-induced K+ efflux was also inhibited by cymarin (3 X 10(-8) M), ouabain (10(-5) M) and digitoxin (10(-5) M). These results suggest that the PTX-induced K+ efflux is less dependent on Ca2+ influx than that due to CCh. Furthermore, the binding sites for PTX in the ileal muscle of guinea-pig may be Na+, K+-ATPase, as has been suggested in other types of cells.

Acrylamides↗
PubMed2025

Ion-selective channels in K562 cells: a patch-clamp analysis.

Four types of ion-selective channels were found by the patch-clamp technique in the human erythroleukemia K562 cells. I) in cell-attached configuration at potentials less negative than -40 mV an 8 ps channel was detected. The potential dependence of channel activity suggests that this is the TTX-sensitive Na+ channel. II) A cation-selective channel was observed with equal permeability for Na+ and K+ and a potential-independent single-channel conductance of 19 pS. The channel is activated by intracellular Ca2+ and inhibited by TEA, III) A predominantly anion-selective channel was identified with the selectivity sequence NO3- > J- > Cl- = Br- >> SO4(2-). The single-channel conductance shows outward rectification, and is in symmetrical NaCl solution 19 pS at -60 mV and 54pS at +50 mV. The open- and closed-time distributions suggest one open and at least four closed states. At submicromolar concentrations, the open state is blocked by H2DIDS leading to channel flicker between open and blocked channel; higher concentrations (apparent KI = 6.8 uM) lead to a longer-lasting blocked state. Both components of inhibition are reversible. IV) In addition, an 8 pS, Na(+)- and K(+)- selective channel could be induced by application of palytoxin. For channel activity, the presence of extracellular Na+ is essential. It is assumed that the Na+, K(+)-pump molecule is involved in the channel formation. Similarly, it is discussed whether the anion-selective channel represents a pore conformation of an electrically silent anion exchanger.

Acrylamides↗
PubMed1992

Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. I. Taxonomy, production, isolation and biological activity.

A screen for antibiotics with activity against tetracycline-resistant microorganisms has led to the isolation of Dactylosporangium sp. (ATCC 53693), a producer of several novel tetracycline derivatives. The major fermentation products, dactylocyclines A and B, were purified and MIC values determined against tetracycline-resistant and tetracycline-sensitive Gram-positive bacteria. The dactylocyclines represent the first naturally occurring tetracycline C2 amides which lack cross resistance with tetracycline.

Actinomycetales↗
PubMed1992

Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. II. Structure elucidation.

Fermentation of Dactylosporangium sp. (ATCC 53693) produces a mixture of tetracycline derivatives from which several related tetracycline glycosides, the dactylocyclines, were isolated and their structures determined. The most abundant glycoside in initial fermentations was found to be dactylocycline A. Each glycoside proved to be acid sensitive and readily hydrolyzed to a common aglycone, dactylocyclinone. While the aglycone was cross resistant with tetracycline, the dactylocyclines proved active against certain tetracycline-resistant organisms.

Actinomycetales↗
PubMed1992

Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. III. Absolute stereochemistry of the dactylocyclines.

The dactylocycline antibiotics were found through circular dichroism measurements, NMR spectroscopy and chemical transformations to possess the usual tetracycline family absolute configuration at carbons 4, 4a, 5a and 12a. The absolute stereochemistry about the C-6 carbon, however, was the reverse of that found with previously investigated tetracyclines.

Actinomycetales↗
PubMed2000

Evidence for palytoxin as one of the sheep erythrocyte lytic in lytic factors in crude extracts of ciguateric and non-ciguateric reef fish tissue.

The occurrence of palytoxin or its congener in fish extracts has been presented in this study. The presences of hemolytic factors in fish extracts of Hawaiian reef fish and their implication in ciguatera poisoning have been shown by the sheep erythrocyte assay. By use of the anti-palytoxin inhibition assay with fish extracts and sheep red blood cell (RBC), it was shown that palytoxin was one of the major factors in the lysis of sheep erythrocytes. Ouabain, an antagonist of palytoxin for the Na+/K+ ATPase receptor on RBC, also showed inhibition of sheep RBC lysis by fish extracts. From these results, it was concluded that, in part, palytoxin and other palytoxin-related, hemolysin-like factors in fish extracts were responsible for sheep cell hemolysis.

Acrylamides↗
PubMed2001

Diversity of marine biotoxins in the near-shore ocean area: presence of a palytoxin-like entity at Barber's Point Harbor, Oahu.

The presence of palytoxin or palytoxin-like compounds in fish extracts has been presented in this study. The hemolytic assay with sheep erythrocytes demonstrated the occurrence of hemolytic factors in fish extracts of Hawaiian reef fish from Barber's Point, Oahu. The rabbit anti-palytoxin inhibition assay with fish extracts and sheep erythrocytes demonstrated that palytoxin or its congener contributed to the lysis of sheep erythrocytes. From these results, it was concluded that sheep erythrocyte hemolysis was caused by palytoxin or palytoxin-like factors present in the fish extracts. Moderate correlation (R2) between mouse toxicity and sheep erythrocyte hemolysis was shown with 50 microg (R2 = 0.48) and 100 microg (R2 = 0.45) extracts. An inverse correlation of R2 = 0.64 was shown between hemolysis and MIA endpoint.

Acrylamides↗
PubMed2002

Occurrence of a food poisoning incident by palytoxin from a serranid Epinephelus sp. in Japan.

Between October 30 and November 4, 2000, eleven persons were intoxicated due to ingestion of a serranid fish Epinephelus sp. in Kochi Prefecture, Japan. Their symptoms were mainly featured by severe muscle pain, low back pain, and discharge of black urine. Serum creatine phosphokinase (CPK) levels of victims were higher (700-23,800 IU/l) than normal values, and their recovery times were more than one month. Immediately after the incident, the leftovers were collected for investigation. The causative agent was identified as palytoxin (PTX) on the basis of delayed haemolytic activity which was inhibited by an anti-PTX antibody and ouabain (g-strophanthin). To our knowledge, this is the first report on palytoxin poisoning with serranid fish.

Acrylamides↗
PubMed2003

Synthesis and biological evaluation of spongistatin/altohyrtin analogues: E-ring dehydration and C46 side-chain truncation.

Simplified analogues of the potent antimitotic marine macrolide spongistatin 1/altohyrtin A were synthesised and evaluated as growth inhibitory agents against a range of human tumour cell lines, including Taxol-resistant strains, revealing that E-ring dehydration leads to enhanced cytotoxicity at the low picomolar level while truncation of the side-chain at C46 results in a drastic decrease in activity.

Antineoplastic Agents↗
PubMed1992

N-(4'-hydroxyphenylacetyl)palytoxin: a palytoxin prodrug that can be activated by a monoclonal antibody-penicillin G amidase conjugate.

Palytoxin (PTX), one of the most toxic nonprotein molecules known, is cytotoxic at picomolar concentrations against a wide variety of cell types. In contrast to most cytotoxins, PTX exerts its activity extracellularly. A method for targeting PTX to tumor cells is described in which a monoclonal antibody-enzyme conjugate activates a PTX prodrug at surfaces of tumor cells. The prodrug, N-(4'-hydroxyphenylacetyl)palytoxin (NHPAP), was prepared by reacting PTX with an active ester of 4-hydroxyphenylacetic acid. NHPAP was 1000 times less toxic than PTX to a panel of carcinoma and lymphoma cell lines. The cytotoxic activity of the combination of penicillin G amidase from Escherichia coli with NHPAP was equal to PTX. Two cell lines that were multidrug resistant showed no enhanced resistance to NHPAP +/- penicillin G amidase. Immunologically specific activation of NHPAP took place when H2981 cells (L6 antigen positive) were treated with the monoclonal antibody conjugate L6-penicillin G amidase followed by NHPAP. This system is distinguished from other prodrug activation schemes, since the released drug exerts its activity extracellularly, has high potency, and may be able to overcome the multidrug resistant phenotype.

Acrylamides↗
PubMed1992

Light and electron microscopic observation of experimental palytoxin poisoning in mice.

The effects of palytoxin on young male ICR mice were compared with the combined effects of palytoxin and ouabain or those of several cations as well as the effects of potassium. The target organs of palytoxin were the heart, kidney, pancreas, small intestine and liver. Pathomorphological changes of the heart induced by palytoxin were similar those of a lethal dose of KC1. However, the KC1-treated animals did not show any changes in the kidney. Mice given ouabain at doses up to 5 mg/kg also showed similar injuries in proximal as well as distal convoluted urinary tubules, while the heart of mice given ouabain at the same doses showed no discernible morphological changes. Ouabain 5 mg/kg did not influence the severity of injuries both in the heart and kidney induced by palytoxin at 4 micrograms/kg. Therefore, it may be assumed that palytoxin poisoning is a symptom-complex of hyperkalemia and causes a profound inhibition of Na+, K(+)-ATPase.

Acrylamides↗
PubMed1989

Palytoxin down-modulates the epidermal growth factor receptor through a sodium-dependent pathway.

Palytoxin, a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter, has been shown to inhibit epidermal growth factor (EGF) binding to both high and low affinity receptors through a protein kinase C-independent pathway. In the present paper, we have investigated the mechanism of palytoxin action in Swiss 3T3 cells. Two lines of evidence indicate that calcium is not required for palytoxin activity. First, palytoxin can induce the loss of EGF binding sites in the absence of external calcium. Second, studies with the photosensitive protein aequorin indicate that palytoxin does not cause the influx of external calcium or the release of calcium from internal stores under the conditions used in these studies. However, palytoxin action does appear to be dependent upon the presence of sodium. When extracellular sodium is replaced by either choline, Tris, or sucrose, palytoxin is unable to decrease EGF binding to either high or low affinity receptors. Studies of sodium influx indicate that palytoxin induces rapid sodium uptake and that the rate of sodium uptake is dose-dependent. Furthermore, there appears to be a direct correspondence between the extent of inhibition of EGF binding by palytoxin and the rate of sodium uptake. Finally, the palytoxin-induced inhibition of EGF binding can be mimicked by monensin, a sodium ionophore. The specificity of this sodium dependence was tested by substituting lithium, potassium, or cesium for sodium. Although lithium is an effective substitute for sodium, palytoxin can no longer inhibit EGF binding when sodium is replaced by either potassium or cesium. Marked inhibition of palytoxin action is also obtained when 5.4 mM potassium or 5.4 mM cesium are added to the sodium-containing medium. These studies suggest that palytoxin is able to down-modulate the EGF receptor through a novel mechanism involving the activation or formation of a sodium pump or channel.

Acrylamides↗