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Blood Jun 1982Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus...
Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.
Topics: Animals; Blood Platelets; Cell Survival; Cyclooxygenase Inhibitors; Dogs; Enzyme Inhibitors; Fibrinogen; Fibrinolytic Agents; Kinetics; Mopidamol; Neoplasms; Phosphodiesterase Inhibitors; Platelet Count; Sulfinpyrazone; Warfarin
PubMed: 6805531
DOI: No ID Found -
The Journal of Neuroscience : the... Dec 1989Long-term facilitation (LTF), a form of synaptic plasticity demonstrated at the crayfish neuromuscular junction, is induced by tetanic stimulation and persists for...
Long-term facilitation (LTF), a form of synaptic plasticity demonstrated at the crayfish neuromuscular junction, is induced by tetanic stimulation and persists for hours. LTF can be divided into 2 phases: a tetanic phase, which occurs during stimulation, and a long-lasting phase, which persists after stimulation. Activators and potentiators of cAMP (forskolin and 3-isobutyl-methyl-xanthine) produce facilitation of excitatory postsynaptic potentials, which attain approximately the amplitude of the long-lasting phase of LTF but last for a shorter time. Localized presynaptic injection of a protein inhibitor ("Walsh inhibitor") specific for the cAMP-dependent protein kinase blocks the long-lasting phase of LTF at synapses near the injection site with no apparent effect on the tetanic phase. Normal LTF develops and persists at synapses of the same axon distant from the injection site. Localization of the injected inhibitor was confirmed by fluorescent tagging. Localized injection of SQ22,536, an adenylate cyclase inhibitor, also blocks the second phase of LTF near the injection site, but not at distant synapses. These experiments establish a role for adenylate cyclase activation in the long-lasting phase of LTF. The phosphatidylinositol second-messenger system is not important in LTF as inhibition of phospholipase C by injection of RA233, which blocks facilitatory effects of serotonin, does not affect any aspect of LTF.
Topics: 1-Methyl-3-isobutylxanthine; Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Astacoidea; Bacterial Toxins; Colforsin; Cyclic AMP; GTP-Binding Proteins; Mopidamol; Neuromuscular Junction; Phospholipases; Protein Kinase Inhibitors; Time Factors
PubMed: 2480401
DOI: 10.1523/JNEUROSCI.09-12-04246.1989 -
The Journal of Biological Chemistry Jan 1984The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a...
The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a delay of about 20 min, they evolved [3H]methanol. This evolution, and the amount of [3H] methanol liberated by treatment with base, was inhibited in a dose-dependent fashion by the cyclic nucleotide phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine, papaverine, dipyridamole, and RA233 (2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d] pyrimidine). Each of these compounds increased the incorporation of [3H]methionine into platelets. The effects of RA233 were studied in more detail. Inhibition of [3H]methanol production was not potentiated by stimulators of the adenylate cyclase or the guanylate cyclase. The majority of the base-labile radioactivity was trichloroacetic acid precipitable. Thin layer chromatography of extracts of platelets incubated with L-[35S]methionine showed that RA233 did not induce a cellular accumulation of [35S]S-adenosylhomocysteine, and that it actually increased the amount of cellular [35S]S-adenosylmethionine. Discontinuous polyacrylamide gel electrophoresis at acid pH using the cationic detergent benzyldimethyl-n-hexadecylammonium chloride of platelets incubated with [3H]methionine showed incorporation of radioactivity into more than 30 protein bands, including one which co-migrates with calmodulin. The incorporation into the majority of these bands was inhibited by RA233 in a dose-dependent fashion. It is suggested that caution should be used in ascribing the pharmacological effects of known phosphodiesterase inhibitors to increases in cyclic nucleotides, because some of these effects could be due to inhibition of protein carboxyl methylation.
Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-AMP Phosphodiesterases; Blood Platelets; Dipyridamole; Humans; Hydrogen-Ion Concentration; Hydrolysis; Methionine; Mopidamol; Papaverine; Protein Methyltransferases; Protein O-Methyltransferase; S-Adenosylmethionine
PubMed: 6198323
DOI: No ID Found