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Evaporation of aqueous aerosols produced by jet nebulizers: effects on particle size and concentration of solution in the droplets.

Aqueous droplets produced by jet nebulizers can lose water by evaporation prior to entry into the patient's mouth, or a sizing device. Evaporation causes increase in the concentration of the solution in the droplet and reduction in size. These changes can complicate interpretation of results from experiments such as in vitro particle sizing or human respiratory tract deposition. We present experimental data obtained by nebulization of isotonic saline using a variety of aerosol delivery systems employing jet nebulizers. The impact of the evaporation phenomena is particularly great when a large volume of dry dilution air is mixed with the aerosol stream--a situation that is quite common in aerosol experiments. The experimental results approach the values calculated from the theoretical mass balance models in the limit of equilibrium between the droplets and the surrounding atmosphere.

Aerosols↗

Synthesis of cinnamic acid derivatives and their inhibitory effects on LDL-oxidation, acyl-CoA:cholesterol acyltransferase-1 and -2 activity, and decrease of HDL-particle size.

A series of cinnamic acid derivatives were synthesized and their biological abilities on lipoprotein metabolism were examined. Among the tested compounds, 4-hydroxycinnamic acid (l-phenylalanine methyl ester) amide (1) and 3,4-dihydroxyhydrocinammic acid (l-aspartic acid dibenzyl ester) amide (2) inhibited human acyl-CoA:cholesterol acyltransferase-1 and -2 activities with apparent IC(50) around 60 and 95 microM, respectively. Compounds 1 and 2 also served as an antioxidant against copper mediated low-density lipoproteins (LDL) oxidation with apparent IC(50)=52 and 3 microM, compound 1 and 2, respectively. Additionally, decrease of HDL-particle size under presence of LDL was inhibited by the 1 at 307 microM of final concentration. Treatment of the 1 or 2 did not influence normal growth of RAW264.7 without detectable cytotoxic activity from a cell viability test. These results suggest that the new cinnamic acid derivatives possess useful biological activity as an anti-atherosclerotic agent with inhibition of cellular cholesterol storage and transport by the both ACAT, inhibition of LDL-oxidation, HDL particle size rearrangement.

Alanine↗

Once-daily niacin extended release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin.

Standard lipoprotein measurements may not adequately reflect the increased atherogenic risk found in patients with abnormalities in lipoprotein particle size and subfraction distribution such as disproportionate amounts of small, dense low-density lipoprotein particles, small high-density lipoprotein particles, or large very-low-density lipoprotein particles. Measurement or anticipation of patients most susceptible to lipoprotein subfraction abnormalities may influence therapeutic choices for the optimal management of dyslipidemia. Previously, the ADvicor Vs. Other Cholesterol-modulating Agents Trial Evaluation demonstrated that niacin extended release/lovastatin provided greater global improvement in lipid parameters such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, lipoprotein (a), apolipoprotein B, and apolipoprotein A-I blood levels compared with atorvastatin and simvastatin monotherapies. In this report, niacin extended release/lovastatin was also more effective than atorvastatin and simvastatin monotherapies in reducing small, dense low-density lipoprotein particles and improving low-density lipoprotein phenotype pattern at relative starting doses, and was more effective in increasing the proportion of high-density lipoprotein in the potentially cardioprotective 2b subclass at all doses.

Aged↗

Particle size distribution of mainstream tobacco and marijuana smoke. Analysis using the electrical aerosol analyzer.

Accurate measurement of cigarette smoke particle size distribution is important for estimation of lung deposition. Most prior investigators have reported a mass median diameter (MMD) in the size range of 0.3 to 0.5 micron, with a small geometric standard deviation (GSD), indicating few ultrafine (less than 0.1 micron) particles. A few studies, however, have suggested the presence of ultrafine particles by reporting a smaller count median diameter (CMD). Part of this disparity may be due tot he inefficiency to previous sizing methods in measuring ultrafine size range, to evaluate size distribution of smoke from standard research cigarettes, commercial filter cigarettes, and from marijuana cigarettes with different delta 9-tetrahydrocannabinol contents. Four 35-cm3, 2-s puffs were generated at 60-s intervals, rapidly diluted, and passed through a charge neutralizer and into a 240-L chamber. Size distribution for six cigarettes of each type was measured, CMD and GSD were determined from a computer-generated log probability plot, and MMD was calculated. The size distribution parameters obtained were similar for all cigarettes tested, with an average CMD of 0.1 micron, a MMD of 0.38 micron, and a GSD of 2.0. The MMD found using the EAA is similar to that previously reported, but the CMD is distinctly smaller and the GSD larger, indicating the presence of many more ultrafine particles. These results may explain the disparity of CMD values found in existing data. Ultrafine particles are of toxicologic importance because their respiratory tract deposition is significantly higher than for particles 0.3 to 0.5 micron and because their large surface area facilitates adsorption and delivery of potentially toxic gases to the lung.

Aerosols↗

Electronic particle size measurements of platelet aggregates formed in vitro.

The aggregation of human platelets induced by adenosine diphosphate (ADP) was used to evaluate electronic particle size analyzer measurements of platelet aggregates in plasma. As platelets began to clump in plasma, the total volume and the diameter of individual aggregates increased; after a time dependent on experimental conditions, the diameter increased but the total volume remained unchanged. Similar but opposite changes in size distribution occurred during platelet deaggregation. The total volume of aggregates formed in plasma varied (linear correlation coefficient = 0.99) with the total volume of platelets which were available to clump and with simultaneous changes in optical density. The diameter of the aggregates varied with the concentration of, and time of exposure to, ADP and with the total volume of platelets and aggregates in plasma was not different from that of control platelets in untreated plasma, the individual platelets aggregated without an accompanying increase in size. This study demonstrates that platelet aggregation can be characterized by electronic measurements of the size distribution of platelet aggregates.

Adenosine Diphosphate↗

NTP Toxicity Study Report on the atmospheric characterization, particle size, chemical composition, and workplace exposure assessment of cellulose insulation (CELLULOSEINS).

Cellulose insulation (CI) is a type of thermal insulation produced primarily from recycled newspapers. The newspapers are shredded, milled, and treated with fire-retardant chemicals. The blowing process for installing CI generates a significant quantity of airborne material that presents a potential inhalation hazard to workers. CI was selected for study based upon the high production volume, the potential for widespread human exposure, and a lack of toxicity data; insufficient information was available to determine whether inhalation studies in laboratory animals were technically feasible or necessary. Studies were conducted to characterize the chemical and physical properties of CI aerosols, to evaluate the potential acute pulmonary toxicity of CI, and to assess occupational exposure of CI installers. Workplace exposure assessments were conducted in collaboration with the National Institute for Occupational Safety and Health (NIOSH, 2001). EVALUATION OF THE CHEMICAL COMPOSITION, PARTICLE SIZE, AND PULMONARY TOXICITY OF CELLULOSE INSULATION: Chemical analyses were performed on samples of bulk CI from four major United States manufacturers. All samples of the bulk CI were found to contain primarily amorphous cellulose (60% to 65%) with a smaller crystalline component (35% to 40%). The crystalline phase was primarily native cellulose (75% to 85%) with a minor amount of cellulose nitrate (15% to 25%). Elemental analyses of acid digests of CI materials indicated that the major components (>0.1% by weight) included aluminum, boron, calcium, sodium, and sulfur. An acid-insoluble residue present in all four materials (3% to 5% of original sample weight) was found to consist primarily of aluminum silicate hydroxide (kaolinite; approximately 85%) with minor amounts (<5% each) of magnesium silicate hydroxide (talc), potassium aluminum silicate hydroxide (muscovite), and titanium oxide (rutile). Solvent extracts of the bulk materials were analyzed for organic components by gas chromatography with flame ionization detection. Analyses revealed a mass of poorly resolved peaks. Because of the very low concentrations, further quantitative and qualitative analyses were not performed. An aerosol generation system was designed to separate CI particles based upon aerodynamic size and to simulate the process used during CI installation at work sites. Less than 0.1% of each of the CI samples was collected as the small respirable particle fraction. The mean equivalent diameter of respirable particles ranged from 0.6 to 0.7 mum. The numbers of fibers in the respirable fractions ranged from 9.7 x 103 to 1.4 x 106 fibers/g of CI. The respirable particle fractions did not contain cellulose material and consisted mainly of fire retardants and small quantities of clays. The respirable fraction from one CI sample was administered by intratracheal instillation to male Fischer 344 rats at doses of 0, 0.625, 1.25, 2.5, 5, or 10 mg/kg body weight; the bronchoalveolar lavage (BAL) fluid cellularity was evaluated 3 days later. Based upon the relatively mild severity of the inflammatory response, a dose of 5 mg/kg body weight was selected for use in a subsequent 28-day study. Rats received CI, titanium dioxide (particle controls), or sterile saline (controls). BAL fluid was evaluated 1, 3, 7, 14, and 28 days after instillation, and lung histopathology was evaluated 14 and 28 days after treatment. CI caused a greater influx of inflammatory cells than titanium dioxide and caused significant increases in BAL fluid protein and lactate dehydrogenase. These CI-induced changes in BAL fluid parameters were transient and by day 14 were not significantly different than those observed in rats treated with titanium dioxide or phosphate-buffered saline. Unlike titanium dioxide, CI treatment caused a minimal to mild nonprogressive, minimally fibrosing granulomatous pneumonitis characterized by nodular foci of macrophages and giant cells. These results indicated that few respirable particles or fibers are likely generated during the CI application and that the acute pulmonary toxicity is minimal. EXPOSURE ASSESSMENT OF CELLULOSE INSULATION APPLICATORS: The CI exposure assessment was conducted with 10 contractors located across the United States. Air samples of total dust and respirable dust were collected for scanning electron microscopy (SEM) to characterize any fibers in the dust. Two SEM air samples for each day of CI activities were collected from the installer and hopper operator. Bulk CI samples were collected and analyzed for metal, boron, and sulfate content. Real-time and video exposure monitoring was conducted to further characterize the CI dust and workers' exposures. The exposure assessment also included a medical component. Investigators collected 175 personal breathing zone (PBZ) total dust, 106 area total dust, and 90 area respirable dust air samples during CI-related activities at the 10 contractor sites. Twenty-six employees' total dust 8-hour time-weighted averages (TWAs) exceeded the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 15 mg/m3, and 42 exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) threshold-limit value (TLV) of 10 mg/m3. Respirable dust air sampling and real-time monitoring with particle size discrimination indicated low levels of respirable dust generation. The SEM analyses revealed that fibers were an average 28 mum in length and ranged from 5 mum to 150 mum. CI installers' PBZ total dust, area total dust, and area respirable dust air samples were all significantly higher during dry attic applications than wet attic applications (P<0.01). Conversely, the hopper operators' total dust exposures were significantly higher during wet wall and ceiling applications than dry wall and ceiling applications (P=0.02). Analyses of variance tests revealed that exposure concentrations in total dust air samples collected in the PBZ of all CI workers, including installers working in attics, installers during wall applications, hopper operators during attic applications, and hopper operators during wall and ceiling applications, varied significantly during dry applications (P<0.01). The respirable dust air samples collected in attic areas, hopper areas during attic applications, and hopper areas during wall and ceiling applications also differed significantly during dry applications (P=0.03). Twenty-three workers participated in the medical phase of the investigation. The workers completed medical and work history questionnaires, performed serial peak flow tests, and completed multiple acute symptom surveys. The medical questionnaires indicated respiratory, nasal, and skin symptoms that employees attributed to CI exposure. The most common symptoms reported while working with CI included nasal symptoms (35%), eye symptoms (35%), and morning phlegm production (25%). There was a temporal association between CI exposure and eye symptoms, but there was little evidence of lower respiratory system health conditions associated with CI exposure. CONCLUSIONS: Chemical analyses of the four bulk CI samples revealed only minor differences in additives. The major elemental components detected were aluminum, boron, calcium, sodium, and sulfur, but they were attributed to the fire retardants aluminum sulfate, boric acid, and sodium sulfate. For all four CI samples, less than 0.1% by weight was collected as the small respirable particle fraction. The fractions consisted mainly of fire retardants and smaller quantities of clays and did not contain cellulose material. Intratracheal instillation of the respirable fraction in rats produced minimal to mild inflammatory responses in the lungs with no increase in severity by 28 days after dosage. Although a significant increase in lung collagen was detected at day 28 in treated rats, microscopic evaluation revealed only a minimal to mild increase in collagen fibrils associated with granulomatous nodules. The results of these studies indicated that few respirable particles or fibers are generated during the aerosolization of CI, and that even at very high doses of respirable CI particles, acute pulmonary toxicity is minimal. These results are supported by the NIOSH workplace exposure assessment conducted on CI workers. Based on the air sample data collected from the 10 contractor site visits, there is a potential for overexposure to CI; however, respirable dust concentrations were typically low. There was increased potential for 8-hour TWAs exceeding the OSHA PEL for total and respirable dust when employees were involved in CI application activities for longer periods of time. There was evidence of work-related eye and mucous membrane irritation among some workers, which were possibly caused by the additives present in CI, such as boric acid. There was little evidence of lower respiratory system health conditions associated with CI exposure. Based upon the results of the CI chemical characterization studies, the pulmonary toxicity study, and the worksite exposure assessment, the NTP concluded that additional studies of CI in laboratory animals are not warranted at this time. However, the animal pulmonary toxicity studies and worker health surveys focused on acute CI exposures and do not preclude the possibility of toxicity resulting from chronic exposure. Although exposure concentrations of respirable CI particulate matter were low, additional information is needed on the biodurability and reactivity of CI particles and fibers in the respiratory tract. CI should continue to be regarded as a nuisance dust, and workers should continue to wear protective masks to prevent inhalation exposure to CI dusts.

Aerosols↗

Particle size distribution by sedimentation/steric field-flow fractionation: development of a calibration procedure based on density compensation.

Because of the important but mathematically complex role played by hydrodynamic lift forces in sedimentation/steric FFF, applied generally to particles greater than 1 micron in diameter, retention cannot readily be related to particle diameter on the basis of simple theory. Consequently, empirical calibration is needed. Unfortunately, retention is based on particle density as well as size so that a purely size-based calibration (e.g., with polystyrene latex standards) is not generally valid. By examining the balance between driving and lift forces, it is concluded that equal retention will be observed for equal size particles subject to equal driving forces irrespective of particle density. Therefore by adjusting the rotation rate to exactly compensate for density, retention can be brought in line with that of standards, a conclusion verified by microscopy. Linear calibration plots of log (retention time) versus log (diameter) can then be used. This approach is applied to two glass bead samples (5-30 and 5-50 microns) using both a conventional and a pinched inlet channel. The resulting size distribution curves are self consistent and in good agreement with results obtained independently.

Calibration↗

Assessment of the upper particle size limit for quantitative analysis of aerosols using laser-induced breakdown spectroscopy.

The laser-induced plasma vaporization of individual silica microspheres in an aerosolized air stream was investigated. The upper size limit for complete particle vaporization corresponds to a silica particle diameter of 2.1 microm for a laser pulse energy of 320 mJ, as determined by the deviation from a linear mass response of the silicon atomic emission signal. Comparison of the measured silica particle sampling rates and those predicted based on Poisson sampling statistics and the overall laser-induced plasma volume suggests that the primary mechanism of particle vaporization is related to direct plasma-particle interactions as opposed to a laser beam-particle interaction. Finally, temporal and spatial plasma evolution is discussed in concert with factors that may influence the vaporization dynamics of individual aerosol particles, such as thermophoretic forces and vapor expulsion.

Aerosols↗

Maintenance of nonviral vector particle size during the freezing step of the lyophilization process is insufficient for preservation of activity: insight from other structural indicators.

The instability of nonviral vectors as liquid formulations has stimulated considerable interest in developing dehydrated formulations that would be resistant to shipping stresses and could be stored at room temperature. Recently, we reported that high sucrose/DNA ratios are capable of maintaining particle size during the freezing step of the lyophilization process and we suggested that the separation of individual particles within sugar matrices is responsible for the reported protection of nonviral vectors during the freezing step of a typical lyophilization protocol. The purpose of this study was to extend these observations to other nonviral vectors that incorporate different cationic components. Cationic lipid-based complexes composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), with helper lipid cholesterol (Chol) or dioleoylphosphatidyl-ethanolamine (DOPE), showed similar protection by sucrose. Formulations of a polyethylenimine (PEI)-based vector required much higher excipient/DNA ratios for size protection compared with protamine- and lipid-based vectors. At low sucrose/DNA ratios, zeta potentials for all complexes were significantly lowered during freezing. Similar results were obtained at high sucrose/DNA ratios, except for DOTAP-DOPE-containing vectors which maintained zeta potential values comparable to unfrozen controls. The changes in zeta potential values indicate that complexes are altered during freezing despite the maintenance of particle size as determined by light scattering. Furthermore, these changes might explain the observed reduction in transfection activity and provide new information about the effects of physicochemical changes of nonviral vectors during the freezing step of lyophilization.

Animals↗

Particle-size distribution of very low density plasma lipoproteins during fat absorption in man.

The size distributions of electrophoretically isolated subfractions of the very low density human plasma lipoproteins have been determined using electron microscopy. The primary and secondary particles observed in plasma of normal subjects after fat ingestion appear to have similar size distributions. Particles produced by corn oil feeding can be fixed by the osmium tetroxide reaction while those produced by butter fat feeding could not be fixed or made visible by this technique. Good agreement between particle size as measured by electron microscopy and particle size as predicted by ultra-centrifugal analysis was obtained.

Blood Protein Electrophoresis↗

Combinatorial approach to the study of particle size effects in electrocatalysis: synthesis of supported gold nanoparticles.

A high-throughput method for physical vapor deposition has been applied to the synthesis of libraries of supported gold particles on amorphous substoichiometric TiO(x)() and carbon supports. The TiO(x)() substrate stoichiometry can be varied or kept constant across a supporting sample, and subsequent deposition of particle sizes on supports are controlled through the nucleation and growth process. TEM measurements indicate nucleation and growth of Au particles takes place, with the smallest particles initially observed at 1.4 nm with a maximum density of 5.5 x 10(12) cm(-2) on titania, and 2.6 nm with concomitantly lower density on carbon. The 1.4-nm particles on titania exhibit a binding energy shift in the Au(4f) core level of 0.3 eV from bulk gold, and the shift is approximately 0.1 eV by the time particles grow to a mean size of 2.5 nm. These shifts are associated with final state effects, and the supported gold particles are metallic and appear to be relatively stable in air. When combined with appropriate substrates and screening techniques, this method provides a highly controllable method for the high-throughput synthesis of model supported catalyst.

Catalysis↗

Effect of particle size on ocular permeability of prednisolone acetate in rabbits.

The ocular permeability of two sieved fractions of prednisolone acetate with a mean particle size of less than 5 microns and 5-10 microns was studied in rabbits. The results show that there was not significant difference between the corneal uptake of the two fractions of prednisolone acetate. Prednisolone acetate was rapidly taken up by the cornea where it is hydrolyzed rapidly to prednisolone. Only prednisolone was detected in the aqueous humor showing that prednisolone acetate is completely hydrolyzed in the cornea. Both fractions produced similar concentrations of prednisolone in the aqueous humor. For prednisolone acetate, the permeability rate rather than the dissolution rate seems to be the rate-limiting step for corneal transport.

Administration, Topical↗

Influence of particle size of autogenous bone grafts on the early stages of bone regeneration: a histologic and stereologic study in rabbit calvarium.

PURPOSE: The aim of this study was to investigate the influence of particle size of autogenous bone grafts on the early stages of bone regeneration. MATERIALS AND METHODS: Bicortical skull bone defects were prepared in 15 rabbits (4 in each rabbit). Two defects were filled at random with either small (0.5 to 2 mm3) or large (10 mm3) autogenous bone particles. In addition, 1 defect was left unfilled (control defect). All defects were covered bicortically by expanded polytetrafluoroethylene membranes. The animals were divided randomly into 3 groups and sacrificed after 1, 2, and 4 weeks, respectively. Histologic and stereologic evaluations were performed after the sections were blinded. RESULTS: No significant differences in total vessel surface area could be identified among the 3 groups. The total volume of newly formed bone in defects with small particles was larger and more mature compared to defects with large particles after 2 and 4 weeks. Furthermore, the resorption of small particles was more pronounced after 4 weeks, documenting a higher level of bone substitution compared to large particles. DISCUSSION: The early stages of bone regeneration were influenced by the particle site of autogenous bone grafts. CONCLUSION: The present study indicated that particles of 0.5 to 2 mm3 in size should be preferred to particles of 10 mm3 in size for bone grafting.

Analysis of Variance↗

Polyvinyl alcohol sponge for embolotherapy: particle size and morphology.

The size and morphology of particulate polyvinyl alcohol (PVA) sponge prepared by a blender technique for embolotherapy were analyzed by light and scanning electron microscopy. Techniques for preparation and sizing of PVA sponge particles are described. Two types of particulate material, differing in both size and morphology, were found. Large particles (greater than 50 micron) had irregular shapes and sharp, jagged edges. Smaller particles (2-50 micron) were more numerous. Attempts to characterize the smaller particles were unsuccessful. Preparation of PVA sponge particles using the blender technique is a viable choice in external carotid neuroembolization procedures. However, the potential effects of small particles possibly causing cranial nerve palsies does need consideration.

Animals↗

Capillary zone electrophoresis of rigid submicron-sized particles in polyacrylamide. Solution selectivity, peak spreading and resolution.

Submicron-sized rigid particles can be separated in a size-dependent fashion by electrophoresis in free solution. Yet it has remained unknown whether the presence of polymers in the solution confers an advantage in size-dependent separation of submicron particles and their resolution. The present study addresses that question, using capillary zone electrophoresis of carboxylate modified polystyrene latex microspheres of 55, 140 and 215 nm radius in solutions of linear polyacrylamide in the M(r) range of 0.4.10(6) to 1.14.10(6). Selectivity of particle separation increases in direct relation to the polymer concentration in the concentration range of 0 to 1% (w/v). Selectivity was found to increase with M(r) of the polymer for the particle sets of 55/140 (nm/nm) and 140/215 (nm/nm) but to decrease with polymer M(r) for the 55/215 (nm/nm) set. Peak spreading is a complex and, in the case of the largest particle, non-monotonic function of polymer concentration, with a minimum at concentrations around the entanglement threshold, c*. Consequently, resolution of the 55/215 and 140/215 (nm/nm) sets also exhibits a maximum around the entanglement threshold while resolution for the 55/140 (nm/nm) set increases with a rise of polymer concentrations above c*. Within the range of optimally resolving polymer concentrations there also occurs a maximum of resolution for all particle sets at a field strength in the range of 150 to 250 V cm-1.

Acrylic Resins↗

Low density lipoprotein particle size phenotyping in healthy persons and patients with myocardial infarction.

AIM: To determine distribution, size, and phenotype of low density lipoprotein (LDL) subclasses and examine the influence of plasma lipid concentrations on lipoprotein particle size in both healthy population and patients with myocardial infarction. METHOD: Nondenaturing gradient (3-31%) gel electrophoresis for lipoprotein separation was used to determine the distribution and size of LDL subclasses in 132 patients with myocardial infarction and 334 healthy control subjects. RESULTS: Large LDL subclasses (LDL1, LDL2, phenotype A) were dominant in 88.5% of the healthy population, whereas in most patients with myocardial infarction (81%) the dominant subclasses were LDL3 and LDL4 (phenotype B). Only 19% of the patients belonged to the phenotype A (LDL1 and LDL2). Mean LDL subclass size (nm) was significantly smaller in patients with myocardial infarction than in controls (24.381.07 nm vs 25.940.89 nm; p<0.001). In both groups, LDL size was independent of LDL plasma cholesterol but associated with high triglyceride plasma concentrations. CONCLUSION: Coronary artery disease is associated with the predominance of small LDL particles and high plasma triglyceride concentrations. The risk of development of cardiovascular disease can be assessed more accurately by determining lipoprotein subclasses.

Adult↗

Sensitivity increase in molecular recognition by decrease of the sensing particle size and by increase of the receptor binding site--a case with chemomechanical polymers.

For the first time it is shown that diminishing the particle size of a chemomechanical polymer leads to a dramatic sensitivity increase, with a large response triggered e.g. by action of external AMP; as illustrated with carbohydrate model complexes in solution, the necessary high binding affinity can be achieved by providing an excess of recognition units in one of the partners.

Binding Sites↗

Oxidized LDL and small LDL particle size are independently predictive of a selective defect in microcirculatory endothelial function in type 2 diabetes.

AIM: To explore the associations of LDL (low-density lipoprotein) particle size and oxidized LDL with endothelium-dependent function of the forearm microcirculation in diabetes. METHODS: Endothelium-dependent function was examined in 43 middle-aged men and women with type 2 diabetes and 10 age-matched controls. All received aspirin to inhibit endothelial cyclo-oxygenase. Forearm blood flow (FBF) was measured using venous occlusion plethysmography with separate administration of acetylcholine (ACh) and bradykinin (BK) into the brachial artery. Endothelium-independent function was assessed using sodium nitroprusside (SNP). N(G)-monomethyl-L-arginine (L-NMMA) was co-infused with ACh (ACh + L-NMMA) and BK (BK + L-NMMA) to assess non-NO-mediated contributions to endothelium-dependent function. RESULTS: Subjects with diabetes had impaired endothelium-dependent and endothelium-independent function compared with controls (p < 0.01 for ACh, BK and SNP). In multivariate regression analysis, LDL size (r = 0.41 and p = 0.007), oxidized LDL (r = -0.41 and p = 0.007) and duration of diabetes (r = -0.37 and p = 0.02) predicted FBF response to ACh independently of age, gender and systolic blood pressure. There were no associations between LDL size, oxidized LDL, duration of diabetes and FBF response to BK, SNP, ACh + L-NMMA or BK + L-NMMA. CONCLUSION: In type 2 diabetes, small dense LDL particles, duration of diabetes and oxidized LDL may independently contribute to endothelial dysfunction of the microcirculation. These disturbances may occur via a selective defect, because ACh and BK activate endothelial NO synthase via different G-protein signal transduction pathways.

Acetylcholine↗