Platelet-activating factor and related ether lipid mediators. Biological activities, metabolism, and regulation.
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Humans↗
Biomedical subjects
M L Blank
Publications and source records attributed to M L Blank.
[Effectiveness of intravenous infusion of ethmozin in patients with chronic ventricular arrhythmias].
Intravenous ethmozin in a dose of 270-730 mg for 4 h had pronounced antiarrhythmic effect in 80% of patients with frequent ventricular extrasystoles. In 10-14% of patients it may have arrhythmogenic effect. Positive correlation between duration and degree of the antiarrhythmic effect and dose and plasma ethmozin concentration was found. The character of the effect (antiarrhythmic or arrhythmogenic) did not depend on the dose and concentration of the drug. The indicated doses of intravenous ethmozin produce no serious side effect and may be recommended for treatment of chronic ventricular arrhythmias.
Adult↗
[Correlations of ECG ST segment changes and indicators of left ventricular function in patients with unstable stenocardia during the atrial stimulation test].
Thirty patients with unstable angina pectoris underwent atrial stimulation test under continuous ECG monitoring and repeat coronary ventriculography. All this made it possible to compare ST-segment dynamics with altered parameters of left ventricular contractility in induced myocardial ischemia. It was shown that ischemia that appeared as ST-segment depression caused abnormal regional myocardial contractility in the area of impaired coronary blood flow. At the same time, ischemias shown by ST-segment elevation resulted in abnormal diastolic myocardial relaxation in the left ventricle.
Adult↗
Stimulation of the de novo pathway for the biosynthesis of platelet-activating factor (PAF) via cytidylyltransferase activation in cells with minimal endogenous PAF production.
Treatment of Ehrlich ascites cells with 2 mM oleic acid causes a greater than 10-fold increase in the formation of platelet-activating factor (PAF; 1-[3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine) from the de novo precursor of PAF, 1-[3H]alkyl-2-acetyl-sn-glycerol. Under these conditions, CTP:phosphocholine cytidylyltransferase activity, which is known to catalyze the rate-limiting step in phosphatidylcholine biosynthesis, was stimulated 32% (p less than 0.001) over control cells. Surprisingly, the dithiothreitol-insensitive choline-phosphotransferase activity, which catalyzes the final step in PAF biosynthesis, was reduced approximately 95% in membranes isolated from cells that were pre-treated with 2 mM oleic acid. However, calculations of product formation at this reduced cholinephosphotransferase activity revealed that it was still sufficient to accommodate the increased synthesis of PAF observed in the intact oleic acid-treated cells. Kinetic studies and experiments done with cells treated with phenylmethylsulfonyl fluoride (an acetylhydrolase inhibitor) indicate the various metabolic products formed are derived through the following sequence of reactions: 1-alkyl-2-acetyl-sn-glycerol----1-alkyl-2-acetyl-sn-glycero-3- phosphocholine----1-alkyl-2-lyso-sn-glycero-3-phosphocholine----1-alkyl- 2(long-chain) acyl-sn-glycero-3-phosphocholine. These results indicate PAF is the source of alkylacylglycerophosphocholine through the action of an acetylhydrolase and a transacylase as shown in other cell systems. The relative amounts of PAF, lyso-PAF, and alkylacylglycerophosphocholine produced after treatment of the cells with oleic acid in the absence of the phenylmethylsulfonyl fluoride inhibitor indicate that the acylation rate for lyso-PAF is considerably slower (i.e. rate-limiting) than the deacetylation of PAF by acetylhydrolase. We further conclude that the final step in the de novo pathway for PAF biosynthesis is under the direct control of CTP:phosphocholine cytidylyltransferase, which emphasizes the importance of this regulatory (rate-limiting) step in the biosynthesis of both phosphatidylcholine and PAF.
Animals↗
[Comparison of methods for computer and visual assessment of stenosing lesions of the coronary arteries. 1].
A system of computer analysis of coronary arteries stenotic lesions developed in the USSR Cardiology Research Centre, Academy of Medical Sciences of the USSR, is described. Reliability of the computer analysis data was assessed, and computer and visual methods were compared on the basis of phantom study. The study was performed in 5 models of stenotic coronary arteries, the main parameters of which were measured mechanically as well as by computer and visual analysis of their images. Both methods proved to give highly reproducible intraobserver and interobserver results. Comparison to mechanically obtained data showed that the results of computer analysis are highly significant while visual evaluation allows no accurate evaluation of the stenosis degree (it is overestimated).
Cardiac Care Facilities↗
[Videodensitometric analysis of the characteristics of coronary blood flow using computed digital angiography in patients with ischemic heart disease].
Videodensitometry with following computer analysis of the image obtained by digital subtraction angiography is a method allowing an objective quantitative evaluation of the volume rate of coronary and myocardial blood flow. The moment of contrast appearance in the myocardium as well as the moment of peak concentration, half elimination period and contrast passage period should be taken into consideration. These parametres were significantly increased in patients with obstruction of the left descending artery (LDA) compared to control. At the same time coronary blood flow indexes in patients with advanced stenosis of LDA did not differ significantly from those in patients with normal LDA which could be associated with unaltered coronary and myocardial hemodynamics at rest.
Adult↗
[Computerized two-dimensional echocardiography in acute myocardial infarction. Possibility of determining the size of necrotic focus].
Myocardial asynergic area was estimated, using a new special mathematical model based on computerized assessment of echocardiographic images, in 42 patients with first acute transmural myocardial infarction. The results were compared with those of other standard methods used for the estimation of the size of damage, and with morphologic findings in 7 fatal cases. The latter comparison demonstrated that the special estimate of asynergic area, unlike the planimetric method, used earlier, showed a high correspondence to the actual size of damage. The comparison of echocardiographic data to those obtained by other techniques showed a significant correlation with the results of serial MB CFK assays and myocardial 201Tl scintigraphy.
Echocardiography↗
Separation and quantitation of phospholipid subclasses as their diradylglycerobenzoate derivatives by normal-phase high-performance liquid chromatography.
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Animals↗
[Dynamics of ventricular arrhythmia in the acute period of myocardial infarction].
Patients with acute myocardial infarction exhibited during the first three days of the disease pronounced intra- and interindividual variability in the amount of ventricular ectopic complexes and significant differences in the dynamics of the number of single premature beats and complexes in the so-called "complex" arrhythmias--paired premature beats, periods of ventricular tachycardia and accelerated idioventricular rhythm. The regularities revealed may be used for the additional evaluation of antiarrhythmic drugs efficacy in myocardial infarction.
Aged↗
[Anti-arrhythmia and arrhythmogenic actions of digoxin in ventricular rhythm disorders in patients with circulatory insufficiency].
Three-day ECG monitoring before and after digitalization of 55 patients with heart failure (HF) was performed. Digoxin did not make a considerable effect on the frequency of detection of high gradations of ventricular arrhythmias. Nevertheless it significantly reduced the mean number of ventricular extrasystoles (VES) per hour and the mean number of complex VES per hour in 8 (33.3%) patients out of 24 with frequent extrasystoles. A significant increase in the VES mean number per hour and in the complex VES mean number per hour was observed in 6 (25%) patients out of 24 with basal frequent extrasystoles. In patients with the antiarrhythmic effect of digoxin indices of the central hemodynamics (diastolic pressure in the pulmonary artery and ejection fraction) were significantly better and in patients with the arrhythmogenic effect of digoxin significantly worse in the absence of a significant difference between digoxin and K+ concentration in the plasma. Digoxin possessed a moderately pronounced antiarrhythmic effect mainly in the patients with HF early stages and in moderately pronounced disturbances of the central hemodynamics. In patients with severe manifestations of HF and with considerable deterioration of indices of the central hemodynamics digoxin in therapeutic concentrations can make an arrhythmogenic effect.
Adolescent↗
Synthesis and biochemical studies of analogs of platelet-activating factor bearing a methyl group at C2 of the glycerol backbone.
Two platelet-activating factor (PAF) analogs containing a methyl group at C2 of the glycerol moiety were synthesized, and some of their biochemical properties were investigated. 1-O-Hexadecyl-2-C,O-dimethyl-rac-glycero-3-phosphocholine (2-methyl-2-methoxy PAF) was prepared in a synthetic scheme beginning with the etherification of 2-methylpropen-1-ol. A reaction sequence involving hydroxylation, tritylation, alkylation, and detritylation afforded 1-O-hexadecyl-2-C,O-dimethyl-rac-glycerol, which was converted into the phosphocholine. A 2-lyso derivative of this PAF analog (2-methyl-lyso PAF) was synthesized from 1-O-hexadecyl-2-C-methyl-3-O-trityl-rac-glycerol. Benzylation followed by detritylation gave 1-O-hexadecyl-2-C-methyl-2-O-benzyl-rac-glycerol, which was converted into the phosphocholine compound. Hydrogenolysis afforded 1-O-hexadecyl-2-C-methyl-rac-glycero-3-phospholine (2-methyl-lyso PAF). The 2-methyl-lyso PAF analog served as a substrate for the acetyl-CoA-dependent acetyltransferase that acetylates 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine. However, 2-methyl-lyso PAF did not have a significant effect on the activities of a CoA-independent transacylase or of the acetylhydrolase that inactivates PAF, and thus does not appear to be a substrate or an inhibitor, respectively, for these enzymes. In addition, this analog exhibited only one-half of the antitumor activity of rac-1-O-alkyl-2-methoxy-rac-glycero-3-phosphocholine in human leukemic (HL-60) cells, and elicited no hypotensive response in rats and no platelet-activating activity.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Plasmalogen biosynthesis in Madin-Darby canine kidney cells: selectivity in the acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphoethanolamine and the subsequent desaturation step.
Acyl group specificity in the acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphoethanolamine (1-alkyl-2-lyso-GroPEtn) to form 1-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine (1-alkyl-2-acyl-GroPEtn) and the subsequent desaturation of 1-alkyl-2-acyl-GroPEtn to form plasmalogens (1-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine, i.e., 1-alk-1'-enyl-2-acyl-GroPEtn) was investigated in intact Madin-Darby canine kidney (MDCK) cells and cell-free membrane preparations. We found 1-[3H]alkyl-2-lyso-GroPEtn was selectively acylated with polyunsaturated fatty acids in the order 20:4 greater than 20:5 greater than 20:3 (n-9) greater than 22:6 by cell-free membrane preparations of MDCK cells. The same pattern of acyl specificity was seen in intact MDCK cells, although the intact cells produced significantly larger amounts of 1-[3H]alkyl-2-acyl-GroPEtn containing oleic acid. There was an increased desaturation of the 1-[3H]alkyl-2-acyl-GroPEtn species containing docosahexaenoic acid to plasmalogens (1-[3H]alk-1'-enyl-2-acyl-GroPEtn) by both intact MDCK cells and the cell-free membrane preparations. The relatively rapid disappearance of the 1-[3H]alk-1'-enyl-2-docosahexaenoyl-GroPEtn species during a 20-h incubation of prelabeled intact MDCK cells suggests a more rapid turnover of this molecular species. Our results indicate there is a high selectivity in the final acylation and desaturation steps of the biosynthetic pathway for plasmalogens.
Acylation↗
Highly unsaturated phospholipid molecular species of rat erythrocyte membranes: selective incorporation of arachidonic acid into phosphoglycerides containing polyunsaturation in both acyl chains.
This study describes for the first time the complete molecular species composition and turnover of [3H]arachidonic acid in various glycerophospholipid classes of rat erythrocytes, a model system that has been extensively used to investigate numerous membrane phenomena. Quantitative analysis of the individual molecular species of the choline, ethanolamine, serine, and inositol glycerophospholipid classes was possible by preparing their diradylglycerobenzoate derivatives that can be quantitated by on-line uv detection in conjunction with high-performance liquid chromatography; turnover of the molecular species containing arachidonate was evaluated in erythrocytes labeled with [3H]arachidonic acid. A unique observation was the significant amounts of 22:6-20:4, 20:4-20:4, and 18:2-20:4 species observed in the diacyl fractions of phosphatidylethanolamine and phosphatidylserine. Moreover, the analysis of the specific radioactivities of individual phospholipid species from erythrocytes incubated with [3H]arachidonic acid demonstrated a selective incorporation of arachidonic acid into the most highly unsaturated molecular species in all of the phospholipid classes examined. Although the 22:6-20:4, 20:4-20:4, and 18:2-20:4 species represented only 4.5% of the total mass of the diacyl phosphoglycerides, these species accounted for a major portion (37%) of the arachidonic acid incorporated into the phospholipids. These results demonstrate the existence of unique populations of phospholipid molecules in rat erythrocytes with a high degree of unsaturation that exhibit a very rapid metabolic turnover rate.
Animals↗
Composition and incorporation of [3H]arachidonic acid into molecular species of phospholipid classes by cultured human endothelial cells.
Based on quantitative high-performance liquid chromatographic analyses of molecular species in selected phospholipid subclasses from culture human umbilical vein endothelial cells, the relative degree of unsaturation was ethanolamine plasmalogens greater than phosphatidylethanolamine greater than phosphatidylcholine. A total of 36 different molecular species were identified in the phosphatidylcholine fraction. Interestingly, the phosphatidylcholine contained a significant amount (11.7%) of the dipalmitoyl species, a lipid normally associated with lung surfactant. The arachidonoyl-containing molecular species of phosphatidylserine/inositol were labeled to the highest extent and the ethanolamine plasmalogens contained the lowest specific radioactivity after incubating [3H]arachidonic acid with human endothelial cells for 4 h. Within each phospholipid subclass the arachidonoyl species where both acyl groups of the phospholipid are unsaturated (20:4-20:4, 18:2-20:4 + 16:1-20:4, and 18:1-20:4) had higher specific radioactivities, after labeling with [3H]arachidonic acid, than those that contained saturated aliphatic chains (16:0-20:4 and 18:0-20:4). This indicates that the unsaturated species have higher turnover rates.
Arachidonic Acid↗
Metabolism of platelet activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) and 1-alkyl-2-acetyl-sn-glycerol by human endothelial cells.
The metabolism of platelet activating factor (1-[1,2-3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine) and 1-[1,2-3H]alkyl-2-acetyl-sn-glycerol was studied in cultures of human umbilical vein endothelial cells. Human endothelial cells deacetylated 1-[1,2-3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine to the corresponding lyso compound (1-[1,2-3H]alkyl-2-lyso-sn-glycerol-3-phosphocholine) and a portion was converted to 1-[1,2-3H]alkyl-2-acyl(long-chain)-sn-glycero-3-phosphocholine. Lyso platelet activating factor (lyso-PAF) (1-[1,2-3H]alkyl-2-lyso-sn-glycero-3-phosphocholine) was detected in the media very early during the incubation and the amount remained higher than the level of the lyso product observed in the cells. Cellular levels of 1-[1,2-3H]alkyl-2-lyso-sn-glycero-3-phosphocholine were significantly higher than the acylated product (1-[1,2-3H]alkyl-2-acyl(long-chain)-sn-glycero-3-phosphocholine) at all times during the 60-min incubation period, which suggests that the ratio of acetylhydrolase to acyltransferase activities is greater in endothelial cells than in most other cells. When endothelial cells were incubated with 1-[1,2-3H]alkyl-2-acetyl-sn-glycerol, a known precursor of PAF, 1-[1,2-3H]alkyl-sn-glycerol was the major metabolite formed (greater than 95% of the 3H-labeled metabolites during 20- and 40-min incubations). At least a portion of the acetate was removed from 1-[1,2-3H]alkyl-2-acetyl-sn-glycerol by a hydrolytic factor released from the endothelial cells into the medium during the incubations. Only negligible amounts of the total cellular radioactivity (0.2%) was incorporated into platelet activating factor (1-[1,2-3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine); therefore, it is unlikely that the previously observed hypotensive activity of 1-alkyl-2-acetyl-sn-glycerols can be explained on the basis of the conversion to platelet activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) by endothelial cells. Results of this investigation indicate that endothelial cells play an important role in PAF catabolism. Undoubtedly, the endothelium is important in the regulation of PAF levels in the vascular system.
Animals↗
Alkylacetylglycerols versus lyso-PAF as precursors in PAF biosynthesis and the role of arachidonic acid in PAF metabolism.
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Acetyltransferases↗
Acylation of lysophospholipids by rabbit alveolar macrophages. Specificities of CoA-dependent and CoA-independent reactions.
Intact alveolar macrophages were found to acylate alkyl- and acyllysophospholipids with a high selectivity for arachidonate. A specific mechanism appears responsible for the incorporation of arachidonate into lysophospholipids in intact cells since the kinetic pattern for the formation of the 20:4 species was different from all other species. This specificity was investigated in more detail by examining the enzymatic acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine by macrophage membranes; in the absence of CoA, ATP, and Mg2+, this lysophospholipid was acylated with a high preference for arachidonate that was independent of added free fatty acids. The addition of CoA alone increased the rate of acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine, mainly due to an increase in the formation of species other than those containing arachidonate. When CoA, ATP, and Mg2+ were present, the macrophage membranes catalyzed the acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine without preference for arachidonate. A different apparent Km and Vmax was observed for reactions involving each cofactor condition. We conclude that the acylation of alkyl- and acyllysophospholipids by rabbit alveolar macrophages occurs by three separate mechanisms: a CoA-independent transacylation, a CoA-dependent transacylation (reverse reaction catalyzed by acyl-CoA acyltransferase), and an acyl-CoA-dependent acylation. The CoA-independent transacylation reaction is unique in that it is specific for arachidonate and accounts for the selective acylation of alkyl- and acyllysophospholipids by arachidonate in membrane preparations of alveolar macrophages. This reaction appears to be extremely important in the remodeling of phospholipid molecular species and the mobilization of arachidonate into ether-linked lipids. The transfer of arachidonate to 1-alkyl-2-lyso-sn-glycero-3-phosphocholine also is of importance in the final inactivation step for platelet activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), whereby 1-alkyl-2-arachidonoyl-sn-glycerol-3-phosphocholine (a stored precursor of both platelet activating factor and arachidonic acid metabolites) is formed.
Acylation↗
Metabolism of unique diarachidonoyl and linoleoylarachidonoyl species of ethanolamine and choline phosphoglycerides in rat testes.
Selected molecular species of rat testicular 1,2-diradyl-sn-glycero-3-phosphocholines and 1,2-diradyl-sn-glycero-3-phosphoethanolamines were quantitated as their diradylglycerobenzoate derivatives, using a recently developed high-performance liquid chromatographic method. Increased amounts of docosapentaenoic acid were found in glycerophospholipids containing ether moieties compared with the diacyl phospholipids (e.g., docosapentaenoate-containing species comprised more than 80% of the alkylacyl subclass of the ethanolamine phosholipids as opposed to 29.3% of the diacyl subclass). Within 2 h after intratesticular injections of [5,6,8,9,11,12,14,15-3H]arachidonic acid, the 20:4-20:4 and 18:2-20:4 molecular species of the diacyl subclass of both the choline and ethanolamine glycerophosphatides had the highest specific radioactivities. These unique molecular species (20:4-20:4 and 18:2-20:4) also exhibited the largest percentage decrease in specific radioactivity 24 h after the intratesticular injections of [3H]arachidonic acid, which indicates these two species possess a high metabolic turnover. Two of the arachidonate-containing molecular species (18:1-20:4 and 18:0-20:4) in the ethanolamine plasmalogens showed only a small decrease in specific radioactivity, whereas a third species (16:0-20:4) actually had a 44% increase in specific radioactivity 24 h after the intratesticular injections of [3H]arachidonate. These data indicate that the 20:4-20:4, 18:2-20:4 and 18:1-20:4 species of phosphatidylcholine and/or phosphatidylethanolamine are most rapidly labeled after administration of [3H]arachidonic acid and that they appear to serve as the source of the [3H]arachidonate that is ultimately transferred to ethanolamine plasmalogens.
Animals↗