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PubMed1977

The mode of contractile action of palytoxin on vascular smooth muscle.

Experiments were designed to assess the mode of action of palytoxin (PTX), isolated from Palythoa tuberculosa, on mechanically denervated rabbit aortic strips. PTX induced a sustained contraction in the muscle dose dependently. The contraction was irreversible. In the depolarized aorta, PTX did not induce a contraction whereas norepinephrine (NE) did. Removal of calcium from the bathing medium prevented PTX and high K+ contractions, whereas phasic responses were elicited by NE. D600 also inhibited the contraction induced by PTX or high K+ but had a lesser effect on that induced by NE. Sodium nitroprusside inhibited only the effect of NE. PTX increased dose dependently the 45Ca uptake of a fraction not removable by La3+ treatment and the increase was inhibited by D600. High K+ also increased the 45Ca uptake although NE did not. It is suggested that PTX increased Ca2+ influx into the smooth muscle cell to cause a contraction, which may be analogous to the action of high K+.

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PubMed1986

The contractile action of palytoxin in the isolated rabbit urinary bladder.

Palytoxin at 10(-10)-10(-7) M caused contractions of the detrusor muscle from rabbit urinary bladder in a concentration-dependent manner. The response to palytoxin was markedly inhibited by indomethacin (a cyclooxygenase inhibitor) or nordihydroguaiaretic acid (a lipoxygenase inhibitor) at 10(-5) M. Indomethacin and nordihydroguaiaretic acid also inhibited the response to arachidonic acid at 10(-3) M. A Ca2+-free medium with EGTA or nifedipine at 10(-5) M, nearly abolished the responses to palytoxin and arachidonic acid. Tetrodotoxin, phentolamine, atropine and chlorpheniramine (all at 10(-5) M) had a slight or no inhibitory effect on the response to palytoxin. These results suggested that in the rabbit bladder, the contractile effect of palytoxin is mainly dependent on an increase in metabolites of arachidonic acid.

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PubMed1984

Sugar moiety of cardiac glycosides is essential for the inhibitory action on the palytoxin-induced K+ release from red blood cells.

Palytoxin (PTX), a highly toxic and sugar-containing substance isolated from Palythoa tuberculosa, caused K+ release from rabbit red blood cells. Cardiac glycosides, such as ouabain, convallatoxin, cymarin, digoxin and digitoxin, inhibited the PTX-induced K+ release. Their corresponding aglycones did not inhibit the K+ release, but antagonized the inhibitory effect of the glycosides. All these cardiotonic steroids equally inhibited the activity of (Na+ + K+)-ATPase prepared from hog cerebral cortex. These results suggest that the sugar moiety of the cardiac glycosides is important for the inhibitory effect on the K+ release induced by PTX and that the inhibition is not related to their inhibitory potency on the (Na+ + K+)-ATPase activity.

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PubMed1984

Inhibitory effect of calmodulin inhibitors on palytoxin-induced K+ release from rabbit erythrocytes.

Palytoxin (PTX) caused K+ release from rabbit erythrocytes at a concentration as low as 10(-11) M. The K+ release due to PTX at a concentration below 10(-9) M was dependent on Ca2+ in medium. The effect of Ca2+ was substituted fully by Sr2+ and partially by Ba2+. W-7 (2 X 10(-4) M), a known inhibitor of calmodulin, markedly inhibited the rate of K+ release due to PTX. W-5 (2 X 10(-4) M), an analog of W-7 with lower affinity to calmodulin than W-7, showed weaker inhibition. Other calmodulin antagonists, such as prenylamine, chlorpromazine and compound 48/80, also inhibited the PTX-induced K+ release. These results suggest that the K+ release induced by PTX involves the process(es) mediated by intracellular Ca2+ and calmodulin.

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PubMed1986

Intracellular Ca2+-calmodulin system involved in the palytoxin-induced K+ release from rabbit erythrocytes.

Palytoxin (PTX) caused K+ release from rabbit erythrocytes which was dependent on the concentrations of extracellular Ca2+ and PTX. In a Ca2+-free solution, PTX still caused a slow K+ release. An intracellular Ca2+ antagonist, TMB-8, an intracellular Ca2+ chelator, quin 2, and calmodulin inhibitors, prenylamine, W-7 and W-5, inhibited the PTX-induced K+ release in a Ca2+-free solution. These results suggest that the PTX-induced K+ release is dependent on the process including intracellular Ca2+ and calmodulin.

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PubMed1990

Palytoxin acidifies chick cardiac cells and activates the Na+/H+ antiporter.

The cardiotoxic action of palytoxin was investigated using embryonic chick ventricular cells. Under normal ionic conditions, palytoxin produced an intracellular acidification which is partially compensated for by the Na+/H+ antiporter thereby leading to an increased rate of ethylisopropylamiloride-sensitive 22Na+ uptake. Under depolarizing membrane conditions, palytoxin produced a cellular acidification, a cellular alkalinization or no change in intracellular pH depending on the value of the extracellular pH. We propose that palytoxin acidifies cardiac cells by opening preexisting H+ conducting pathways in the plasma membrane.

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PubMed1987

Production of antibodies to palytoxin: neutralization of several biological properties of palytoxin.

Palytoxin stimulated arachidonic acid metabolism (in bovine aorta endothelial and smooth muscle cells, rat keratinocytes, porcine aorta endothelial cells and rat liver cells), hemolyzed rat erythrocytes and was lethal to mice when administered intraperitoneally. Serum from rabbits immunized with a conjugate in which palytoxin was covalently bound to bovine albumin through its free amino group neutralized these biologic activities of palytoxin. Ninety-nine per cent of the neutralizing activity of the immunized rabbit serum was removed after precipitation of the rabbit IgG with a goat anti-rabbit IgG.

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PubMed1987

Does palytoxin open a sodium-sensitive channel in cardiac muscle?

The effect of palytoxin (PTX) on transmembrane potentials and currents of frog atrial fibres was studied using the double sucrose gap technique. PTX irreversibly depolarized the membrane. This depolarization was reversed only when Na ions were removed from the Ringer solution and replaced by a non-permeant cation such as choline. The depolarization was tetrodotoxin (TTX) insensitive and a function of the external Na concentration. In voltage clamp experiments PTX induced the development of a large inward resting current which did not inactivate and was insensitive to ouabain and to a lowering of the temperature. PTX and ouabain did not share the same receptor. Dose-response curves indicated a stoichiometry of 2, which suggested the aggregation of 2 molecules of PTX to form a channel. The channel formed by PTX remained insensitive to TTX, 4 aminopyridine, tetramethyl-ammonium, Cs and Cd, the classical blockers of Na, K and Ca conductances. PTX reduced the Na current, but not the apparent reversal potential for Na ions. It was concluded that PTX might act on frog atrial fibres as a Na ionophore.

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PubMed1988

Palytoxin induces a relatively non-selective cation permeability in frog sciatic nerve which can be inhibited by cardiac glycosides.

The effect of palytoxin (PTX) on compound resting potential and compound action potential of frog sciatic nerve was studied using the sucrose-gap technique. PTX irreversibly depolarized the compound resting potential and reduced the amplitude of the compound action potential. PTX evoked a marked depolarization when extracellular Na+ was replaced by Li+, Cs+ and the organic cations methylammonium, hydroxylammonium, and methylhydroxylammonium but not by tetramethylammonium, tetraethylammonium, choline or the divalent cations, Ca2+ and Ba2+. The maintained depolarization was not sensitive to inhibition by saxitoxin (300 nM) or procaine (10 mM). The depolarization was inhibited by ouabain or cymarin but not by the aglycon, strophanthidin. However, strophanthidin did antagonize the inhibitory action of cymarin which suggests that PTX and cardiac glycosides do not share an identical binding site but there may be some overlap. We conclude that in frog sciatic nerve, PTX interacts with the (Na+-K+) pump to induce the opening or formation of a relatively non-selective cation pore within or near the pump protein.

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PubMed1988

A radioimmunoassay for palytoxin.

Palytoxin, labelled with 125I-Bolton-Hunter reagent on its terminal amino group, bound specifically to rabbit anti-palytoxin. The extent of binding increased progressively with repeated immunizations. After absorption of the rabbit IgGs with a goat anti-rabbit IgG, binding was reduced greater than 95%. For 50% inhibition of binding in the 125I-palytoxin-antipalytoxin reaction 0.27 pmoles of unlabelled palytoxin was required. Maitotoxin, teleocidin, okadaic acid, debromoaplysiatoxin and 12-O-tetradecanoylphorbol-13-acetate, when tested at 10-100-fold higher concentrations than palytoxin did not affect binding. Palytoxin's serologic activity was stable after 60 min exposure to 100 degrees C and after 60 min exposure to 0.1 N HCl at 50 degrees C, but its capacity to stimulate the arachidonic acid metabolism of rat liver cells was reduced after the 60 min exposure to 0.1 N HCl treatments at 35 degrees C or 0.01 N HCl at 50 degrees C. The average binding constant (K0) as determined by separation of antibody-bound palytoxin from free palytoxin by the double antibody technique was 4.9 x 10(9) M-1 at 0 degrees C. This apparent average association constant increased with increasing temperature suggesting that palytoxin's epitope, most likely hydrophilic, is bound to H2O and the H2O is displaced before binding to the antibody's paratope.

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PubMed1989

Palytoxin promotes potassium outflow from erythrocytes, HeLa and bovine adrenomedullary cells through its interaction with Na+, K+ -ATPase.

Erythrocytes from four mammalian species were compared with regard to K+ loss triggered by palytoxin, to Na+, K+ -ATPase activity, and to ouabain sensitivity of both events. Palytoxin sensitivity (EC50) decreased in the order rat, man (approximately equal to 1 pM) greater than cattle (approximately equal to 500 pM) greater than dog (greater than 10 nM). Na+, K+ -ATPase activity, as measured by Rb uptake, was in the series rat greater than man greater than cattle greater than dog. The glycoside potently inhibited both palytoxin action and ATPase activity in man, cattle and dog erythrocytes, but weakly in those from rats. Ca2+ promoted the palytoxin effects on all erythrocytes. As shown for human erythrocytes, Sr2+ and Ba2+ but not Mg2+ can substitute for Ca2+, and sucrose can substitute for sodium chloride. Human HeLa and bovine adrenomedullary cells also lost their K+ within a few min when exposed to palytoxin (1-10 pM). Ouabain acted as a palytoxin antagonist on both cell types. We conclude that: (a) the ouabain binding site of Na+, K+ -ATPase is part of the palytoxin receptor in every cell type tested, (b) high palytoxin sensitivity is not necessarily accompanied by high ouabain sensitivity, and (c) active ion transport is not a precondition for the action of palytoxin or for its inhibition by ouabain.

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PubMed1993

A rapid and sensitive hemolysis neutralization assay for palytoxin.

The hemolytic action of palytoxin was exploited to develop a simple, sensitive assay with specificity based on a palytoxin neutralizing monoclonal antibody. Suspensions of murine erythrocytes incubated at 37 degrees C in round-bottom microtiter trays formed visible cell pellets which could be lysed by palytoxin. Hemolysis by palytoxin was time- and temperature-dependent, with a 24 hr detection limit of 1 pg/ml. The assay selectively detected palytoxin in a crude extract of Palythoa tuberculosa.

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PubMed1996

Intestinal injuries caused by experimental palytoxicosis in mice.

Intestinal injuries in mice caused by i.p. administration of palytoxin at 1 microgram/kg were studied microscopically. Within 1 hr, bleeding started from small intestinal villi. At 6 hr, congestion in the villi and edema in the lamina propria in the crypt layer developed prominently. Edema and necrosis of lamina propria in the villus appeared after 16 hr. At 24 hr, villi lost their epithelial cells and then their length decreased to 1/4 to 1/8 of normal. Diarrhea was seen after 16 hr, accompanying severe peritonitis. Hypersecretion of mucus from the large intestine was considered to be physically stimulated by peritonitis, which then induced diarrhea.

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PubMed1986

Combinations of palytoxin or 12-O-tetradecanoylphorbol-13-acetate and recombinant human insulin growth factor-I or insulin synergistically stimulate prostaglandin production in cultured rat liver cells and squirrel monkey aorta smooth muscle cells.

In the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) or the non-TPA-type tumor promoter, palytoxin, recombinant human insulin growth factor-I (IGF-I) and insulin synergistically stimulate prostaglandin production in rat liver cells (the C-9 cell line). Combinations of palytoxin or TPA with recombinant human IGF-I or insulin also synergistically stimulate deesterification of cellular lipids in C-9 cells prelabelled with [3H]arachidonic acid. With both types of stimulations, prostaglandin production or deesterification, the synergistic response of the IGF-I and insulin is greater with palytoxin than with TPA. Production of prostaglandin E2 and F2 alpha by squirrel monkey smooth muscle cells incubated in the presence of TPA and insulin also is greater than the sum of the two effects taken independently.

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PubMed1991

Mechanism of palytoxin-induced Na+ influx into cultured bovine adrenal chromaffin cells: possible involvement of Na+/H+ exchange system.

To elucidate the mechanism of palytoxin (PTX)-induced Na+ influx, we examined the effect of amiloride, an inhibitor of Na+/H(+)-antiporter, on PTX-induced Na+ influx into cultured bovine adrenal chromaffin cells in relation to its effects on Ca2+ influx and catecholamine secretion. Amiloride dose-dependently inhibited PTX-induced 22Na+ influx, whereas tetrodotoxin (TTX) had no effect. Amiloride also inhibited PTX-induced Na(+)-dependent 45Ca2+ influx and catecholamine secretion. PTX alone did not significantly affect the intracellular pH, but it decreased in the presence of PTX and amiloride. These results indicate that an amiloride-sensitive Na+/H+ exchange mechanism is probably involved in PTX-induced, TTX-insensitive Na+ influx that triggers Ca2+ influx and catecholamine secretion from the cells.

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PubMed1987

Effects of palytoxin on contractile response and calcium movement in guinea-pig taenia coli.

PTX (10(-8)M) induced a rapid increase followed by a gradual decrease in muscle tension in normal physiological salt solution (PSS), while it induced a slow increase in muscle tension in low-Na+ solution. These contractions were inhibited by Ca2+ channel blockers, verapamil and nicardipine. PTX rapidly increased tissue Na+ and decreased tissue K+ contents in normal PSS. In low-Na+ solution, PTX decreased tissue K+ content with a slower rate than that in normal PSS. PTX increased uptake of 45Ca2+ in normal as well as low-Na+ solutions with similar time course as the increase in muscle tension. However, 45Ca2+ uptake still remained high when the PTX-induced transient contraction ceased. These results suggest that PTX increases Ca2+ influx through voltage-dependent Ca2+ channels to cause contraction. After a prolonged exposure to PTX, however, muscle tension is uncoupled from Ca2+ influx.

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PubMed2003

Rat brain guanosine binding site. Biological studies and pseudo-receptor construction.

Rat brain guanosine binding sites were studied by (i). a pharmacological approach to confirm the hypothesis of the existence of specific G-coupled receptors for guanosine (1) and, for the first time, delineate a structure-activity relationship for a series of guanosine derivatives; (ii). a molecular modelling approach to design a pseudo-receptor construction. GTP and its non-hydrolysable analogue Gpp[NH]p decreased [3H]-guanosine binding to rat brain membranes. Gpp[NH]p 30 and 100 microM induced a dose-dependent decrease in [3H]-guanosine affinity and PTX pretreatment of rat brain membranes caused a 50% reduction in binding. In slices from rat brain cortex, guanosine induced a dose-dependent increase in intracellular cAMP. This increase is specific for guanosine, since neither the pretreatment with adenosine deaminase nor the A(1) and A(2) adenosine receptor antagonists were able to modify the guanosine-induced cAMP accumulation. The structure-activity relationship showed that the potency order of the best substances able to displace 50 nM [3H]-guanosine was guanosine (1)=6-thioguanosine (3)>8-bromoguanosine (4)>inosine (10)>7-methylguanosine (6)=3'-deoxyguanosine (9)>2'-deoxyguanosine (8)=guanine (11)=6-thioguanine (12)>>N(2)-methylguanosine (5). The competition studies confirmed that [3H]-guanosine site was distinct from the well characterized ATP and adenosine binding sites. The present results are rationalized in terms of a putative pseudo-receptor construct which includes all the relevant physicochemical interaction between guanosine analogues and their putative binding sites. This construct will be useful for the in silico screening of compound libraries in search for new potent and structurally diverse pharmacological tools.

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