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Some characteristics of the presynaptic effect of neurotoxins with phospholipase A2 activity
8t.hWorldCongrelson~nimnI, plant andMic~roblltlTo0dns SOME
CHARAcI'~ISTICS
OF THE PRESYNAPTIC EFFECT OF NEUROTOXINS WITH PHOSPHOLIPASE A. ACTIVITY C. C. CHANG° Dept. of Phaz1~acol°, Col~ege of Medicine, National Talwan University, Talpel, Talwan 100, ROC. Neurotoxlns wlth phosphollpase A~ (PLA) activity isolated from snake venoms (such as B-bungarotoxln, ~alpoxln, notexln and crotoxln) affect preferentially the motor nerve terminal. Binding of these toxins causes an immediate inhibition followed by a facilitation of the transmitter release in the mouse diaphragm. Then, progressive inhibition of transmitter ensu-es In I to 3 h ~ r s . The early blphaslc response is less significant in hlgh Mg---Tyrode. In the rat diaphragm, the facilitation is not preceded by depression° This blphaslc effect df PLA toxins ~s nelth~r antagonized nor d e l a y ~ by loT~rlng the temperature from 37vC to 27vc or by substituting Sr TT for Ca T~, In spite of the marked delay for the onset of the late phase inhibition° Notexln is an exception that no facilitation occurs in Sr ++- or In hlgh Mg++-Tyrode. The above results indicate that the early blphaslc response Is not due to a phosphollpolysls of axolemma° However, the late phase block is clearly related to the enzymatic activity. Binding sites for toxins with different chemical composition appear to be different. Interestingly, the increase of transmitter release during facilitation Is already accompanied wlth a reduction of the maximal transmltter-releaslng activity. The maximal releasing capacity Is then further decreased without slgnlfican~ change of the slope of the curve relating release activity vs. Ca T, concentration. Dlamlnopyrldlne enhances the transmitter release affected by PLA toxins without recovering the maximal release. These results suggest that the number of active slte for transmitter release is decreased by the PLA toxins. It is inferred that when phosphollpolysls reaches a critical level there may occur irreversible change of the nerve terminal membrane and loss of release function° KEY WORDS: Neurotoxln; Phosphollpase A2; Transmitter release.
ENDOTOXIN-INDUCEDVITAMIN K DEFICIENCY
By J.J. CORRIGAN,Jr. and M. JETER. Dept. of Pediatrics, Sectlon of Hematology/ Oncology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA. Bacteria] endotoxtn ts well known to cause changes in the hemestettc mechanism such as thrembocytopenta and disseminated tntravascular coaqulatton (DIC). A second type of coagulopethy has been observed in humans wtth gram-negative septicemia which consists of a prolonged perttal thromboplastln time (PTT), prolonged prothrombtn time (PT) and normal to elevated ftbrtnogen concentration. Further studies on these cases revealed reduced levels of factor I I , factor V I I , arid factor X coagulant a c t i v i t y with normal or elevated factor V I I I levels. Male rats were given 100 micrograms per lO0 gram body weight of E. colt eedotoxtn tntraperttonealy. Control rats were given either s t e r i l e endoto--~Tn-freenormal saline or warfarin (1.Omg/lOOgmbody wt), I.P. Blood was collected 24 hours l a t e r and anttcoagulated wtth sodium c i t r a t e . The plasma was used for assay of various coagulation factors. The results showed that the coagulopathy associated wtth endotoxtn was stmtlar to that produced by werfartn-(a known inducer of a vitamin K deficent state). This coagulopathy associated with endotoxemta appears to be due to endotoxln's a b i l i t y to either impair the vttemtn K cycle or the vttemtn K dependent carboxylase reaction. I t ts speculated that thts ts a protective mechanism against DIC.
REFERENCES Corrtgan, O.J.,Jr., Ray, W.L. and May, N. (1968) New Eng J Mad 279, 851. McGehee, W.G., Rapaport, S.I. and ItJort, P.F. (1967) Ann Intern Mad 67, 250. Corrtgan, O.J. ,Jr. (1984) Allter J Dis Child 138, 240. KEY WORDS Endotoxtn; Coagulation defect; Vitamin K
S59
CHARAcI'~ISTICS
OF THE PRESYNAPTIC EFFECT OF NEUROTOXINS WITH PHOSPHOLIPASE A. ACTIVITY C. C. CHANG° Dept. of Phaz1~acol°, Col~ege of Medicine, National Talwan University, Talpel, Talwan 100, ROC. Neurotoxlns wlth phosphollpase A~ (PLA) activity isolated from snake venoms (such as B-bungarotoxln, ~alpoxln, notexln and crotoxln) affect preferentially the motor nerve terminal. Binding of these toxins causes an immediate inhibition followed by a facilitation of the transmitter release in the mouse diaphragm. Then, progressive inhibition of transmitter ensu-es In I to 3 h ~ r s . The early blphaslc response is less significant in hlgh Mg---Tyrode. In the rat diaphragm, the facilitation is not preceded by depression° This blphaslc effect df PLA toxins ~s nelth~r antagonized nor d e l a y ~ by loT~rlng the temperature from 37vC to 27vc or by substituting Sr TT for Ca T~, In spite of the marked delay for the onset of the late phase inhibition° Notexln is an exception that no facilitation occurs in Sr ++- or In hlgh Mg++-Tyrode. The above results indicate that the early blphaslc response Is not due to a phosphollpolysls of axolemma° However, the late phase block is clearly related to the enzymatic activity. Binding sites for toxins with different chemical composition appear to be different. Interestingly, the increase of transmitter release during facilitation Is already accompanied wlth a reduction of the maximal transmltter-releaslng activity. The maximal releasing capacity Is then further decreased without slgnlfican~ change of the slope of the curve relating release activity vs. Ca T, concentration. Dlamlnopyrldlne enhances the transmitter release affected by PLA toxins without recovering the maximal release. These results suggest that the number of active slte for transmitter release is decreased by the PLA toxins. It is inferred that when phosphollpolysls reaches a critical level there may occur irreversible change of the nerve terminal membrane and loss of release function° KEY WORDS: Neurotoxln; Phosphollpase A2; Transmitter release.
ENDOTOXIN-INDUCEDVITAMIN K DEFICIENCY
By J.J. CORRIGAN,Jr. and M. JETER. Dept. of Pediatrics, Sectlon of Hematology/ Oncology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA. Bacteria] endotoxtn ts well known to cause changes in the hemestettc mechanism such as thrembocytopenta and disseminated tntravascular coaqulatton (DIC). A second type of coagulopethy has been observed in humans wtth gram-negative septicemia which consists of a prolonged perttal thromboplastln time (PTT), prolonged prothrombtn time (PT) and normal to elevated ftbrtnogen concentration. Further studies on these cases revealed reduced levels of factor I I , factor V I I , arid factor X coagulant a c t i v i t y with normal or elevated factor V I I I levels. Male rats were given 100 micrograms per lO0 gram body weight of E. colt eedotoxtn tntraperttonealy. Control rats were given either s t e r i l e endoto--~Tn-freenormal saline or warfarin (1.Omg/lOOgmbody wt), I.P. Blood was collected 24 hours l a t e r and anttcoagulated wtth sodium c i t r a t e . The plasma was used for assay of various coagulation factors. The results showed that the coagulopathy associated wtth endotoxtn was stmtlar to that produced by werfartn-(a known inducer of a vitamin K deficent state). This coagulopathy associated with endotoxemta appears to be due to endotoxln's a b i l i t y to either impair the vttemtn K cycle or the vttemtn K dependent carboxylase reaction. I t ts speculated that thts ts a protective mechanism against DIC.
REFERENCES Corrtgan, O.J.,Jr., Ray, W.L. and May, N. (1968) New Eng J Mad 279, 851. McGehee, W.G., Rapaport, S.I. and ItJort, P.F. (1967) Ann Intern Mad 67, 250. Corrtgan, O.J. ,Jr. (1984) Allter J Dis Child 138, 240. KEY WORDS Endotoxtn; Coagulation defect; Vitamin K
S59