Artificial HDL as an anti-atherosclerotic drug.
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Arteriosclerosis↗
Biomedical subjects
V S Repin
Publications and source records attributed to V S Repin.
Decrease of platelet aggregation and spreading via inhibition of the cAMP phosphodiesterase by trapidil.
Trapidil (N,N-diethyl-5-methyl[1,2,4]triazolo[1,5-alpha]pyrimidine-7-amine ) inhibits platelet spreading and aggregation induced by arachidonic acid (AA), a stable analogue of prostaglandin (PG) endoperoxides (U46619), ADP, and low concentrations of thrombin, but not by A23187 and high concentrations of thrombin. Trapidil does not affect platelet adenylate cyclase but inhibits the cAMP PDE by approx. 50%. PDE inhibition proceeds via a competitive mechanism (Ki = 0.52 mM) and is not mediated by calmodulin inhibition. Trapidil does not change the platelet basal cAMP level but potentiates an increase of cAMP induced by the stable prostacyclin analogue (6 beta-PGI1). These results suggest that trapidil antiplatelet effects may be due to the inhibition of platelet PDE.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Step-by-step analysis of adhesion of human platelets to a collagen-coated surface defect in initial attachment and spreading of platelets in von Willebrand's disease.
Adhesion of platelets from the platelet-rich plasma (PRP) of patients with von Willebrand's disease (vWD) and healthy donors has been studied in a simple model system - wells of multiwell tissue culture plates coated with fibrillar calf skin collagen (CSC). This model is characterized by: (i) the presence of only one constituent of the vessel wall connective tissue matrix (collagen), (ii) the absence of surface-bound aggregates and thrombi, (iii) absence of overlapping of neighbouring spread platelets. A morphometric quantitation of adhesion by scanning electron microscopy (SEM) has been carried out. It allows to subdivide this process into three stages: 1) initial attachment of unspread platelets to the substrate, 2) platelet spreading on the substrate, and 3) attachment of unspread platelets to the upper surface of spread platelets. It was established that the PRP of vWD patients, compared to that of healthy donors, is characterized by a decreased total adhesion of platelets to a CSC-coated surface, which is manifested in the impairment of both the initial attachment and subsequent spreading of platelets. Addition of platelet-free plasma from healthy donors to the vWD PRP completely restores platelet spreading on collagen but little affects the initial attachment. These experiments performed on isolated collagen preparations provide further evidence for the initial attachment and spreading of platelets on collagenous constituents of the subendothelium being factor VIII/von Willebrand factor (FVIII/vWF)-dependent. In contrast to the adhesion on the collagen substrate, the adhesion of platelets from vWD PRP to a foreign surface, polystyrene plastic of uncoated wells, is the same as that of the normal PRP and, thus, FVIII/vWF-independent.
Collagen↗
Heterogeneity of endothelium in human aorta. A quantitative analysis by scanning electron microscopy.
Scanning electron microscopy was used to characterize a silver-stained endothelial surface of human aorta and iliac artery. The autopsy material was taken 1-3 h after death from two age groups: group A (0-7 yr) and group B (40-75 yr). The mean cell density per 1 mm2 in the arteries of group A was significantly higher than in the arteries of group B which lie outside ostia, fatty streaks and plaques. In adult arteries the cell density over the plaque was significantly lower than in the regions overlying a fatty streak or uninvolved surface. The luminal surface of child arteries outside high hemodynamic stress zones is a homogeneous sheet covered with exceptionally small (less than 400 micron2) and medium (400-800 micron2) cells. Large (800-1200 micron2) and giant (1200-8000 micron2) endothelial cells emerge only in fatty streaks of child arteries. The luminal surface of adult arteries is a heterogeneous monolayer covered with polymorphic cells both in regions unaffected by atherosclerosis and over the fatty streak and plaque. Giant and large endothelial cells account for 25-41% of the total cell population of adult arteries, occupying more than 40% of the surface in the latter.
Adult↗
[Inhibiting action of anti-arrhythmia agents of the phenothiazine series--etmozin and its diethylamino analog--on platelet aggregation and metabolism of endogenous arachidonic acid].
Effect of the cardiotropic drugs of the phenothiazine series ethmozine, and its diethylamine analogue (DAAE), on platelet aggregation and formation of arachidonic acid metabolites has been studied. Both drugs inhibit the ADP-induced aggregation in the platelet-rich plasma. Ethmozine inhibits only the second (irreversible) wave of aggregation, while DAAE inhibits both the first (reversible) and the second one. 50% inhibition (ID50) of the second wave of aggregation is observed at the following concentrations of the two agents: 300-500 micrograms/ml (ethmozine) and 20 micrograms/ml (DAAE). DAAE completely inhibits the irreversible aggregation of platelets washed off plasma, induced by arachidonic acid (ID50 approximately 30 micrograms/ml) and Ca2+-ionophore A23187 (ID approximately 55 micrograms/ml); the aggregation, induced by thrombin is inhibited by 80-90% (ID approximately 130 micrograms/ml). Formation of arachidonic acid metabolites in platelets effected by these inducers was measured by the accumulation of malondialdehyde (MDA). DAAE fails to inhibit MDA formation induced by exogenous arachidonic acid, but completely prevents the synthesis of MDA induced by A23187 and thrombin. These data suggest that DAAE inhibits the release of endogenous arachidonic acid from membrane phospholipids catalysed by phospholipase A2, but does not affect its subsequent metabolic transformations. In all probability, ethmozine and DAAE, just as other phenothiazines, affect platelets via the inhibition of Ca2+-calmodulin-dependent reactions and processes.
Adenosine Diphosphate↗
[Thrombocyte interaction with a collagen substrate: the role of thrombocyte-synthesized prostaglandin endoperoxides and thromboxane A2].
The effects of (i) the exogenous arachidonic acid (AA), (ii) stable prostaglandin endoperoxide analogue--U46619, and (iii) cyclooxygenase inhibitor--aspirin on the interaction of platelets with a surface coated with fibrillar calf skin collagen were studied using scanning electron microscopy. AA and U46619 stimulate massive spreading of platelets (on the collagen substrate and formation of surface-bound multilayer (thrombi-like) aggregates. The stimulation of spreading and formation of thrombi-like aggregates by AA correlate with the thromboxane A2 (TXA2) synthesis in platelets. Unlike AA, U46619 induces these processes without transformation into TXA2 and stimulation of its synthesis in platelets. Cyclooxygenase inhibitor--aspirin prevents the AA-induced platelet spreading, formation of the surface-bound thrombi-like aggregates, and TXA2 synthesis. In the absence of soluble platelet inducers, aspirin inhibits the substrate-induced spreading, but doesn't affect the initial attachment of nonactivated platelets to the collagen substrate.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Platelet prostanoids in interaction of platelets with collagen substrates. II. Effects of exogenous arachidonic acid, stable PG endoperoxides analogue, and aspirin.
The effects of (i) the exogenous arachidonic acid (AA), (ii) stable PG endoperoxide analogue U46619, and (iii) cyclooxygenase inhibitor aspirin on the interaction of platelets with a surface coated with commercial fibrillar calf skin collagen (CSC) were studied using scanning electron microscopy. AA and U46619 stimulate massive spreading of platelets on the CSC substrate and formation of the surface-bound multilayer (thrombi-like) aggregates. The stimulation of spreading and formation of thrombi-like aggregates induced by AA correlate with the TXA2 synthesis in platelets. Unlike AA, U46619 induces these processes without transformation into TXA2 and stimulation of its synthesis in platelets. Aspirin prevents the AA-induced platelet spreading, formation of the surface-bound thrombi-like aggregates, and TXA2 synthesis. In the absence of soluble platelet inducers, aspirin decreases the CSC substrate-induced disc - sphere transformation and spreading of platelets, but doesn't affect the initial attachment of platelets to the CSC substrate.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
[Deleterious action of adrenaline on the endothelial lining of the vessels].
Perfusion of the aorta of anesthesized rabbits with medium 199 containing adrenaline at a concentration of 10(-6)-10(-4) M results in multiple morphological damages of the endothelial lining: contraction of endotheliocytes with the dilation of intercellular borders, appearance of areas of swelling (from a diffuse edema of single cells up to massive swelling of several hundred cells). The surface of the deendothelized aorta was greater at the highest dose of adrenaline. Inclusion into the perfusate of adrenaline blockers, such as phentolamine and propranolol at a concentration of 10(-5) M prevented endothelial constriction and edema. Similar focal swelling in the intima of aorta and coronary arteries was found in children dying from grave stress (trauma, asphyxia). The data obtained indicate that adrenaline after its therapeutic intravenous or local use may exert a direct damaging effect on the vascular endothelium.
Animals↗
Platelet prostanoids in interaction of platelets with collagen substrates. I. Activation of platelets by surfaces coated with different types of human collagen.
We have studied the interaction of human platelets with surfaces coated with human type I, III, IV, and V collagen (CI, CIII, CIV, and CV). It was established using scanning electron microscopy that the reactivity of the collagen substrates for platelets varies widely. On CV, only the initial attachment of platelets takes place; spreading actively goes on CIV while on CI and CIII, along with spreading, the formation of multilayer thrombi-like platelet aggregates occurs. The production of malondialdehyde induced by the interaction of platelets with CI and CIII substantially exceeds that stimulated by CIV and CV. Indomethacin practically completely inhibits the formation of thrombi-like aggregates but only by 25% inhibits platelet spreading. An ADP-scavenger creatine phosphate/creatine phosphokinase inhibits the formation of thrombi-like aggregates and platelet spreading by 25-30%. The obtained data demonstrate that: (i) the formation of thrombi-like aggregates on CI and CIII is mediated mainly by the synthesis of platelet prostanoids, and not by the ADP release; (ii) the spreading of platelets on CIV, CIII, and CI is only partially mediated by prostanoid synthesis and ADP release which suggests a participation of other mechanisms in this process.
Blood Platelets↗
[Distribution of myosin in a primary culture of human aortic intimal cells].
Using antiserum against smooth muscle myosin of human uterus the distribution of myosin was investigated in primary cell culture of human aortic intima. It was discovered that during the first 5 days of cultivation, 74.5% of cells manifested homogenous distribution of myosin. Single cells contained myosin in the form of continuous fibrils and 25% of cells were not stained by antiserum. In the next days of cultivation the cells experienced modulation and on the 14th day less than 6% of cells were stained homogeneously, while 58.5% of cells were not stained by antiserum. It is assumed that part of human aortic intima cells might be phenotypically modulated.
Adult↗
[Adhesive and thrombogenic properties of vascular prostheses].
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Biocompatible Materials↗
Antianginal drug trapidil (Rocornal) inhibits spreading of platelets and formation of surface-bound thrombi-like aggregates.
Effects of an antianginal drug trapidil (Rocornal) on platelet interaction with a surface coated with fibrillar calf skin collagen (CSC) have been studied by scanning electron microscopy. Gel filtered human platelets were incubated with the CSC substrate in the absence or in the presence of soluble inducers of platelet activity: arachidonic acid (AA), stable analogue of prostaglandin (PG) endoperoxides, U46619, and thrombin. In the absence of soluble inducers, trapidil does not alter the total number of adherent platelets. At the same time, trapidil inhibits the shape change of adherent platelets, induced by the CSC substrate, increasing the percentage of discoid and decreasing the percentage of spread platelets. It was demonstrated earlier (1) and in the present study that soluble inducers of platelet activity stimulate massive spreading of platelets and formation of surface-bound thrombi-like aggregates on the CSC substrate. Trapidil completely prevents the effects of the exogenous AA and U46619 on platelet-substrate interactions, but inhibits the AA-stimulated synthesis of thromboxane A2 (TXA2) in platelets by 40-50% only. Trapidil also blocks platelet aggregation in suspension, spreading and formation of surface-bound aggregates induced by low, but not high, concentrations of thrombin. Possible sites of trapidil action are discussed.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Arachidonic acid and stable analogue of prostaglandin endoperoxides (U46619) induce platelet spreading and thrombi-like aggregate formation on a collagen substrate. Effect of fluid dynamics.
Soluble plasma inducers and inhibitors of platelet activity and fluid dynamics of the blood stream are effective modulators of platelet-vessel wall interactions. Effects of platelet activity inducers, arachidonic acid (AA) and stable prostaglandin endoperoxides analogue (U46619), on platelet disposition on the bottom of multiwell tissue culture plates coated with fibrillar calf skin collagen (CSC) have been studied by scanning electron microscopy (SEM). Both agents stimulate platelet spreading and formation of large surface-bound multilayer (thrombi-like) aggregates on a CSC substrate. AA and U46619 effects on spreading and thrombi-like aggregate formation depend on the speed of platelet suspension shaking during platelet deposition on the surface. In the absence of shaking, both inducers mainly stimulate the spreading of platelets: spread platelets fuse and form widespread sheets covering up to 50% of the CSC-coated surface. An increase in the shaking speed leads to the decrease of the platelet spreading, while the number of surface-bound thrombi-like aggregates grows, reaching the maximum at a shaking speed of 40 back and forth cycles per min. The thrombi-like aggregates mainly consist of fused platelets and always contain the basal sheet of spread platelets, which suggests the participation of the latter in aggregate attachment to the surface. Large aggregates are absent in the population of nonadherent platelets. The obtained data indicate that AA metabolites participate in platelet spreading and thrombi-like aggregate formation, the processes specific for platelet-surface interactions. The use of the suggested model for the in vitro study of platelet spreading and mural thrombi formation, and for screening of antithrombotic and thrombolytic drugs is discussed.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Quantitative SEM-analysis of adhesive and thrombogenic properties of vascular prostheses.
The perfusion technique to measure the relative adhesive and thrombogenic indices of vascular prostheses by a quantitative scanning electron microscopy has been described. To normalize the experiments with different samples of plasma we compared the adhesive and thrombogenic properties of the analyzed prostheses with those of normal and denuded human umbilical vein. The results indicate that adhesive and thrombogenic indices of Dardik, Bakulev and Gore-Tex grafts approximate to those of the non-damaged umbilical vein, while the same indices of Solcograft-P prostheses are considerably higher. The method may be useful for standardizing the properties of new prostheses and bioimplants for cardiovascular surgery.
Bioprosthesis↗
[125I]LDL uptake in rabbit arteries perfused in situ. Effect of HDL on intact and de-endothelialized vessels.
The uptake of [125I]LDL by rabbit abdominal and thoracic aortae, and carotid arteries perfused in situ was studied. [125I]LDL uptake in vessels with intact endothelial covering was saturable, Ca2+, Mg2+-dependent and was inhibited by a 100-fold excess of LDL and HDL, on the average by 30% and 60%, respectively. In de-endothelialized vessels [125I]LDL uptake increased by approximately 3-fold, and was not reduced in the presence of excess of unlabeled LDL and HDL.
Animals↗
[Effect of dibutyryl-cAMP on the cholesterol ester content in human atherosclerotic aorta cells].
Dibutyrly-cAMP (db-cAMP) reduces the content of cholesterol esters in intimal cells obtained from atherosclerotic areas of human aorta. This effect depends on the nucleotide concentration. Db-cAMP has no effect on the content of cholesterol esters in the cells obtained from unaffected aortic areas. It can be assumed that cAMP derivatives and agents that give rise to the increased cAMP level in the cells may impede the development of the atherosclerotic manifestation such as lipoidosis.
Adult↗
[Heterogeneity of human aortic and arterial endothelium: quantitative study using scanning electron microscopy].
Endothelial lining of the aorta and iliac artery of children under 7 years of age is a homogeneous layer covered with small and medium-sized cells. Large and giant endotheliocytes can only be seen in lipid streaks. In adults with marked atherosclerosis aged 40-75 years, the surface of aortal and arterial lumen is a heterogeneous monolayer covered with polymorphous cells. In lipid streaks and on plaques large and giant endotheliocytes account for 25-41% of total cell population, with giant cells covering up to 50% of the plaque surface. It is suggested that monolayer areas of low and very low density, covered with large and giant cells, can be morphologic markers of arterial involvement in the atheromatous process.
Adult↗
[3H-thymidine incorporation into human aorta cells in primary culture. An autoradiographic study].
Primary cell culture has been obtained from intima and media of unaffected zones of human aorta and from atherosclerotic lesions (fatty infiltration, fatty streaks, atherosclerotic plaques). Cellular polymorphism was found in these cultures. Four morphological types of aortic cells are described: elongated, asymmetric, polygonal, and stellate cells. These cell types also differed in their proliferative activity. On the 7th day of culturing, polygonal cells do not incorporate 3H-thymidine; the thymidine index of other three cell types was similar. The thymidine index of medial cells was higher than that of intimal ones.
Aorta↗