Significance of myocardial eicosanoid production

Summary The precise role of eicosanoids in the development of myocardial injury during ischemia and reperfusion is still a matter of debate. Enhanced local production of these bioactive compounds appears to be a common response to tissue injury. Most likely, the cardiac tissue has the capacity to generate prostaglandins, thromboxanes as well as leukotrienes. Prostacyclin (PGI,) is the major eicosanoid produced by the jeopardized myocardium. In addition, at sites of tissue injury activation of platelets and infiltrating leukocytes results in the formation of considerable amounts of thromboxanes and leukotrienes. The production of eicosanoids requires prior release of arachidonic acid (AA) from phospholipids. Both ischemia and reperfusion are associated with a rise in the tissue level of AA. The absence of a proportional relationship between the tissue level of AA and the amounts of PGI, produced suggests that the sites of AA accumulation and PGI₂ formation are different. It is conceivable that AA accumulation is mainly confined to myocytes, whereas the capacity to synthesize PGI, mainly resides in vascular cells. Both beneficial and detrimental effects of eicosanoids on cardiac tissue have been described. Prostaglandins act as vasodilators. Besides, some of the prostaglandins, especially PGI,, are thought to possess cyto-protective properties. Thromboxanes and leukotrienes may impede blood supply by increasing smooth muscle tone. Besides, leukotrienes augment vascular permeability. Experimental studies, designed to evaluate the effect of pharmacological agents, like PGI₂-analogues and lipoxygenase and cyclo-oxygenase inhibitors, indicat that eicosanoids influence the outcome of myocardial injury. However, the delineation of the physiological significance of the locally produced eicosanoids is complicated by such factors as the wide variety of AA derivatives produced and the dose-dependency of their effects.     

An experimental analysis of the flow field in a three-dimensional model of the human carotid artery bifurcation

Steady flow measurements were carried out in a rigid three-dimensional model of the human carotid artery bifurcation at a Reynolds number of 640 and a flow division ratio of 50/50. Both axial and secondary velocities were measured with a laser-Doppler anemometer. In the bulb opposite to the flow divider a zone with negative axial velocities was found with a maximal diameter of about 60% of the local diameter of the branch and a cross-sectional extent of about 25% of the local cross-sectional area. In the bulb the maximum axial velocity shifted towards the divider wall and at the end of the bulb an axial velocity plateau arose near the non-divider wall. Halfway through the bulb, secondary flow showed a vortex through which fluid flowed towards the divider wall near the bifurcation plane and back towards the non-divider wall near the upper walls.     

A numerical analysis of steady flow in a three-dimensional model of the carotid artery bifurcation

A finite element approximation of steady flow in a rigid three-dimensional model of the carotid artery bifurcation is presented. A Reynolds number of 640 and a flow division ratio of about 50/50, simulating systolic flow, was used. To limit the CPU- and I/O-times needed for solving the systems of equations, a mesh-generator was developed, which gives full control over the number of elements into which the bifurcation is divided. A mini-supercomputer, based on parallel and vector processing techniques, was used to solve the system of equations. The numerical results of axial and secondary flow compare favorably with those obtained from previously performed laser-Doppler velocity measurements. Also, the influence of the Reynolds number, the flow division ratio, and the bifurcation angle on axial and secondary flow in the carotid sinus were studied in the three-dimensional model. The influence of the interventions is limited to a relatively small variation in the region with reversed axial flow, more or less pronounced C-shaped axial velocity contours, and increasing or decreasing axial velocity maxima.     

Formation of multilamellar vesicles by addition of tannic acid to phosphatidylcholine-containing small unilamellar vesicles

Tannic acid induces aggregation and formation of multilamellar vesicles when added to preparations of small unilamellar vesicles, specifically those containing phosphatidylcholine. Aggregation and clustering of vesicles was demonstrated by cryo-electron microscopy of thin films and by freeze-fracture technique. Turbidity measurements revealed an approximately one-to-one molar ratio between tannic acid and phosphatidylcholine necessary for a fast and massive aggregation of the small unilamellar vesicles. When tannic acid-induced aggregates were dehydrated and embedded for conventional thin-section electron microscopy, multilamellar vesicles were retrieved in thin sections. It is concluded from morphological studies, as well as previous tracer studies, that tannic acid, at least to a great extent, prevents the extraction of phosphatidylcholine. Multilamellar vesicles were also observed in tannic acid-treated vesicles prepared from total lipid extracts from either rabbit or rat hearts. Substantially more multilamellar vesicles were retrieved in the rabbit vesicle preparation. This difference can probably be explained by the difference in the proportion of the plasmalogen phosphatidylcholine, and possibly the content of sphingomyelin, in lipid extracts of rabbit and rat hearts. It is concluded that the dual effect (reduced extraction and aggregation) of tannic acid on phosphatidylcholines should be taken into consideration when tannic acid is used in tissue preparation.     

Introduction of oxygen into the alkyl chain of N-decyl-dNM decreases lipophilicity and results in increased retention of glucose residues on N-linked oligosaccharides

N-Alkylation of the -glucosidase inhibitor 1-deoxynojirimycin(dNM) dramatically increases its inhibitory potency (Tan etal., J. Biol. Chem., 266, 14504–14510, 1991). However,the possibility of extending the alkyl chain to N-decyl-dNMis limited by an increase of detergent-like (amphiphilic) propertiesof long-chain alkylated dNM derivatives. Substitution of methylenegroups in the N-decyl chain by oxygen reduced the amphiphilicityof N-decyl-dNM derivatives, while retaining their superior inhibitoryproperties. In intact HepG2 cells, the compound N-7-oxadecyl-dNMwas found to result in the most pronounced retention of glucoseresidues on N-linked glycans. Permeabilization of the plasmamembrane with the bacterial toxin Streptolysin O improves theinhibitory properties of the derivatives N-3,6,9-trioxadecyl-,N-7,10,13-trioxatetradecyl-, N-3-oxadecyl- and N-7-oxadecyl-dNM,but not those of dNM. These observations suggest differencesin the mode of entry of the oxygen-substituted dNM derivativesin comparison with dNM. We observed that the dNM derivativeN-3,6,9-trioxadecyl-dNM, devoid of inhibitory activity in intactcells, was inhibitory in Streptolysh O-permeabilized cells.Thus, the permeability barriers posed by plasma membrane andendoplasmic reticulum membrane are not equivalent. The use ofa permeabilized cell system thus allows the elaboration of inhibitoryprinciples for novel bioactive compounds where study of theisolated enzymes may not be possible, and where intact cellsare not a suitable target due to permeability barriers. -glucosidase inhibition N-linked glycosylation oxygen-substituted N-decyl-dNM derivatives permeabilized cells     

Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall.

Pumping power as delivered by the heart is generated by the cells in the myocardial wall. In the present model study global left-ventricular pump function as expressed in terms of cavity pressure and volume is related to local wall tissue function as expressed in terms of myocardial fiber stress and strain. On the basis of earlier studies in our laboratory, it may be concluded that in the normal left ventricle muscle fiber stress and strain are homogeneously distributed. So, fiber stress and strain may be approximated by single values, being valid for the whole wall. When assuming rotational symmetry and homogeneity of mechanical load in the wall, the dimensionless ratio of muscle fiber stress (sigma f) to left-ventricular pressure (Plv) appears to depend mainly on the dimensionless ratio of cavity volume (Vlv) to wall volume (Vw) and is quite independent of other geometric parameters. A good (+/- 10%) and simple approximation of this relation is sigma f/Plv = 1 + 3 Vlv/Vw. Natural fiber strain is defined by ef = In (lf/lf,ref), where lf,ref indicates fiber length (lf) in a reference situation. Using the principle of conservation of energy for a change in ef, it holds delta ef = (1/3)delta In (1 + 3Vlv/Vw).     

A two-dimensional numerical analysis of unsteady flow in the carotid artery bifurcation. A comparison with three-dimensional in-vitro measurements and the influence of minor stenoses

In the present study a two-dimensional finite element model for incompressible Newtonian flow is applicated to the modelling of carotid artery flow. In earlier studies, the numerical model was validated experimentally for several flow configurations. In general the pulsatile flow is characterized by reversed flow regions at the non-divider side walls of both the internal and external carotid arteries. The unsteadiness of the flow is associated with rather complex spatial and temporal velocity distributions and leads to temporal variations of the location and length of the reversed flow regions. As a consequence, pronounced spatial and temporal variations in the wall shear stresses are found. At the non-divider side walls, wall shear stresses are relatively low and exhibits an oscillatory behaviour in space and time. At the divider side walls, wall shear stresses are relatively high and approximately follow the flow rate distribution in time. The aim of this study is not only to present two-dimensional calculations but also to compare the calculated two-dimensional velocity profiles with those from three-dimensional experiments. It is observed that in the common carotid artery and in the proximal parts of the internal and external carotid arteries, the two-dimensional numerical model provides valuable information with respect to the three-dimensional configuration. In the more distal parts of especially the internal carotid artery, deviations are found between the two-dimensional numerical and three-dimensional experimental model. These deviations can mainly be attributed to the neglect of the secondary velocity distribution in the two-dimensional model. In the two-dimensional numerical model the influence of a minor stenosis in the internal carotid artery is hardly distinguishable from a minor geometrical variation without stenosis. Full three-dimensional analyses of the influence of minor stenoses are needed to prove numerically whether in-vivo measurements of the axial velocity distribution are useful in the detection of minor stenoses.